Provided are methods, systems, and kits for selecting a patient for treatment with a therapeutic agent based on a presence of a genotype associated with a positive therapeutic response to the therapeutic agent. The therapeutic agent, in some embodiments, is an inhibitor of TL1A activity or expression, such as for example, an anti-TL1A antibody.

Description

67 parts

›CROSS-REFERENCE

This is a continuation of International Application No. PCT/US2020/032679 filed May 13, 2020 which claims the benefit of U.S. Patent Application No. 62/847,798, filed May 14, 2019, each of which is hereby incorporated by reference in its entirety.

›SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Dec. 9, 2020, is named 56884-761_301_SL.txt and is 14,467,905 bytes in size.

›BACKGROUND

Inflammatory disease, fibrostenotic disease, and fibrotic disease pose a significant health burden worldwide due to the vast number of individuals affected and heterogeneous disease pathogenesis and varied clinical manifestations. One such disease is inflammatory bowel disease (IBD), which has two common forms, Crohn's disease (CD) and ulcerative colitis (UC). IBD is the chronic, relapsing inflammatory disorders of the gastrointestinal tract. Incidences of IBD are prevalent, affecting nearly three million individuals in the United States alone.

Few treatment options are available to patients that suffer from inflammatory disease, fibrostenotic disease, and fibrotic disease. Existing anti-inflammatory therapy such as steroids and tumor necrosis factor (TNF) inhibitors are typically used as a first line treatment for treating IBD. Unfortunately, a significant number of patients experience a lack of response or a loss of response to existing anti-inflammatory therapies, especially TNF inhibitors. While the patient is treated with an anti-inflammatory therapy that is ineffective, the disease worsens. Surgery, in the form of structureplasty (reshaping of the intestine) or resection (removal of the intestine), is the only treatment option for patients that do not respond to first line therapies. Surgical treatments for IBD are invasive, causing post-operative risks for an estimated third of patients undergoing surgery, such as anastomotic leak, infection, and bleeding.

The pathogenesis of inflammatory disease, fibrostenotic disease, and fibrotic disease, like IBD, is thought to involve an uncontrolled immune response that may be triggered by certain environmental factors in a genetically susceptible individual. The heterogeneity of disease pathogenesis and clinical course, combined with the variable response to treatment and its associated side effects, suggests a personalized medicine approach to treating these diseases is the best treatment strategy. Yet there are very few personalized therapies available to patients. Accordingly, there is a need to identify targeted therapeutic approaches for the treatment of inflammatory disease, fibrostenotic disease, and fibrotic disease and subclinical phenotypes thereof, and an even greater need to develop reliable methodology to identifying patients who, based on their genotype, may respond to any given therapeutic approach. The needed methodologies would also identify subjects not yet diagnosed who are at risk of developing the disease, for which preventative interventions could be prescribed to reduce the growing health burden.

Genome Wide Association Studies (GWAS) have provided researchers the ability to identify genetic variants (e.g., polymorphisms) that are significantly associated with IBD and subclinical phenotypes of IBD. GWAS compare the allele frequency in a given population of a particular genetic variant between unrelated cases and controls, each case representing an affected individual (e.g., patient with IBD) and each control representing an individual without IBD. GWAS, the Immunochip, and their meta-analysis have enabled the discovery of over 200 polymorphisms associated with IBD, including CD and UC.

The first GWAS on IBD identified TNFSF15 as an IBD locus containing several polymorphisms associated with IBD. TNFSF15 protein, also known as TL1A, is a proinflammatory molecule which stimulates proliferation and effector functions of CD8 (+) cytotoxic T cells as well as Th1, Th2, and Th17 cells in the presence of TCR stimulation. TL1A is believed to be involved in the pathogenesis of IBD by bridging the innate and adaptive immune response, modulating adaptive immunity by augmenting Th1, Th2, and Th17 effector cell function, and T-cell accumulation and immunopathology of inflamed tissue. Studies have demonstrated that patients with IBD who carry certain risk alleles at the TNFSF15 locus show an increase in TNFSF15 (TL1A) expression and are more likely to develop severe forms of IBD, as compared to individuals who do not carry the risk alleles. These findings suggest that inhibiting TL1A expression and/or activity may be a promising therapeutic strategy in a variety of T cell-dependent autoimmune diseases, including IBD. These findings also suggest that certain TNFSF15 genotypes in patients that confer a risk of increased TL1A expression and/or severe forms of disease may prove useful in the prognosis, diagnosis and treatment of these individuals.

Identifying potential therapeutic targets for the treatment of disease and methods of selecting patients for treatment on the basis of GWAS alone suffer from significant drawbacks. For example, GWAS relies on linear polymorphism-polymorphism associations between known risk loci and phenotypic traits, which fail to capture high-dimensional non-linear polymorphism interactions, such as the types of relationships reflective of unknown biology. In addition, individual polymorphisms identified using GWAS often have small effect sizes in a given population. Thus, polymorphisms identified by GWAS are of limited use in predicting a susceptibility to complex diseases, such as IBD (e.g., CD, UC). Further, GWAS fail to convey or account for the biological mechanisms underlying the genetic associations between a genetic variant and a phenotypic outcome (e.g., IBD), rendering them of limited use in identifying therapeutic targets.

›SUMMARY · 1 of 11

Provided herein are genotypes associated with, and therefore predictive of, a positive therapeutic response of a subject or patient to an inhibitor of TL1A activity or expression (e.g., anti-TL1A antibody) that have been identified using a machine-learning based approach. The machine-learning based approach described herein enables the identification of combinations of polymorphisms with linear and non-linear interactions that more accurately predict phenotypes of complex disease, such as IBD, as compared to traditional GWAS alone. The genotypes described herein are associated with an increase in a level of TNFSF15 (TL1A) protein expression in a sample obtained from a subject or patient, as compared to a reference level of TNFSF15 (TL1A) protein expression (e.g., derived from a normal individual). The genotypes disclosed herein are located at gene or genetic loci that are involved either directly or indirectly with TL1A-mediated or T-cell dependent inflammatory pathways. In addition, some of the genotypes provided herein are also significantly associated with inflammatory bowel disease (IBD), such as Crohn's disease (CD). The genotypes are useful for selecting a patient or a subject for treatment with an inhibitor of TL1A activity or expression. The patient may be diagnosed with IBD, CD, or both. The subject may be suspected of having IBD, CD, or both.

Non-limiting practical applications of the associations between the genotypes described herein and incidences of clinical and subclinical phenotypes in certain populations of individuals are provided herein. For example, some genotypes of the present disclosure can be used to predict a risk that a subject will develop a TL1A-mediated inflammatory disease, fibrostenotic disease, or a fibrotic disease. The genotypes are also useful to predict whether a patient diagnosed with some form of an inflammatory, fibrotic or fibrostenotic disease will develop a severe form of the disease, such as a subclinical phenotype thereof.

Further practical applications of the associations between the genotypes described herein include, without limitation, methods, systems, and kits for selecting a patient diagnosed with IBD or a subject suspected of having IBD for treatment with an inhibitor of TL1A activity or expression, provided the patient or the subject is a carrier of the genotype described herein. In addition, or alternatively, practical applications of the associations between the genotypes disclosed herein and a variation in an expression of TNFSF15 (TL1A) are provided herein. In some cases, the genotypes can be used to identify a patient who may be suitable for treatment with a targeted TL1A therapy (e.g., a patient carrying a genotype associated with an increase in TL1A may be suitable for a treatment with an anti-TL1A therapy). An exemplary condition includes Crohn's disease (CD). An exemplary inhibitor of TL1A activity or expression is an anti-TL1A antibody. In some instances, the anti-TL1A antibody is a neutralizing anti-TL1A antibody.

Aspects disclosed herein provide methods of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising administering to the subject a therapeutically effective amount of an inhibitor of Tumor necrosis factor-like cytokine 1A (TL1A) activity or expression, provided a presence of at least three polymorphisms is detected in a sample obtained from the subject, wherein the at least three polymorphisms are predictive that the subject will therapeutically respond to the inhibitor of TL1A at a positive predictive value of at least about 70%. In some embodiments, the at least three polymorphisms comprises rs1892231, rs56124762, rs6478109, rs2070558, rs2070561, rs11897732, rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557, rs4246905, rs10974900, rs12434976, rs16901748, rs2815844, rs889702, rs2409750, rs1541020, rs4942248, rs12934476, rs12457255, rs2297437, rs41309367, rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs951279, rs9806914, rs7935393, rs1690492, rs420726, rs7759385, rs10974900, rs1326860, rs2548147, rs2815844, rs889702, rs9806914, rs7278257, or rs11221332, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85, or a combination thereof.

In some embodiments, the at least three polymorphisms comprise: rs6478109, rs56124762, and rs1892231; rs6478109, rs56124762, and rs16901748; rs6478109, rs1892231, and rs16901748; rs56124762, rs1892231, and rs16901748; rs6478109, rs2070558, and rs1892231; rs6478109, rs2070558, and rs16901748; rs6478109, rs1892231, and rs16901748; rs2070558, rs1892231, and rs16901748; rs6478109, rs2070561, and rs1892231; rs6478109, rs2070561, and rs16901748; rs6478109, rs1892231, and rs16901748; rs2070561, rs1892231, and rs16901748; rs6478109, rs7935393, and rs1892231; rs6478109, rs7935393, and rs9806914; rs6478109, rs7935393, and rs7278257; rs6478109, rs7935393, and rs2070557; rs6478109, rs1892231, and rs9806914; rs6478109, rs1892231, and rs7278257; rs6478109, rs1892231, and rs2070557; rs6478109, rs9806914, and rs7278257; rs6478109, rs9806914, and rs2070557; rs6478109, rs7278257, and rs2070557; rs7935393, rs1892231, and rs9806914; rs7935393, rs1892231, and rs7278257; rs7935393, rs1892231, and rs2070557; rs7935393, rs9806914, and rs7278257; rs7935393, rs9806914, and rs2070557; rs7935393, rs7278257, and rs2070557; rs1892231, rs9806914, and rs7278257; rs1892231, rs9806914, and rs2070557; rs1892231, rs7278257, and rs2070557; or rs9806914, rs7278257, and rs2070557. In some embodiments, the at least three polymorphisms further comprises a fourth polymorphism comprising rs16901748, rs1892231, rs56124762, rs6478109, rs2070558, rs2070561, rs11897732, rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557, rs4246905, rs10974900, rs12434976, rs2815844, rs889702, rs2409750, rs1541020, rs4942248, rs12934476, rs12457255, rs2297437, rs41309367, rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs951279, rs9806914, rs7935393, rs1690492, rs420726, rs7759385, rs10974900, rs1326860, rs2548147, rs2815844, rs889702, rs9806914, rs7278257, or rs11221332, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85, or a combination thereof. In some embodiments, the at least three polymorphisms comprise rs6478109, rs56124762, and rs1892231. In some embodiments, the at least three polymorphisms comprise rs6478109, rs56124762, and rs16901748. In some embodiments, the at least three polymorphisms comprise rs6478109, rs1892231, and rs16901748. In some embodiments, the at least three polymorphisms comprise rs56124762, rs1892231, and rs16901748. In some embodiments, the proxy polymorphism in linkage disequilibrium is independently associated with a clinical phenotype associated with the inflammatory, the fibrotic, or the fibrostenotic disease or condition in the subject. In some embodiments, the clinical phenotype is stricturing and penetrating disease.

›SUMMARY · 2 of 11

In some embodiments, the presence of the at least three polymorphisms is predictive that the subject will therapeutically respond to the inhibitor of TL1A at a positive predictive value of at least about 75%. In some embodiments, the presence of the at least three polymorphisms is predictive that the subject will therapeutically respond to the inhibitor of TL1A at a positive predictive value of at least about 80%. In some embodiments, the presence of the at least three polymorphisms is predictive that the subject will therapeutically respond to the inhibitor of TL1A at a positive predictive value of at least about 85%. In some embodiments, the presence of the at least three polymorphisms is predictive that the subject will therapeutically respond to the inhibitor of TL1A at a positive predictive value of at least about 90%. In some embodiments, the presence of the at least three polymorphisms is predictive that the subject will therapeutically respond to the inhibitor of TL1A at a positive predictive value of at least about 95%. In some embodiments, the presence of the at least three polymorphisms is predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 70%. In some embodiments, the presence of the at least three polymorphisms is predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 75%. In some embodiments, the presence of the at least three polymorphisms is predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 80%. In some embodiments, the presence of the at least three polymorphisms is predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 85%. In some embodiments, the presence of the at least three polymorphisms is predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 90%. In some embodiments, the presence of the at least three polymorphisms is predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 95%.

In some embodiments, the at least three polymorphisms are detected in the sample by subjecting the sample to an assay configured to detect a presence of at least three nucleotides corresponding to nucleic acid position 501 within SEQ ID NOS: 1-41, or 57-59. In some embodiments, the assay comprises polymerase chain reaction (PCR), quantitative reverse-transcription PCR (qPCR), automated sequencing, or genotype array.

In some embodiments, the inflammatory, fibrotic, or fibrostenotic disease or condition comprises inflammatory bowel disease, Crohn's disease, obstructive Crohn's disease, ulcerative colitis, intestinal fibrosis, intestinal fibrostenosis, rheumatoid arthritis, or primary sclerosing cholangitis. In some embodiments, the Crohn's disease is ileal, ileocolonic, or colonic Crohn's disease. In some embodiments, the subject has, or is at risk for developing, a non-response or loss-of-response to a standard therapy comprising glucocorticosteriods, anti-TNF therapy, anti-a4-b7 therapy, anti-IL12p40 therapy, or a combination thereof. In some embodiments, the inhibitor of TL1A is an anti-TL1A antibody or antigen-binding fragment. In some embodiments, the anti-TL1A antibody binds to the same region of human TL1A as a reference antibody selected from Table 2B. In some embodiments, methods further comprise administering an additional therapeutic agent to the subject.

›SUMMARY · 3 of 11

In some embodiments, the presence of the at least three polymorphisms is predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 70%. In some embodiments, the presence of the at least three polymorphisms is predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 75%. In some embodiments, the presence of the at least three polymorphisms is predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 80%. In some embodiments, the presence of the at least three polymorphisms is predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 85%. In some embodiments, the presence of the at least three polymorphisms is predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 90%. In some embodiments, the presence of the at least three polymorphisms is predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 95%.

Aspects disclosed herein provide methods of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: (a) determining whether the subject with an inflammatory, a fibrotic, or a fibrostenotic disease or condition is suitable for treatment with an inhibitor of TL1A activity or expression by: (i) obtaining or having obtained a sample from the subject; and (ii) subjecting the sample to an assay adapted to detect at least three polymorphisms that are predictive of the subject exhibiting a therapeutic response to the inhibitor of TL1A activity or expression at a positive predictive value of at least about 70%; and (b) treating the subject by administering a therapeutically effective amount of the inhibitor of TL1A activity or expression to the subject provided the at least three polymorphisms are detected. In some embodiments, the at least three polymorphisms comprise rs1892231, rs56124762, rs6478109, rs2070558, rs2070561, rs11897732, rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557, rs4246905, rs10974900, rs12434976, rs16901748, rs2815844, rs889702, rs2409750, rs1541020, rs4942248, rs12934476, rs12457255, rs2297437, rs41309367, rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs951279, rs9806914, rs7935393, rs1690492, rs420726, rs7759385, rs10974900, rs1326860, rs2548147, rs2815844, rs889702, rs9806914, rs7278257, rs11221332, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85, or a combination thereof.

In some embodiments, the at least three polymorphisms comprise: rs6478109, rs56124762, and rs1892231; rs6478109, rs56124762, and rs16901748; rs6478109, rs1892231, and rs16901748; rs56124762, rs1892231, and rs16901748; rs6478109, rs2070558, and rs1892231; rs6478109, rs2070558, and rs16901748; rs6478109, rs1892231, and rs16901748; rs2070558, rs1892231, and rs16901748; rs6478109, rs2070561, and rs1892231; rs6478109, rs2070561, and rs16901748; rs6478109, rs1892231, and rs16901748; rs2070561, rs1892231, and rs16901748; rs6478109, rs7935393, and rs1892231; rs6478109, rs7935393, and rs9806914; rs6478109, rs7935393, and rs7278257; rs6478109, rs7935393, and rs2070557; rs6478109, rs1892231, and rs9806914; rs6478109, rs1892231, and rs7278257; rs6478109, rs1892231, and rs2070557; rs6478109, rs9806914, and rs7278257; rs6478109, rs9806914, and rs2070557; rs6478109, rs7278257, and rs2070557; rs7935393, rs1892231, and rs9806914; rs7935393, rs1892231, and rs7278257; rs7935393, rs1892231, and rs2070557; rs7935393, rs9806914, and rs7278257; rs7935393, rs9806914, and rs2070557; rs7935393, rs7278257, and rs2070557; rs1892231, rs9806914, and rs7278257; rs1892231, rs9806914, and rs2070557; rs1892231, rs7278257, and rs2070557; or rs9806914, rs7278257, and rs2070557. In some embodiments, the at least three polymorphisms further comprises a fourth polymorphism comprising rs16901748, rs1892231, rs56124762, rs6478109, rs2070558, rs2070561, rs11897732, rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557, rs4246905, rs10974900, rs12434976, rs2815844, rs889702, rs2409750, rs1541020, rs4942248, rs12934476, rs12457255, rs2297437, rs41309367, rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs951279, rs9806914, rs7935393, rs1690492, rs420726, rs7759385, rs10974900, rs1326860, rs2548147, rs2815844, rs889702, rs9806914, rs7278257, or rs11221332 or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85, or a combination thereof. In some embodiments, the at least three polymorphisms comprise rs6478109, rs56124762, and rs1892231. In some embodiments, the at least three polymorphisms comprise rs6478109, rs56124762, and rs16901748. In some embodiments, the at least three polymorphisms comprise rs6478109, rs1892231, and rs16901748. In some embodiments, the at least three polymorphisms comprise rs56124762, rs1892231, and rs16901748.

›SUMMARY · 4 of 11

In some embodiments, the at least three polymorphisms are predictive that the subject will therapeutically respond to the inhibitor of TL1A at a positive predictive value of at least about 70%. In some embodiments, the at least three polymorphisms are predictive that the subject will therapeutically respond to the inhibitor of TL1A at a positive predictive value of at least about 75%. In some embodiments, the at least three polymorphisms are predictive that the subject will therapeutically respond to the inhibitor of TL1A at a positive predictive value of at least about 80%. In some embodiments, the at least three polymorphisms are predictive that the subject will therapeutically respond to the inhibitor of TL1A at a positive predictive value of at least about 85%. In some embodiments, the at least three polymorphisms are predictive that the subject will therapeutically respond to the inhibitor of TL1A at a positive predictive value of at least about 90%. In some embodiments, the at least three polymorphisms are predictive that the subject will therapeutically respond to the inhibitor of TL1A at a positive predictive value of at least about 95%.

In some embodiments, the at least three polymorphisms are predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 70%. In some embodiments, the at least three polymorphisms are predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 75%. In some embodiments, the at least three polymorphisms are predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 80%. In some embodiments, the at least three polymorphisms are predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 85%. In some embodiments, the at least three polymorphisms are predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 90%. In some embodiments, the at least three polymorphisms are predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 95%.

In some embodiments, the inflammatory, fibrotic, or fibrostenotic disease or condition comprises inflammatory bowel disease, Crohn's disease, obstructive Crohn's disease, ulcerative colitis, intestinal fibrosis, intestinal fibrostenosis, rheumatoid arthritis, or primary sclerosing cholangitis. In some embodiments, the Crohn's disease is ileal, ileocolonic, or colonic Crohn's disease. In some embodiments, the wherein the inhibitor of TL1A activity or expression is an anti-TL1A antibody or antigen-binding fragment. In some embodiments, the anti-TL1A antibody binds to the same region of human TL1A as a reference antibody selected from Table 2B. In some embodiments, methods further comprise administering an additional therapeutic agent to the subject.

In some embodiments, the subject is at risk of developing a non-response or loss-of-response to a standard therapy comprising glucocorticosteriods, anti-TNF therapy, anti-a4-b7 therapy, anti-IL12p40 therapy, or a combination thereof. In some embodiments, the proxy polymorphism in linkage disequilibrium is independently associated with a clinical phenotype associated with the inflammatory, the fibrotic, or the fibrostenotic disease or condition in the subject. In some embodiments, the clinical phenotype is stricturing and penetrating disease.

Aspects disclosed herein provide methods of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: (a) determining whether the subject with an inflammatory, a fibrotic, or a fibrostenotic disease or condition is suitable for treatment with an inhibitor of TL1A activity or expression by: (i) obtaining or having obtained a sample from the subject; and (ii) subjecting the sample to an assay adapted to detect at least three polymorphisms comprising rs1892231, rs56124762, rs6478109, rs2070558, rs2070561, rs11897732, rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557, rs4246905, rs10974900, rs12434976, rs16901748, rs2815844, rs889702, rs2409750, rs1541020, rs4942248, rs12934476, rs12457255, rs2297437, rs41309367, rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs951279, rs9806914, rs7935393, rs1690492, rs420726, rs7759385, rs10974900, rs1326860, rs2548147, rs2815844, rs889702, rs9806914, rs7278257, rs11221332, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85, or a combination thereof; and (b) treating the subject by administering a therapeutically effective amount of the inhibitor of TL1A activity or expression to the subject.

In some embodiments, the at least three polymorphisms comprise: rs6478109, rs56124762, and rs1892231; rs6478109, rs56124762, and rs16901748; rs6478109, rs1892231, and rs16901748; rs56124762, rs1892231, and rs16901748; rs6478109, rs2070558, and rs1892231; rs6478109, rs2070558, and rs16901748; rs6478109, rs1892231, and rs16901748; rs2070558, rs1892231, and rs16901748; rs6478109, rs2070561, and rs1892231; rs6478109, rs2070561, and rs16901748; rs6478109, rs1892231, and rs16901748; rs2070561, rs1892231, and rs16901748; rs6478109, rs7935393, and rs1892231; rs6478109, rs7935393, and rs9806914; rs6478109, rs7935393, and rs7278257; rs6478109, rs7935393, and rs2070557; rs6478109, rs1892231, and rs9806914; rs6478109, rs1892231, and rs7278257; rs6478109, rs1892231, and rs2070557; rs6478109, rs9806914, and rs7278257; rs6478109, rs9806914, and rs2070557; rs6478109, rs7278257, and rs2070557; rs7935393, rs1892231, and rs9806914; rs7935393, rs1892231, and rs7278257; rs7935393, rs1892231, and rs2070557; rs7935393, rs9806914, and rs7278257; rs7935393, rs9806914, and rs2070557; rs7935393, rs7278257, and rs2070557; rs1892231, rs9806914, and rs7278257; rs1892231, rs9806914, and rs2070557; rs1892231, rs7278257, and rs2070557; or rs9806914, rs7278257, and rs2070557. In some embodiments, the at least three polymorphisms further comprises a fourth polymorphism comprising rs16901748, rs1892231, rs56124762, rs6478109, rs2070558, rs2070561, rs11897732, rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557, rs4246905, rs10974900, rs12434976, rs2815844, rs889702, rs2409750, rs1541020, rs4942248, rs12934476, rs12457255, rs2297437, rs41309367, rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs951279, rs9806914, rs7935393, rs1690492, rs420726, rs7759385, rs10974900, rs1326860, rs2548147, rs2815844, rs889702, rs9806914, rs7278257, or rs11221332 or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85, or a combination thereof. In some embodiments, the at least three polymorphisms comprise rs6478109, rs56124762, and rs1892231. In some embodiments, the at least three polymorphisms comprise rs6478109, rs56124762, and rs16901748. In some embodiments, the at least three polymorphisms comprise rs6478109, rs1892231, and rs16901748. In some embodiments, the at least three polymorphisms comprise rs56124762, rs1892231, and rs16901748.

›SUMMARY · 5 of 11

In some embodiments, the wherein the inhibitor of TL1A activity or expression is an anti-TL1A antibody or antigen-binding fragment. In some embodiments, the anti-TL1A antibody binds to the same region of human TL1A as a reference antibody selected from Table 2B. In some embodiments, methods further comprise administering an additional therapeutic agent to the subject.

Aspects disclosed herein provide methods of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising administering to the subject a therapeutically effective amount of an inhibitor of TL1A activity or expression, wherein the subject expresses at least three polymorphisms comprising rs16901748, rs6478109, rs56124762, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85. In some embodiments, the at least three polymorphisms further comprises a fourth polymorphism comprising rs16901748, rs1892231, rs56124762, rs6478109, rs2070558, rs2070561, rs11897732, rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557, rs4246905, rs10974900, rs12434976, rs2815844, rs889702, rs2409750, rs1541020, rs4942248, rs12934476, rs12457255, rs2297437, rs41309367, rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs951279, rs9806914, rs7935393, rs1690492, rs420726, rs7759385, rs10974900, rs1326860, rs2548147, rs2815844, rs889702, rs9806914, rs7278257, or rs11221332 or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85, or a combination thereof. In some embodiments, the at least three polymorphisms are predictive that the subject will therapeutically respond to the inhibitor of TL1A at a positive predictive value of at least about 70%. In some embodiments, the at least three polymorphisms are predictive that the subject will therapeutically respond to the inhibitor of TL1A at a positive predictive value of at least about 75%. In some embodiments, the at least three polymorphisms are predictive that the subject will therapeutically respond to the inhibitor of TL1A at a positive predictive value of at least about 80%. In some embodiments, the at least three polymorphisms are predictive that the subject will therapeutically respond to the inhibitor of TL1A at a positive predictive value of at least about 85%. In some embodiments, the at least three polymorphisms are predictive that the subject will therapeutically respond to the inhibitor of TL1A at a positive predictive value of at least about 90%. In some embodiments, the at least three polymorphisms are predictive that the subject will therapeutically respond to the inhibitor of TL1A at a positive predictive value of at least about 95%. In some embodiments, the at least three polymorphisms are predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 70%. In some embodiments, the at least three polymorphisms are predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 75%. In some embodiments, the at least three polymorphisms are predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 80%. In some embodiments, the at least three polymorphisms are predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 85%. In some embodiments, the at least three polymorphisms are predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 90%. In some embodiments, the at least three polymorphisms are predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 95%.=In some embodiments, the inflammatory, fibrotic, or fibrostenotic disease or condition comprises inflammatory bowel disease, Crohn's disease, obstructive Crohn's disease, ulcerative colitis, intestinal fibrosis, intestinal fibrostenosis, rheumatoid arthritis, or primary sclerosing cholangitis. In some embodiments, the Crohn's disease is ileal, ileocolonic, or colonic Crohn's disease. In some embodiments, the wherein the inhibitor of TL1A activity or expression is an anti-TL1A antibody or antigen-binding fragment. In some embodiments, the anti-TL1A antibody binds to the same region of human TL1A as a reference antibody selected from Table 2B. In some embodiments, methods further comprise administering an additional therapeutic agent to the subject. In some embodiments, the subject is at risk of developing a non-response or loss-of-response to a standard therapy comprising glucocorticosteriods, anti-TNF therapy, anti-a4-b7 therapy, anti-IL12p40 therapy, or a combination thereof. In some embodiments, the proxy polymorphism in linkage disequilibrium is independently associated with a clinical phenotype associated with the inflammatory, the fibrotic, or the fibrostenotic disease or condition in the subject. In some embodiments, the clinical phenotype is stricturing and penetrating disease.

›SUMMARY · 6 of 11

Aspects disclosed herein provide methods comprising: (a) providing a sample obtained from a subject with an inflammatory, a fibrotic, or a fibrostenotic disease or condition; and (b) detecting a presence of at least three polymorphisms in the sample with a genotyping assay, wherein the presence of the at least three polymorphisms is predictive of a therapeutic response in the subject to a treatment with an inhibitor of TL1A activity or expression at a positive predictive value of at least about 70%. In some embodiments, the at least three polymorphisms comprise rs1892231, rs56124762, rs6478109, rs2070558, rs2070561, rs11897732, rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557, rs4246905, rs10974900, rs12434976, rs16901748, rs2815844, rs889702, rs2409750, rs1541020, rs4942248, rs12934476, rs12457255, rs2297437, rs41309367, rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs951279, rs9806914, rs7935393, rs1690492, rs420726, rs7759385, rs10974900, rs1326860, rs2548147, rs2815844, rs889702, rs9806914, rs7278257, rs11221332, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85, or a combination thereof.

In some embodiments, detecting the at least three polymorphisms comprises detecting at least three genotypes corresponding to nucleic acid position 501 within at least three of SEQ ID NOS: 1-41, or 57-59. In some embodiments, the presence of at least three polymorphisms is predictive that the subject will therapeutically respond to the inhibitor of TL1A at a positive predictive value of at least about 75%. In some embodiments, the presence of at least three polymorphisms is predictive that the subject will therapeutically respond to the inhibitor of TL1A at a positive predictive value of at least about 80%. In some embodiments, the presence of at least three polymorphisms is predictive that the subject will therapeutically respond to the inhibitor of TL1A at a positive predictive value of at least about 85%. In some embodiments, the presence of at least three polymorphisms is predictive that the subject will therapeutically respond to the inhibitor of TL1A at a positive predictive value of at least about 90%. In some embodiments, the presence of at least three polymorphisms is predictive that the subject will therapeutically respond to the inhibitor of TL1A at a positive predictive value of at least about 95%.

In some embodiments, the presence of at least three polymorphisms is predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 70%. In some embodiments, the presence of at least three polymorphisms is predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 75%. In some embodiments, the presence of at least three polymorphisms is predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 80%. In some embodiments, the presence of at least three polymorphisms is predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 85%. In some embodiments, the presence of at least three polymorphisms is predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 90%. In some embodiments, the presence of at least three polymorphisms is predictive that the subject will therapeutically respond to the inhibitor of TL1A with a specificity of at least about 95%.

In some embodiments, methods further comprise administering to the subject a therapeutically effective amount of the inhibitor of TL1A activity or expression to treat the inflammatory, fibrotic, or fibrostenotic disease or condition. In some embodiments, the subject is at risk of developing a non-response or loss-of-response to a standard therapy comprising glucocorticosteriods, anti-TNF therapy, anti-a4-b7 therapy, anti-IL12p40 therapy, or a combination thereof. In some embodiments, the inflammatory, fibrotic, or fibrostenotic disease or condition comprises inflammatory bowel disease, Crohn's disease, obstructive Crohn's disease, ulcerative colitis, intestinal fibrosis, intestinal fibrostenosis, rheumatoid arthritis, or primary sclerosing cholangitis. In some embodiments, the Crohn's disease is ileal, ileocolonic, or colonic Crohn's disease.

In some embodiments, the at least three polymorphisms comprise: rs6478109, rs56124762, and rs1892231; rs6478109, rs56124762, and rs16901748; rs6478109, rs1892231, and rs16901748; rs56124762, rs1892231, and rs16901748; rs6478109, rs2070558, and rs1892231; rs6478109, rs2070558, and rs16901748; rs6478109, rs1892231, and rs16901748; rs2070558, rs1892231, and rs16901748; rs6478109, rs2070561, and rs1892231; rs6478109, rs2070561, and rs16901748; rs6478109, rs1892231, and rs16901748; rs2070561, rs1892231, and rs16901748; rs6478109, rs7935393, and rs1892231; rs6478109, rs7935393, and rs9806914; rs6478109, rs7935393, and rs7278257; rs6478109, rs7935393, and rs2070557; rs6478109, rs1892231, and rs9806914; rs6478109, rs1892231, and rs7278257; rs6478109, rs1892231, and rs2070557; rs6478109, rs9806914, and rs7278257; rs6478109, rs9806914, and rs2070557; rs6478109, rs7278257, and rs2070557; rs7935393, rs1892231, and rs9806914; rs7935393, rs1892231, and rs7278257; rs7935393, rs1892231, and rs2070557; rs7935393, rs9806914, and rs7278257; rs7935393, rs9806914, and rs2070557; rs7935393, rs7278257, and rs2070557; rs1892231, rs9806914, and rs7278257; rs1892231, rs9806914, and rs2070557; rs1892231, rs7278257, and rs2070557; or rs9806914, rs7278257, and rs2070557. In some embodiments, the at least three polymorphisms further comprises a fourth polymorphism comprising rs16901748, rs1892231, rs56124762, rs6478109, rs2070558, rs2070561, rs11897732, rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557, rs4246905, rs10974900, rs12434976, rs2815844, rs889702, rs2409750, rs1541020, rs4942248, rs12934476, rs12457255, rs2297437, rs41309367, rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs951279, rs9806914, rs7935393, rs1690492, rs420726, rs7759385, rs10974900, rs1326860, rs2548147, rs2815844, rs889702, rs9806914, rs7278257, or rs11221332, or a combination thereof. In some embodiments, the at least three polymorphisms comprise rs6478109, rs56124762, and rs1892231. In some embodiments, the at least three polymorphisms comprise rs6478109, rs56124762, and rs16901748. In some embodiments, the at least three polymorphisms comprise rs6478109, rs1892231, and rs16901748. In some embodiments, the at least three polymorphisms comprise rs56124762, rs1892231, and rs16901748. In some embodiments, the proxy polymorphism in linkage disequilibrium is independently associated with a clinical phenotype associated with the inflammatory, the fibrotic, or the fibrostenotic disease or condition in the subject. In some embodiments, the clinical phenotype is stricturing and penetrating disease.

›SUMMARY · 7 of 11

Aspects disclosed herein provide methods comprising: (a) providing a sample obtained from a subject with an inflammatory, a fibrotic, or a fibrostenotic disease or condition; and (b) detecting a presence of at least three polymorphisms in the sample with a genotyping assay, said at least three polymorphisms comprising rs1892231, rs56124762, rs6478109, rs2070558, rs2070561, rs11897732, rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557, rs4246905, rs10974900, rs12434976, rs16901748, rs2815844, rs889702, rs2409750, rs1541020, rs4942248, rs12934476, rs12457255, rs2297437, rs41309367, rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs951279, rs9806914, rs7935393, rs1690492, rs420726, rs7759385, rs10974900, rs1326860, rs2548147, rs2815844, rs889702, rs9806914, rs7278257, rs11221332, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85, or a combination thereof.

In some embodiments, detecting the at least three polymorphisms comprises detecting at least three genotypes corresponding to nucleic acid position 501 within at least three of SEQ ID NOS: 1-41, or 57-59. In some embodiments, the presence of at least three polymorphisms is predictive of a therapeutic response in a subject to a treatment with the inhibitor of TL1A at a positive predictive value of at least about 70%. In some embodiments, the presence of at least three polymorphisms is predictive of a therapeutic response in a subject to a treatment with the inhibitor of TL1A at a positive predictive value of at least about 75%. In some embodiments, the presence of at least three polymorphisms is predictive of a therapeutic response in a subject to a treatment with the inhibitor of TL1A at a positive predictive value of at least about 80%. In some embodiments, the presence of at least three polymorphisms is predictive of a therapeutic response in a subject to a treatment with the inhibitor of TL1A at a positive predictive value of at least about 85%. In some embodiments, the presence of at least three polymorphisms is predictive of a therapeutic response in a subject to a treatment with the inhibitor of TL1A at a positive predictive value of at least about 90%. In some embodiments, the presence of at least three polymorphisms is predictive of a therapeutic response in a subject to a treatment with the inhibitor of TL1A at a positive predictive value of at least about 95%.

In some embodiments, the presence of at least three polymorphisms is predictive of a therapeutic response in a subject to a treatment with the inhibitor of TL1A with a specificity of at least about 70%. In some embodiments, the presence of at least three polymorphisms is predictive of a therapeutic response in a subject to a treatment with the inhibitor of TL1A with a specificity of at least about 75%. In some embodiments, the presence of at least three polymorphisms is predictive of a therapeutic response in a subject to a treatment with the inhibitor of TL1A with a specificity of at least about 80%. In some embodiments, the presence of at least three polymorphisms is predictive of a therapeutic response in a subject to a treatment with the inhibitor of TL1A with a specificity of at least about 85%. In some embodiments, the presence of at least three polymorphisms is predictive of a therapeutic response in a subject to a treatment with the inhibitor of TL1A with a specificity of at least about 90%. In some embodiments, the presence of at least three polymorphisms is predictive of a therapeutic response in a subject to a treatment with the inhibitor of TL1A with a specificity of at least about 95%.

In some embodiments, the at least three polymorphisms comprise: rs6478109, rs56124762, and rs1892231; rs6478109, rs56124762, and rs16901748; rs6478109, rs1892231, and rs16901748; rs56124762, rs1892231, and rs16901748; rs6478109, rs2070558, and rs1892231; rs6478109, rs2070558, and rs16901748; rs6478109, rs1892231, and rs16901748; rs2070558, rs1892231, and rs16901748; rs6478109, rs2070561, and rs1892231; rs6478109, rs2070561, and rs16901748; rs6478109, rs1892231, and rs16901748; rs2070561, rs1892231, and rs16901748; rs6478109, rs7935393, and rs1892231; rs6478109, rs7935393, and rs9806914; rs6478109, rs7935393, and rs7278257; rs6478109, rs7935393, and rs2070557; rs6478109, rs1892231, and rs9806914; rs6478109, rs1892231, and rs7278257; rs6478109, rs1892231, and rs2070557; rs6478109, rs9806914, and rs7278257; rs6478109, rs9806914, and rs2070557; rs6478109, rs7278257, and rs2070557; rs7935393, rs1892231, and rs9806914; rs7935393, rs1892231, and rs7278257; rs7935393, rs1892231, and rs2070557; rs7935393, rs9806914, and rs7278257; rs7935393, rs9806914, and rs2070557; rs7935393, rs7278257, and rs2070557; rs1892231, rs9806914, and rs7278257; rs1892231, rs9806914, and rs2070557; rs1892231, rs7278257, and rs2070557; or rs9806914, rs7278257, and rs2070557. In some embodiments, the at least three polymorphisms further comprises a fourth polymorphism comprising rs16901748, rs1892231, rs56124762, rs6478109, rs2070558, rs2070561, rs11897732, rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557, rs4246905, rs10974900, rs12434976, rs2815844, rs889702, rs2409750, rs1541020, rs4942248, rs12934476, rs12457255, rs2297437, rs41309367, rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs951279, rs9806914, rs7935393, rs1690492, rs420726, rs7759385, rs10974900, rs1326860, rs2548147, rs2815844, rs889702, rs9806914, rs7278257, or rs11221332, or a combination thereof. In some embodiments, the at least three polymorphisms comprise rs6478109, rs56124762, and rs1892231. In some embodiments, the at least three polymorphisms comprise rs6478109, rs56124762, and rs16901748. In some embodiments, the at least three polymorphisms comprise rs6478109, rs1892231, and rs16901748. In some embodiments, the at least three polymorphisms comprise rs56124762, rs1892231, and rs16901748. In some embodiments, the proxy polymorphism in linkage disequilibrium is independently associated with a clinical phenotype associated with the inflammatory, the fibrotic, or the fibrostenotic disease or condition in the subject. In some embodiments, the clinical phenotype is stricturing and penetrating disease.

›SUMMARY · 8 of 11

Aspects disclosed herein provide computer-implemented methods comprising: (a) receiving genotype data of a subject with an inflammatory, a fibrotic, or a fibrostenotic disease or condition; and (b) analyzing the genotype data to detect a presence of at least three genotypes predictive of a therapeutic response in the subject to a treatment with an inhibitor of Tumor necrosis factor-like cytokine 1A (TL1A) activity or expression to treat the inflammatory, the fibrotic, or the fibrostenotic disease or condition with a positive predictive value of at least about 70%. In some embodiments, the at least three genotypes comprise at least three polymorphisms comprising rs1892231, rs56124762, rs6478109, rs2070558, rs2070561, rs11897732, rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557, rs4246905, rs10974900, rs12434976, rs16901748, rs2815844, rs889702, rs2409750, rs1541020, rs4942248, rs12934476, rs12457255, rs2297437, rs41309367, rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs951279, rs9806914, rs7935393, rs1690492, rs420726, rs7759385, rs10974900, rs1326860, rs2548147, rs2815844, rs889702, rs9806914, rs7278257, or rs11221332, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85, or a combination thereof.

In some embodiments, methods further comprise generating a TNFSF15 profile comprising a positive, a negative, or an indeterminant result for a therapeutic response to a treatment with the inhibitor of TL1A activity or expression.

In some embodiments, determining the likelihood that the subject will therapeutically respond to the treatment with the inhibitor of TL1A activity or expression is performed at a positive predictive value of at least about 70%. In some embodiments, determining the likelihood that the subject will therapeutically respond to the treatment with the inhibitor of TL1A activity or expression is performed at a positive predictive value of at least about 75%. In some embodiments, determining the likelihood that the subject will therapeutically respond to the treatment with the inhibitor of TL1A activity or expression is performed at a positive predictive value of at least about 80%. In some embodiments, determining the likelihood that the subject will therapeutically respond to the treatment with the inhibitor of TL1A activity or expression is performed at a positive predictive value of at least about 85%. In some embodiments, determining the likelihood that the subject will therapeutically respond to the treatment with the inhibitor of TL1A activity or expression is performed at a positive predictive value of at least about 90%. In some embodiments, determining the likelihood that the subject will therapeutically respond to the treatment with the inhibitor of TL1A activity or expression is performed at a positive predictive value of at least about 95%.

In some embodiments, determining the likelihood that the subject will therapeutically respond to the treatment with the inhibitor of TL1A activity or expression is performed at with a specificity of at least about 70%. In some embodiments, determining the likelihood that the subject will therapeutically respond to the treatment with the inhibitor of TL1A activity or expression is performed at with a specificity of at least about 75%. In some embodiments, determining the likelihood that the subject will therapeutically respond to the treatment with the inhibitor of TL1A activity or expression is performed at with a specificity of at least about 80%. In some embodiments, determining the likelihood that the subject will therapeutically respond to the treatment with the inhibitor of TL1A activity or expression is performed at with a specificity of at least about 85%. In some embodiments, determining the likelihood that the subject will therapeutically respond to the treatment with the inhibitor of TL1A activity or expression is performed at with a specificity of at least about 90%. In some embodiments, determining the likelihood that the subject will therapeutically respond to the treatment with the inhibitor of TL1A activity or expression is performed at with a specificity of at least about 95%.

›SUMMARY · 9 of 11

In some embodiments, methods further comprise generating a report comprising the TNFSF15 profile for display to a user. In some embodiments, the inflammatory, the fibrotic, and the fibrostenotic disease or condition comprises inflammatory bowel disease, Crohn's disease, obstructive Crohn's disease, ulcerative colitis, intestinal fibrosis, intestinal fibrostenosis, rheumatoid arthritis, or primary sclerosing cholangitis. In some embodiments, the Crohn's disease is ileal, ileocolonic, or colonic Crohn's disease. In some embodiments, the inhibitor of TL1A activity or expression is an anti-TL1A antibody or antigen-binding fragment. In some embodiments, the anti-TL1A antibody binds to the same region of human TL1A as a reference antibody selected from Table 2B. In some embodiments, the proxy polymorphism in linkage disequilibrium is independently associated with a clinical phenotype associated with the inflammatory, the fibrotic, or the fibrostenotic disease or condition in the subject. In some embodiments, the clinical phenotype is stricturing and penetrating disease.

Aspects disclosed herein provide kits comprising: (a) at least three primer pairs, each primer pair comprising a first primer and a second primer, where said first primer comprises at least 10 contiguous nucleic acids corresponding to nucleotides 4090-500 of SEQ ID NOS: 1-41, or 57-59, and wherein said second primer comprises at least 10 contiguous nucleic acids corresponding to nucleotides 4090-500 of a reverse complement to SEQ ID NOS: 1-41, or 57-59; and (b) at least three polynucleotide molecules, each polynucleotide molecule comprising a detectable moiety, wherein the polynucleotide molecule comprises a nucleic acid sequence comprising a nucleotide corresponding to nucleotide position 501 of SEQ ID NOS: 1-41, or 57-59. In some embodiments, the kit is useful for selecting a patient with an inflammatory, a fibrotic, or a fibrostenotic disease or condition for treatment with an inhibitor of TL1A activity or expression, provided the presence of the at least three polymorphisms is detected in a sample obtained from the patient.

Aspects disclosed herein provide kits comprising: (a) a first primer pair comprising a first forward primer provided in any one of SEQ ID NOS: 364101-364110 and a corresponding first reverse primer provided in SEQ ID NO: in any one of SEQ ID NOS: 364111-364120; (b) a second primer pair comprising a second forward primer provided in any one of SEQ ID NOS: 364101-364110 and a corresponding second reverse primer provided in any one of SEQ ID NOS: 364111-364120; (c) a third primer pair comprising a third forward primer provided in any one of SEQ ID NOS: 364101-364110 and a corresponding third reverse primer provided in any one of SEQ ID NOS: 364111-364120, wherein the first primer pair, the second primer pair, and the third primer pair are not the same; and (d) at least three polynucleotide molecules, each polynucleotide molecule comprising a detectable moiety, wherein the polynucleotide molecule comprises a nucleic acid sequence comprising a nucleotide corresponding to nucleotide position 501 of SEQ ID NOS: 1-41, or 57-59. In some embodiments, the kit is useful for selecting a patient with an inflammatory, a fibrotic, or a fibrostenotic disease or condition for treatment with an inhibitor of TL1A activity or expression, provided the presence of the at least three polymorphisms is detected in a sample obtained from the patient.

Aspects disclosed herein provide methods of selecting a patient with an inflammatory, a fibrotic, or a fibrostenotic disease or condition for treatment with an inhibitor of TL1A activity or expression, the method comprising: (a) assaying a sample obtained from the subject using the kit of the present disclosure; (b) detecting at least three genotypes in the sample; and (c) selecting the patient for treatment with an inhibitor of TL1A activity or expression to treat an inflammatory, a fibrotic, or a fibrostenotic disease or condition in the subject. In some embodiments, methods further comprise administering the inhibitor of TL1A activity or expression to the patient to treat the inflammatory, the fibrotic, or the fibrostenotic disease or condition in the subject.

Aspects of the present disclosure provide a non-transitory computer readable medium comprising machine executable code that, upon execution by one or more computer processors, implements any of the methods above or elsewhere herein.

Aspects of the present disclosure provide a system comprising one or more computer processors and computer memory coupled thereto. The computer memory comprises machine executable code that, upon execution by the one or more computer processors, implements any of the methods above or elsewhere herein.

Aspects provided herein provide methods of treating at least one of an inflammatory, a fibrotic, and a fibrostenotic disease or condition in a subject, the method comprising administering to the subject a therapeutically effective amount of an inhibitor of TL1A activity or expression, provided a presence of a genotype is detected in a sample obtained from the subject, the genotype comprising at least three polymorphisms provided in Table 1. In some embodiments, the at least three polymorphisms is selected from the group consisting of rs11897732, rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557, rs4246905, rs10974900, rs12434976, rs16901748, rs2815844, rs889702, rs2409750, rs1541020, rs4942248, rs12934476, rs12457255, rs2297437, rs41309367, rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs1892231, rs951279, rs9806914, rs7935393, rs1690492, rs420726, rs7759385, rs10974900, rs1326860, rs2548147, rs2815844, rs889702, rs9806914, rs6478109, rs7278257, and rs11221332. In some embodiments, the at least three polymorphisms are selected from the group consisting of a “G” allele at rs11897732, an “A” allele at rs6740739, a “G” allele at rs17796285, an “A” allele at rs7935393, a “G” allele at rs12934476, an “A” allele at rs12457255, an “A” allele at rs2070557, an “A” allele at rs4246905, an “A” allele at rs10974900, a “C” allele at rs12434976, an “A” allele at rs16901748, an “A” allele at rs2815844, a “G” allele at rs889702, a “C” allele at rs2409750, an “A” allele at rs1541020, a “T” allele at rs4942248, a “G” allele at rs12934476, an “A” allele at rs12457255, an “A” allele at rs2297437, a “G” allele at rs41309367, an “A” allele at rs10733509, a “G” allele at rs10750376, a “G” allele at rs10932456, an “A” allele at rs1326860, a “G” allele at rs1528663, a “C” allele at rs1892231, an “A” allele at rs951279, an “A” allele at rs9806914, an “A” allele at rs7935393, a “G” allele at rs1690492, an “A” allele at rs420726, a “T” allele at rs7759385, an “A” allele at rs10974900, an “A” allele at rs1326860, a “C” allele at rs2548147, an “A” allele at rs2815844, a “G” allele at rs889702, an “A” allele at rs9806914, an “A” allele at rs6478109, a “C” allele at rs7278257, and an “A” allele at rs11221332. In some embodiments, a polymorphism of the at least three polymorphisms comprises a minor allele provided in Table 1. In some embodiments, a polymorphism of the at least three polymorphisms comprises a major allele provided in Table 1. In some embodiments, the genotype is heterozygous. In some embodiments, the genotype is homozygous. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, imm_11_127948309, and rs1892231. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, imm_11_127948309, and rs9806914. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, imm_11_127948309, and imm_21_44478192. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, imm_11_127948309, and imm_21_44479552. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, rs1892231, and rs9806914. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, rs1892231, and imm_21_44478192. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, rs1892231, and imm_21_44479552. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, rs9806914, and imm_21_44478192. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, rs9806914, and imm_21_44479552. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, imm_21_44478192, and imm_21_44479552. In some embodiments, the at least three polymorphisms comprise imm_11_127948309, rs1892231, and rs9806914. In some embodiments, the at least three polymorphisms comprise imm_11_127948309, rs1892231, and imm_21_44478192. In some embodiments, the at least three polymorphisms comprise imm_11_127948309, rs1892231, and imm_21_44479552. In some embodiments, the at least three polymorphisms comprise imm_11_127948309, rs9806914, and imm_21_44478192. In some embodiments, the at least three polymorphisms comprise imm_11_127948309, rs9806914, and imm_21_44479552. In some embodiments, the at least three polymorphisms comprise imm_11_127948309, imm_21_44478192, and imm_21_44479552. In some embodiments, the at least three polymorphisms comprise rs1892231, rs9806914, and imm_21_44478192. In some embodiments, the at least three polymorphisms comprise rs1892231, rs9806914, and imm_21_44479552. In some embodiments, the at least three polymorphisms comprise rs1892231, imm_21_44478192, and imm_21_44479552. In some embodiments, the at least three polymorphisms comprise rs9806914, imm_21_44478192, and imm_21_44479552. In some embodiments, the at least three polymorphisms are detected in the sample obtained from the subject by a process of: (a) subjecting the sample obtained from the subject to an assay configured to detect at least 10 contiguous nucleic acid molecules in at least three nucleic acid sequences within SEQ ID NOS: 1-41, or 57-59, the at least 10 contiguous nucleic acid molecules comprising a risk allele at a nucleoposition 251 or 501 within SEQ ID NOS: 1-41, or 57-59; and (b) detecting the at least 10 contiguous nucleic acid molecules in the at least three nucleic acid sequences within SEQ ID NOS: 1-41, or 57-59. In some embodiments, the assay is selected from the group consisting of polymerase chain reaction (PCR), quantitative reverse-transcription PCR (qPCR), automated sequencing, genotype array, or a combination thereof. In some embodiments, the inflammatory disease or condition is selected from the group consisting of inflammatory bowel disease (IBD), Crohn's disease (CD), obstructive CD, ulcerative colitis (UC), intestinal fibrosis, intestinal fibrostenosis, and primary sclerosing cholangitis. In some embodiments, the CD is ileal, ileocolonic, or colonic CD. In some embodiments, the subject has, or is at risk for developing, a non-response or loss-of-response to a standard therapy, the standard therapy selected from the group consisting of glucocorticosteriods, anti-TNF therapy, anti-a4-b7 therapy (vedolizumab), anti-IL12p40 therapy (ustekinumab), Thalidomide, and Cytoxan. In some embodiments, the inhibitor of TL1A is an anti-TL1A antibody or antigen-binding fragment. In some embodiments, the anti-TL1A antibody binds to the same region of human TL1A as a reference antibody, the reference antibody is selected from Table 2B. In some embodiments, the anti-TL1A antibody is a neutralizing TL1A antibody or antigen-binding fragment.

›SUMMARY · 10 of 11

Aspects disclosed herein provide methods of selecting a subject for treatment with an inhibitor of TL1A activity or expression, the method comprising: (a) contacting a sample obtained from a subject comprising genetic material with an assay adapted to detect a presence of a genotype, the genotype comprising at least three polymorphisms provided in Table 1; and (b) selecting the subject for treatment with an inhibitor of TL1A activity or expression, provided the presence of the genotype is detected in (a). In some embodiments, methods further comprise administering or prescribing to the subject a therapeutically effective amount of the inhibitor of TL1A activity or expression. In some embodiments, methods further comprise determining whether the subject is at risk of developing a non-response or loss-of-response to a standard therapy, the standard therapy selected from the group consisting of glucocorticosteriods, anti-TNF therapy, anti-a4-b7 therapy (vedolizumab), anti-IL12p40 therapy (ustekinumab), Thalidomide, and Cytoxin. In some embodiments, the inhibitor of TL1A is an anti-TL1A antibody or antigen-binding fragment. In some embodiments, the anti-TL1A antibody binds to the same region of human TL1A as a reference antibody, the reference antibody is selected from Table 2B. In some embodiments, the anti-TL1A antibody is a neutralizing TL1A antibody or antigen-binding fragment. In some embodiments, the at least three polymorphisms is selected from the group consisting of rs11897732, rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557, rs4246905, rs10974900, rs12434976, rs16901748, rs2815844, rs889702, rs2409750, rs1541020, rs4942248, rs12934476, rs12457255, rs2297437, rs41309367, rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs1892231, rs951279, rs9806914, rs7935393, rs1690492, rs420726, rs7759385, rs10974900, rs1326860, rs2548147, rs2815844, rs889702, rs9806914, rs6478109, rs7278257, and rs11221332. In some embodiments, a polymorphism of the at least three polymorphisms comprises a minor allele provided in Table 1. In some embodiments, a polymorphism of the at least three polymorphisms comprises a major allele provided in Table 1. In some embodiments, the genotype is heterozygous. In some embodiments, the genotype is homozygous. In some embodiments, the at least three polymorphisms are selected from the group consisting of a “G” allele at rs11897732, an “A” allele at rs6740739, a “G” allele at rs17796285, an “A” allele at rs7935393, a “G” allele at rs12934476, an “A” allele at rs12457255, an “A” allele at rs2070557, an “A” allele at rs4246905, an “A” allele at rs10974900, a “C” allele at rs12434976, an “A” allele at rs16901748, an “A” allele at rs2815844, a “G” allele at rs889702, a “C” allele at rs2409750, an “A” allele at rs1541020, a “T” allele at rs4942248, a “G” allele at rs12934476, an “A” allele at rs12457255, an “A” allele at rs2297437, a “G” allele at rs41309367, an “A” allele at rs10733509, a “G” allele at rs10750376, a “G” allele at rs10932456, an “A” allele at rs1326860, a “G” allele at rs1528663, a “C” allele at rs1892231, an “A” allele at rs951279, an “A” allele at rs9806914, an “A” allele at rs7935393, a “G” allele at rs1690492, an “A” allele at rs420726, a “T” allele at rs7759385, an “A” allele at rs10974900, an “A” allele at rs1326860, a “C” allele at rs2548147, an “A” allele at rs2815844, a “G” allele at rs889702, an “A” allele at rs9806914, an “A” allele at rs6478109, a “C” allele at rs7278257, and an “A” allele at rs11221332. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, imm_11_127948309, and rs1892231. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, imm_11_127948309, and rs9806914. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, imm_11_127948309, and imm_21_44478192. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, imm_11_127948309, and imm_21_44479552. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, rs1892231, and rs9806914. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, rs1892231, and imm_21_44478192. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, rs1892231, and imm_21_44479552. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, rs9806914, and imm_21_44478192. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, rs9806914, and imm_21_44479552. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, imm_21_44478192, and imm 21_44479552. In some embodiments, the at least three polymorphisms comprise imm_11_127948309, rs1892231, and rs9806914. In some embodiments, the at least three polymorphisms comprise imm_11_127948309, rs1892231, and imm_21_44478192. In some embodiments, the at least three polymorphisms comprise imm_11_127948309, rs1892231, and imm_21_44479552. In some embodiments, the at least three polymorphisms comprise imm_11_127948309, rs9806914, and imm_21_44478192. In some embodiments, the at least three polymorphisms comprise imm_11_127948309, rs9806914, and imm_21_44479552. In some embodiments, the at least three polymorphisms comprise imm_11_127948309, imm_21_44478192, and imm_21_44479552. In some embodiments, the at least three polymorphisms comprise rs1892231, rs9806914, and imm_21_44478192. In some embodiments, the at least three polymorphisms comprise rs1892231, rs9806914, and imm_21_44479552. In some embodiments, the at least three polymorphisms comprise rs1892231, imm_21_44478192, and imm_21_44479552. In some embodiments, the at least three polymorphisms comprise rs9806914, imm_21_44478192, and imm_21_44479552.

Aspects disclosed herein provide methods of treating at least one of an inflammatory, a fibrotic, and a fibrostenotic disease or condition in a subject, the method comprising: (a) determining whether a subject is, or is at risk for developing, non-response or loss-of-response to a standard therapy; (b) determining whether the subject is suitable for treatment with an inhibitor of TL1A activity or expression by a process of: (i) contacting a sample obtained from the subject with an assay adapted to detect a presence of a genotype, the genotype comprising at least three polymorphisms selected from Table 1; and (ii) detecting the genotype in the sample obtained from the subject; and (c) if the subject is not determined to have, or be at risk for developing, the non-response or loss-of-response to the standard therapy, then treating the subject by administering a therapeutically effective amount of the standard therapy to the subject; and (d) if the subject is determined to have, or be at risk for developing, the non-response or loss-of-response to the standard therapy, and the subject is determined to be suitable for treatment with the inhibitor of TL1A activity or expression, then treating the subject by administering a therapeutically effective amount of the inhibitor of TL1A activity or expression to the subject. In some embodiments, the at least three polymorphisms is selected from the group consisting of rs11897732, rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557, rs4246905, rs10974900, rs12434976, rs16901748, rs2815844, rs889702, rs2409750, rs1541020, rs4942248, rs12934476, rs12457255, rs2297437, rs41309367, rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs1892231, rs951279, rs9806914, rs7935393, rs1690492, rs420726, rs7759385, rs10974900, rs1326860, rs2548147, rs2815844, rs889702, rs9806914, rs6478109, rs7278257, and rs11221332. In some embodiments, a polymorphism of the at least three polymorphisms comprises a minor allele provided in Table 1. In some embodiments, a polymorphism of the at least three polymorphisms comprises a major allele provided in Table 1. In some embodiments, the genotype is heterozygous. In some embodiments, the genotype is homozygous. In some embodiments, the at least three polymorphisms are selected from the group consisting of a “G” allele at rs11897732, an “A” allele at rs6740739, a “G” allele at rs17796285, an “A” allele at rs7935393, a “G” allele at rs12934476, an “A” allele at rs12457255, an “A” allele at rs2070557, an “A” allele at rs4246905, an “A” allele at rs10974900, a “C” allele at rs12434976, an “A” allele at rs16901748, an “A” allele at rs2815844, a “G” allele at rs889702, a “C” allele at rs2409750, an “A” allele at rs1541020, a “T” allele at rs4942248, a “G” allele at rs12934476, an “A” allele at rs12457255, an “A” allele at rs2297437, a “G” allele at rs41309367, an “A” allele at rs10733509, a “G” allele at rs10750376, a “G” allele at rs10932456, an “A” allele at rs1326860, a “G” allele at rs1528663, a “C” allele at rs1892231, an “A” allele at rs951279, an “A” allele at rs9806914, an “A” allele at rs7935393, a “G” allele at rs1690492, an “A” allele at rs420726, a “T” allele at rs7759385, an “A” allele at rs10974900, an “A” allele at rs1326860, a “C” allele at rs2548147, an “A” allele at rs2815844, a “G” allele at rs889702, an “A” allele at rs9806914, an “A” allele at rs6478109, a “C” allele at rs7278257, and an “A” allele at rs11221332. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, imm_11_127948309, and rs1892231. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, imm_11_127948309, and rs9806914. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, imm_11_127948309, and imm_21_44478192. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, imm_11_127948309, and imm_21_44479552. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, rs1892231, and rs9806914. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, rs1892231, and imm_21_44478192. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, rs1892231, and imm_21_44479552. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, rs9806914, and imm_21_44478192. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, rs9806914, and imm_21_44479552. In some embodiments, the at least three polymorphisms comprise imm_9_116608587, imm_21_44478192, and imm_21_44479552. In some embodiments, the at least three polymorphisms comprise imm_11_127948309, rs1892231, and rs9806914. In some embodiments, the at least three polymorphisms comprise imm_11_127948309, rs1892231, and imm_21_44478192. In some embodiments, the at least three polymorphisms comprise imm_11_127948309, rs1892231, and imm_21_44479552. In some embodiments, the at least three polymorphisms comprise imm_11_127948309, rs9806914, and imm_21_44478192. In some embodiments, the at least three polymorphisms comprise imm_11_127948309, rs9806914, and imm_21_44479552. In some embodiments, the at least three polymorphisms comprise imm_11_127948309, imm_21_44478192, and imm_21_44479552. In some embodiments, the at least three polymorphisms comprise rs1892231, rs9806914, and imm_21_44478192. In some embodiments, the at least three polymorphisms comprise rs1892231, rs9806914, and imm_21_44479552. In some embodiments, the at least three polymorphisms comprise rs1892231, imm_21_44478192, and imm_21_44479552. In some embodiments, the at least three polymorphisms comprise rs9806914, imm_21_44478192, and imm_21_44479552. In some embodiments, the standard therapy is selected from the group consisting of glucocorticosteriods, anti-TNF therapy, anti-a4-b7 therapy (vedolizumab), anti-IL12p40 therapy (ustekinumab), Thalidomide, and Cytoxin.

›SUMMARY · 11 of 11

Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.

›INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material.

›BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the inventive concepts set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also “Figure” and “FIG.” herein), of which:

FIG. 1 shows a workflow according to an embodiment of the present disclosure for processing a biological sample obtained from a subject to inform the selection of a therapeutic agent to treat a disease or a condition of the subject.

FIG. 2 shows a computer-implemented workflow according to an embodiment of the present disclosure for generating an electronic report to a user, such as a physician, comprising a TNFSF15 profile of a subject based on an analysis of genotype data from the subject.

FIG. 3 shows a computer system that is programmed or otherwise configured to implement methods provided herein.

FIG. 4 shows a computer-implemented workflow according to an embodiment of the present disclosure for producing a TNFSF15 profile.

FIG. 5A-5C shows a clustering analysis within our the TL1A companion diagnostic (CDx) dataset, FIG. 5A shows cluster 1 , FIG. 5B shows cluster 2 , and FIG. 5C shows cluster 3 , from the TL1A CDx dataset.

FIG. 6 shows that the 3 clusters from FIG. 5A-5C were collapsed into 2 clusters (high TL1A expression clusters shown on the left) and (low TL1A expression clusters on the right).

›DETAILED DESCRIPTION · 1 of 5

Provided herein are methods, systems, and kits for identifying a subject who may be suitable for treatment with an inhibitor of Tumor Necrosis Factor (Ligand) Superfamily, Member 15 (TL1A) activity or expression, provided the subject is a carrier of a genotype. The subject may be a patient, who may be diagnosed with an inflammatory disease, a fibrostenotic disease, or a fibrotic disease, such as inflammatory bowel disease (IBD) or Crohn's disease (CD). The subject may not be a patient, but may be suspected of having the inflammatory disease, the fibrostenotic disease, or the fibrotic disease. The genotype may, in some cases, be useful for characterizing the inflammatory fibrostenotic, or fibrotic disease or condition, as mediated by TL1A. The subject, in some embodiments, is treated by administering the inhibitor of TL1A activity or expression (e.g., anti-TL1A antibody) to the subject, provided the genotype is detected. In some cases, identifying the subject as being suitable for treatment with the inhibitor of activity or expression is required in order to administer the inhibitor to the subject.

Referring to FIG. 1 , the methods, systems and kits of the present disclosure involve, in some embodiments, the steps of providing a buccal swab sample from a subject 101 , optionally purifying DNA from the sample by processing the sample 102 , assaying the optionally processed sample to detect genotypes of at least three genetic loci in the sample 103 , processing the genotypes to produce a TNFSF15 profile 104 , and selecting a therapy to treat a disease or disorder of the subject based on the TNFSF15 profile 105 .

The genotypes described herein are detected using suitable genotyping devices (e.g., array, sequencing). In some instances, a sample is obtained from the subject or patient indirectly or directly. In some instances, the sample may be obtained by the subject. In other instances, the sample may be obtained by a healthcare professional, such as a nurse or physician. The sample may be derived from virtually any biological fluid or tissue containing genetic information, such as blood.

The subject disclosed herein can be a mammal, such as for example a mouse, rat, guinea pig, rabbit, non-human primate, or farm animal. In some instances, the subject is human. In some instances, the subject is suffering from a symptom related to a disease or condition disclosed herein (e.g., abdominal pain, cramping, diarrhea, rectal bleeding, fever, weight loss, fatigue, loss of appetite, dehydration, and malnutrition, anemia, or ulcers).

In some embodiments, the subject is susceptible to, or is inflicted with, thiopurine toxicity, or a disease caused by thiopurine toxicity (such as pancreatitis or leukopenia). The subject may experience, or is suspected of experiencing, non-response or loss-of-response to a standard treatment (e.g., anti-TNF alpha therapy, anti-a4-b7 therapy (vedolizumab), anti-IL12p40 therapy (ustekinumab), Thalidomide, or Cytoxin).

The disease or condition disclosed herein may be an inflammatory disease, a fibrostenotic disease, or a fibrotic disease. In some instances, the disease or the condition is a TL1A-mediated disease or condition. The term, “TL1A-mediated disease or condition” refers to a disease or a condition pathology or pathogenesis that is driven, at least in part, by TL1A signaling. In some instances, the disease or the condition is immune-mediated disease or condition, such as those mediated by TL1A.

In some embodiments the disease or the condition is an inflammatory disease or disorder that is mediated, at least in part, by TL1A signaling. Non-limiting examples of inflammatory disease include, allergy, ankylosing spondylitis, asthma, atopic dermatitis, autoimmune diseases or disorders, cancer, celiac disease, chronic obstructive pulmonary disease (COPD), chronic peptic ulcer, cystic fibrosis, diabetes (e.g., type 1 diabetes and type 2 diabetes), glomerulonephritis, gout, hepatitis (e.g., active hepatitis), an immune-mediated disease or disorder, inflammatory bowel disease (IBD) such as Crohn's disease and ulcerative colitis, myositis, osteoarthritis, pelvic inflammatory disease (PID), multiple sclerosis, neurodegenerative diseases of aging, periodontal disease (e.g., periodontitis), preperfusion injury transplant rejection, psoriasis, pulmonary fibrosis, rheumatic disease, scleroderma, sinusitis, tuberculosis.

In some embodiments, the disease or the condition is an autoimmune disease that is mediated, at least in part, by TL1A signaling. Non-limiting examples of autoimmune disease or disorder include Achalasia, Addison's disease, Adult Still's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome, Autoimmune angioedema, Autoimmune dysautonomia, Autoimmune encephalomyelitis, Autoimmune hepatitis, Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune orchitis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune urticaria, Axonal & neuronal neuropathy (AMAN), Baló disease, Behcet's disease, Benign mucosal pemphigoid, Bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss Syndrome (CSS) or Eosinophilic Granulomatosis (EGPA), Cicatricial pemphigoid, Cogan's syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, Dermatitis herpetiformis, Dermatomyositis, Devic's disease (neuromyelitis optica), Discoid lupus, Dressler's syndrome, Endometriosis, Eosinophilic esophagitis (EoE), Eosinophilic fasciitis, Erythema nodosum, Essential mixed cryoglobulinemia, Evans syndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Giant cell myocarditis, Glomerulonephritis, Goodpasture's syndrome, Granulomatosis with Polyangiitis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis (PG), Hidradenitis Suppurativa (HS) (Acne Inversa), Hypogammalglobulinemia, IgA Nephropathy, IgG4-related sclerosing disease, Immune thrombocytopenic purpura (ITP), Inclusion body myositis (IBM), Interstitial cystitis (IC), Juvenile arthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus, Lyme disease chronic, Meniere's disease, Microscopic polyangiitis (MPA), Mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, Multifocal Motor Neuropathy (MMN) or MMNCB, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neonatal Lupus, Neuromyelitis optica, Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism (PR), PANDAS, Paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Pars planitis (peripheral uveitis), Parsonage-Turner syndrome, Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis, Pernicious anemia (PA), POEMS syndrome, Polyarteritis nodosa, Polyglandular syndromes type I, II, III, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Primary biliary cirrhosis, Primary sclerosing cholangitis, Progesterone dermatitis, Psoriasis, Psoriatic arthritis, Pure red cell aplasia (PRCA), Pyoderma gangrenosum, Raynaud's phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy, Relapsing polychondritis, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjögren's syndrome, Sperm & testicular autoimmunity, Stiff person syndrome (SPS), Subacute bacterial endocarditis (SBE), Susac's syndrome, Sympathetic ophthalmia (SO), Takayasu's arteritis, Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), Transverse myelitis, Type 1 diabetes, Ulcerative colitis (UC), Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vitiligo, and Vogt-Koyanagi-Harada Disease.

›DETAILED DESCRIPTION · 2 of 5

In some embodiments, the disease or the condition is a cancer that is mediated, at least in part, by TL1A signaling. Non-limiting examples of cancers include Adenoid Cystic Carcinoma, Adrenal Gland Cancer, Amyloidosis, Anal Cancer, Ataxia-Telangiectasia, Atypical Mole Syndrome, Basal Cell Carcinoma, Bile Duct Cancer, Birt Hogg Dube Syndrome, Bladder Cancer, Bone Cancer, Brain Tumor, Breast Cancer, Breast Cancer in Men, Carcinoid Tumor, Cervical Cancer, Colorectal Cancer, Ductal Carcinoma, Endometrial Cancer, Esophageal Cancer, Gastric Cancer, Gastrointestinal Stromal Tumor (GIST), HER2-Positive Breast Cancer, Islet Cell Tumor, Juvenile Polyposis Syndrome, Kidney Cancer, Laryngeal Cancer, Leukemia—Acute Lymphoblastic Leukemia, Leukemia—Acute Lymphocytic (ALL), Leukemia—Acute Myeloid AML, Leukemia—Adult, Leukemia—Childhood, Leukemia—Chronic Lymphocytic (CLL), Leukemia—Chronic Myeloid (CML), Liver Cancer, Lobular Carcinoma, Lung Cancer, Lung Cancer—Small Cell (SCLC), Lung Cancer—Non-small Cell (NSCLC), Lymphoma—Hodgkin's, Lymphoma—Non-Hodgkin's, Malignant Glioma, Melanoma, Meningioma, Multiple Myeloma, Myelodysplastic Syndrome (MDS), Nasopharyngeal Cancer, Neuroendocrine Tumor, Oral Cancer, Osteosarcoma, Ovarian Cancer, Pancreatic Cancer, Pancreatic Neuroendocrine Tumors, Parathyroid Cancer, Penile Cancer, Peritoneal Cancer, Peutz-Jeghers Syndrome, Pituitary Gland Tumor, Polycythemia Vera, Prostate Cancer, Renal Cell Carcinoma, Retinoblastoma, Salivary Gland Cancer, Sarcoma, Sarcoma—Kaposi, Skin Cancer, Small Intestine Cancer, Stomach Cancer, Testicular Cancer, Thymoma, Thyroid Cancer, Uterine (Endometrial) Cancer, Vaginal Cancer, and Wilms' Tumor.

In some embodiments, the disease or the condition is an inflammatory bowel disease, such as Crohn's disease (CD) or ulcerative colitis (UC). A subject may suffer from fibrosis, fibrostenosis, or a fibrotic disease, either isolated or in combination with an inflammatory disease. In some cases, the CD is severe CD. The severe CD may result from inflammation that has led to the formation of scar tissue in the intestinal wall (fibrostenosis) and/or swelling. In some cases, the severe CD is characterized by the presence of fibrotic and/or inflammatory strictures. The strictures may be determined by computed tomography enterography (CTE), and magnetic resonance imaging enterography (MRE). The disease or condition may be characterized as refractory, which in some cases, means the disease is resistant to a standard treatment (e.g., anti-TNFα therapy). Non-limiting examples of standard treatment include glucocorticosteriods, anti-TNF therapy, anti-a4-b7 therapy (vedolizumab), anti-IL12p40 therapy (ustekinumab), Thalidomide, and Cytoxin.

Genotypes

Disclosed herein are genotypes that may be detected in a sample obtained from a subject by analyzing the genetic material in the sample. In some instances, the subject may be human. In some embodiments, the genetic material is obtained from a subject having a disease or condition disclosed herein. In some cases, the genetic material is obtained from blood, serum, plasma, sweat, hair, tears, urine, and other techniques known by one of skill in the art. In some cases, the genetic material is obtained from a biopsy, e.g., from the intestinal track of the subject.

The genotypes of the present disclosure comprise genetic material that is deoxyribonucleic acid (DNA). In some instances, the genotype comprises a denatured DNA molecule or fragment thereof. In some instances, the genotype comprises DNA selected from: genomic DNA, viral DNA, mitochondrial DNA, plasmid DNA, amplified DNA, circular DNA, circulating DNA, cell-free DNA, or exosomal DNA. In some instances, the DNA is single-stranded DNA (ssDNA), double-stranded DNA, denaturing double-stranded DNA, synthetic DNA, and combinations thereof. The circular DNA may be cleaved or fragmented.

The genotypes disclosed herein comprise at least one polymorphism at a gene or genetic locus described herein. In some instances, the gene or genetic locus is selected from the group consisting of Tumor Necrosis Factor (Ligand) Superfamily, Member 15 (TNFSF15), THADA Armadillo Repeat Containing (THADA), Pleckstrin Homology, MyTH4 And FERM Domain Containing H2 (PLEKHH2), XK Related 6 (XKR6), Myotubularin Related Protein 9 (MTMR9), ETS Proto-Oncogene 1, Transcription Factor (ETS1), C-Type Lectin Domain Containing 16A (CLEC16A), Suppressor Of Cytokine Signaling 1 (SOCS1), Protein Tyrosine Phosphatase Non-Receptor Type 2 (PTPN2), Inducible T Cell Costimulator Ligand (ICOSLG), Janus Kinase 2 (JAK2), Catenin Delta 2 (CTNND2), Regulator Of G Protein Signaling 7 (RGS7), RNA Binding Fox-1 Homolog 1 (RBFOX1), RNA Binding Motif Protein 17 (RBM17), 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 (PFKFB3), Ecto-NOX Disulfide-Thiol Exchanger 1 (ENOX1), Coiled-Coil Domain Containing 122 (CCDC122), Regulator Of Telomere Elongation Helicase 1 (RTEL1), TNF Receptor Superfamily Member 6b (TNFRSF6B), GLIS Family Zinc Finger 3 (GLIS3), Solute Carrier Family 1 Member 1 (SLC1A1), IKAROS Family Zinc Finger 2 (IKZF2), Fatty Acyl-CoA Reductase 1 (FAR1), Spondin 1(SPON1), Plexin A2 (PLXNA2), MIR205 Host Gene (MIR205HG), C-Type Lectin Domain Containing 16A (CLEC16A), PR/SET Domain 14 (PRDM), Autophagy Related 5 (ATG5), and Prostaglandin E Receptor 4 (PTGER4). In some instances, the gene or genetic locus comprises a gene or genetic locus provided in Table 1. The genotypes disclosed herein are, in some cases, a haplotype. In some instances, the genotype comprises a particular polymorphism, a polymorphism in linkage disequilibrium (LD) therewith, or a combination thereof. In some cases, LD is defined by an r 2 of at least or about 0.70, 0.75, 0.80, 0.85, 0.90, or 1.0. The genotypes disclosed herein can comprise at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more polymorphisms. In preferred embodiments, the genotypes disclosed herein comprise a combination of 3 polymorphisms, such as those provided in Table 1.

›DETAILED DESCRIPTION · 3 of 5

The polymorphisms described herein can be a single nucleotide polymorphism, or an indel (insertion/deletion). In some instances, the polymorphism is an insertion or a deletion of at least one nucleobase (e.g., an indel). In some instances, the genotype may comprise a copy number variation (CNV), which is a variation in a number of a nucleic acid sequence between individuals in a given population. In some instances, the CNV comprises at least or about two, three, four, five, six, seven, eight, nine, ten, twenty, thirty, forty or fifty nucleic acid molecules. In some instances, the genotype is heterozygous. In some instances, the genotype is homozygous.

Disclosed herein, in the following embodiments, are genotypes disclosed herein:

1. A genotype comprising at least one polymorphism at a gene or genetic locus. 2. The genotype of embodiment 1 comprising a polymorphism provided in Table 1. 3. The genotype of embodiments 1-2 that is heterozygous. 4. The genotype of embodiments 1-2 that is homozygous. 5. The genotype of embodiments 1-4, wherein the genotype comprises at least two polymorphisms. 6. The genotype of embodiments 1-4, wherein the genotype comprises at least three polymorphisms. 7. The genotype of embodiments 1-4, wherein the genotype comprises at least four polymorphisms. 8. The genotype of embodiment 1, comprising a polymorphism in linkage disequilibrium with a polymorphism provided in Table 1. 9. The genotype of embodiment 8, wherein LD is defined by (i) a D′ value of at least about 0.70, or (ii) a D′ value of 0 and an r 2 value of at least about 0.70. 10. The genotype of embodiment 8, wherein LD is defined by (i) a D′ value of at least about 0.80, or (ii) a D′ value of 0 and an r 2 value of at least about 0.80. 11. The genotype of embodiment 8, wherein LD is defined by (i) a D′ value of at least about 0.90, or (ii) a D′ value of 0 and an r 2 value of at least about 0.90. 12. The genotype of embodiment 8, wherein LD is defined by (i) a D′ value of at least about 0.95, or (ii) a D′ value of 0 and an r 2 value of at least about 0.95. 13. The genotype of embodiments 1-12, wherein the gene or genetic locus is selected from the group consisting of Tumor Necrosis Factor (Ligand) Superfamily, Member 15 (TNFSF15), THADA Armadillo Repeat Containing (THADA), Pleckstrin Homology, MyTH4 And FERM Domain Containing H2 (PLEKHH2), XK Related 6 (XKR6), Myotubularin Related Protein 9 (MTMR9), ETS Proto-Oncogene 1, Transcription Factor (ETS1), C-Type Lectin Domain Containing 16A (CLEC16A), Suppressor Of Cytokine Signaling 1 (SOCS1), Protein Tyrosine Phosphatase Non-Receptor Type 2 (PTPN2), Inducible T Cell Costimulator Ligand (ICOSLG), Janus Kinase 2 (JAK2), Catenin Delta 2 (CTNND2), Regulator Of G Protein Signaling 7 (RGS7), RNA Binding Fox-1 Homolog 1 (RBFOX1), RNA Binding Motif Protein 17 (RBM17), 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 (PFKFB3), Ecto-NOX Disulfide-Thiol Exchanger 1 (ENOX1), Coiled-Coil Domain Containing 122 (CCDC122), Regulator Of Telomere Elongation Helicase 1 (RTEL1), TNF Receptor Superfamily Member 6b (TNFRSF6B), GLIS Family Zinc Finger 3 (GLIS3), Solute Carrier Family 1 Member 1 (SLC1A1), IKAROS Family Zinc Finger 2 (IKZF2), Fatty Acyl-CoA Reductase 1 (FAR1), Spondin 1(SPON1), Plexin A2 (PLXNA2), MIR205 Host Gene (MIR205HG), C-Type Lectin Domain Containing 16A (CLEC16A), PR/SET Domain 14 (PRDM), Autophagy Related 5 (ATG5), and Prostaglandin E Receptor 4 (PTGER4). 14. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from:

(1) rs16901748, rs7759385, rs4246905; (2) rs16901748, rs7759385, rs7935393; (3) rs16901748, rs7759385, rs1892231; (4) rs16901748, rs7759385, rs12934476; (5) rs16901748, rs7759385, rs9806914; (6) rs16901748, rs7759385, rs2297437; (7) rs16901748, rs7759385, rs2070557; (8) rs16901748, rs7759385, rs7278257; (9) rs16901748, rs7759385, rs11221332; (10) rs16901748, rs7759385, rs41309367; (11) rs16901748, rs7759385, rs6478109; (12) rs16901748, rs4246905, rs7935393; (13) rs16901748, rs4246905, rs1892231; (14) rs16901748, rs4246905, rs12934476; (15) rs16901748, rs4246905, rs9806914; (16) rs16901748, rs4246905, rs2297437; (17) rs16901748, rs4246905, rs2070557; (18) rs16901748, rs4246905, rs7278257; (19) rs16901748, rs4246905, rs11221332; (20) rs16901748, rs4246905, rs41309367; (21) rs16901748, rs4246905, rs6478109; (22) rs16901748, rs7935393, rs1892231; (23) rs16901748, rs7935393, rs12934476; (24) rs16901748, rs7935393, rs9806914; (25) rs16901748, rs7935393, rs2297437; (26) rs16901748, rs7935393, rs2070557; (27) rs16901748, rs7935393, rs7278257; (28) rs16901748, rs7935393, rs11221332; (29) rs16901748, rs7935393, rs41309367; (30) rs16901748, rs7935393, rs6478109; (31) rs16901748, rs1892231, rs12934476; (32) rs16901748, rs1892231, rs9806914; (33) rs16901748, rs1892231, rs2297437; (34) rs16901748, rs1892231, rs2070557; (35) rs16901748, rs1892231, rs7278257; (36) rs16901748, rs1892231, rs11221332; (37) rs16901748, rs1892231, rs41309367; (38) rs16901748, rs1892231, rs6478109; (39) rs16901748, rs12934476, rs9806914; (40) rs16901748, rs12934476, rs2297437; (41) rs16901748, rs12934476, rs2070557; (42) rs16901748, rs12934476, rs7278257; (43) rs16901748, rs12934476, rs11221332; (44) rs16901748, rs12934476, rs41309367; (45) rs16901748, rs12934476, rs6478109; (46) rs16901748, rs9806914, rs2297437; (47) rs16901748, rs9806914, rs2070557; (48) rs16901748, rs9806914, rs7278257; (49) rs16901748, rs9806914, rs11221332; (50) rs16901748, rs9806914, rs41309367; (51) rs16901748, rs9806914, rs6478109; (52) rs16901748, rs2297437, rs2070557; (53) rs16901748, rs2297437, rs7278257; (54) rs16901748, rs2297437, rs11221332; (55) rs16901748, rs2297437, rs41309367; (56) rs16901748, rs2297437, rs6478109; (57) rs16901748, rs2070557, rs7278257; (58) rs16901748, rs2070557, rs11221332; (59) rs16901748, rs2070557, rs41309367; (60) rs16901748, rs2070557, rs6478109; (61) rs16901748, rs7278257, rs11221332; (62) rs16901748, rs7278257, rs41309367; (63) rs16901748, rs7278257, rs6478109; (64) rs16901748, rs11221332, rs41309367; (65) rs16901748, rs11221332, rs6478109; (66) rs16901748, rs41309367, rs6478109; (67) rs7759385, rs4246905, rs7935393; (68) rs7759385, rs4246905, rs1892231; (69) rs7759385, rs4246905, rs12934476; (70) rs7759385, rs4246905, rs9806914; (71) rs7759385, rs4246905, rs2297437; (72) rs7759385, rs4246905, rs2070557; (73) rs7759385, rs4246905, rs7278257; (74) rs7759385, rs4246905, rs11221332; (75) rs7759385, rs4246905, rs41309367; (76) rs7759385, rs4246905, rs6478109; (77) rs7759385, rs7935393, rs1892231; (78) rs7759385, rs7935393, rs12934476; (79) rs7759385, rs7935393, rs9806914; (80) rs7759385, rs7935393, rs2297437; (81) rs7759385, rs7935393, rs2070557; (82) rs7759385, rs7935393, rs7278257; (83) rs7759385, rs7935393, rs11221332; (84) rs7759385, rs7935393, rs41309367; (85) rs7759385, rs7935393, rs6478109; (86) rs7759385, rs1892231, rs12934476; (87) rs7759385, rs1892231, rs9806914; (88) rs7759385, rs1892231, rs2297437; (89) rs7759385, rs1892231, rs2070557; (90) rs7759385, rs1892231, rs7278257; (91) rs7759385, rs1892231, rs11221332; (92) rs7759385, rs1892231, rs41309367; (93) rs7759385, rs1892231, rs6478109; (94) rs7759385, rs12934476, rs9806914; (95) rs7759385, rs12934476, rs2297437; (96) rs7759385, rs12934476, rs2070557; (97) rs7759385, rs12934476, rs7278257; (98) rs7759385, rs12934476, rs11221332; (99) rs7759385, rs12934476, rs41309367; (100) rs7759385, rs12934476, rs6478109; (101) rs7759385, rs9806914, rs2297437; (102) rs7759385, rs9806914, rs2070557; (103) rs7759385, rs9806914, rs7278257; (104) rs7759385, rs9806914, rs11221332; (105) rs7759385, rs9806914, rs41309367; (106) rs7759385, rs9806914, rs6478109; (107) rs7759385, rs2297437, rs2070557; (108) rs7759385, rs2297437, rs7278257; (109) rs7759385, rs2297437, rs11221332; (110) rs7759385, rs2297437, rs41309367; (111) rs7759385, rs2297437, rs6478109; (112) rs7759385, rs2070557, rs7278257; (113) rs7759385, rs2070557, rs11221332; (114) rs7759385, rs2070557, rs41309367; (115) rs7759385, rs2070557, rs6478109; (116) rs7759385, rs7278257, rs11221332; (117) rs7759385, rs7278257, rs41309367; (118) rs7759385, rs7278257, rs6478109; (119) rs7759385, rs11221332, rs41309367; (120) rs7759385, rs11221332, rs6478109; (121) rs7759385, rs41309367, rs6478109; (122) rs4246905, rs7935393, rs1892231; (123) rs4246905, rs7935393, rs12934476; (124) rs4246905, rs7935393, rs9806914; (125) rs4246905, rs7935393, rs2297437; (126) rs4246905, rs7935393, rs2070557; (127) rs4246905, rs7935393, rs7278257; (128) rs4246905, rs7935393, rs11221332; (129) rs4246905, rs7935393, rs41309367; (130) rs4246905, rs7935393, rs6478109; (131) rs4246905, rs1892231, rs12934476; (132) rs4246905, rs1892231, rs9806914; (133) rs4246905, rs1892231, rs2297437; (134) rs4246905, rs1892231, rs2070557; (135) rs4246905, rs1892231, rs7278257; (136) rs4246905, rs1892231, rs11221332; (137) rs4246905, rs1892231, rs41309367; (138) rs4246905, rs1892231, rs6478109; (139) rs4246905, rs12934476, rs9806914; (140) rs4246905, rs12934476, rs2297437; (141) rs4246905, rs12934476, rs2070557; (142) rs4246905, rs12934476, rs7278257; (143) rs4246905, rs12934476, rs11221332; (144) rs4246905, rs12934476, rs41309367; (145) rs4246905, rs12934476, rs6478109; (146) rs4246905, rs9806914, rs2297437; (147) rs4246905, rs9806914, rs2070557; (148) rs4246905, rs9806914, rs7278257; (149) rs4246905, rs9806914, rs11221332; (150) rs4246905, rs9806914, rs41309367; (151) rs4246905, rs9806914, rs6478109; (152) rs4246905, rs2297437, rs2070557; (153) rs4246905, rs2297437, rs7278257; (154) rs4246905, rs2297437, rs11221332; (155) rs4246905, rs2297437, rs41309367; (156) rs4246905, rs2297437, rs6478109; (157) rs4246905, rs2070557, rs7278257; (158) rs4246905, rs2070557, rs11221332; (159) rs4246905, rs2070557, rs41309367; (160) rs4246905, rs2070557, rs6478109; (161) rs4246905, rs7278257, rs11221332; (162) rs4246905, rs7278257, rs41309367; (163) rs4246905, rs7278257, rs6478109; (164) rs4246905, rs11221332, rs41309367; (165) rs4246905, rs11221332, rs6478109; (166) rs4246905, rs41309367, rs6478109; (167) rs7935393, rs1892231, rs12934476; (168) rs7935393, rs1892231, rs9806914; (169) rs7935393, rs1892231, rs2297437; (170) rs7935393, rs1892231, rs2070557; (171) rs7935393, rs1892231, rs7278257; (172) rs7935393, rs1892231, rs11221332; (173) rs7935393, rs1892231, rs41309367; (174) rs7935393, rs1892231, rs6478109; (175) rs7935393, rs12934476, rs9806914; (176) rs7935393, rs12934476, rs2297437; (177) rs7935393, rs12934476, rs2070557; (178) rs7935393, rs12934476, rs7278257; (179) rs7935393, rs12934476, rs11221332; (180) rs7935393, rs12934476, rs41309367; (181) rs7935393, rs12934476, rs6478109; (182) rs7935393, rs9806914, rs2297437; (183) rs7935393, rs9806914, rs2070557; (184) rs7935393, rs9806914, rs7278257; (185) rs7935393, rs9806914, rs11221332; (186) rs7935393, rs9806914, rs41309367; (187) rs7935393, rs9806914, rs6478109; (188) rs7935393, rs2297437, rs2070557; (189) rs7935393, rs2297437, rs7278257; (190) rs7935393, rs2297437, rs11221332; (191) rs7935393, rs2297437, rs41309367; (192) rs7935393, rs2297437, rs6478109; (193) rs7935393, rs2070557, rs7278257; (194) rs7935393, rs2070557, rs11221332; (195) rs7935393, rs2070557, rs41309367; (196) rs7935393, rs2070557, rs6478109; (197) rs7935393, rs7278257, rs11221332; (198) rs7935393, rs7278257, rs41309367; (199) rs7935393, rs7278257, rs6478109; (200) rs7935393, rs11221332, rs4130936; 7 (201) rs7935393, rs11221332, rs6478109; (202) rs7935393, rs41309367, rs6478109; (203) rs1892231, rs12934476, rs9806914; (204) rs1892231, rs12934476, rs2297437; (205) rs1892231, rs12934476, rs2070557; (206) rs1892231, rs12934476, rs7278257; (207) rs1892231, rs12934476, rs11221332; (208) rs1892231, rs12934476, rs41309367; (209) rs1892231, rs12934476, rs6478109; (210) rs1892231, rs9806914, rs2297437; (211) rs1892231, rs9806914, rs2070557; (212) rs1892231, rs9806914, rs7278257; (213) rs1892231, rs9806914, rs11221332; (214) rs1892231, rs9806914, rs41309367; (215) rs1892231, rs9806914, rs6478109; (216) rs1892231, rs2297437, rs2070557; (217) rs1892231, rs2297437, rs7278257; (218) rs1892231, rs2297437, rs11221332; (219) rs1892231, rs2297437, rs41309367; (220) rs1892231, rs2297437, rs6478109; (221) rs1892231, rs2070557, rs7278257; (222) rs1892231, rs2070557, rs11221332; (223) rs1892231, rs2070557, rs41309367; (224) rs1892231, rs2070557, rs6478109; (225) rs1892231, rs7278257, rs11221332; (226) rs1892231, rs7278257, rs41309367; (227) rs1892231, rs7278257, rs6478109; (228) rs1892231, rs11221332, rs41309367; (229) rs1892231, rs11221332, rs6478109; (230) rs1892231, rs41309367, rs6478109; (231) rs12934476, rs9806914, rs2297437; (232) rs12934476, rs9806914, rs2070557; (233) rs12934476, rs9806914, rs7278257; (234) rs12934476, rs9806914, rs11221332; (235) rs12934476, rs9806914, rs41309367; (236) rs12934476, rs9806914, rs6478109; (237) rs12934476, rs2297437, rs2070557; (238) rs12934476, rs2297437, rs7278257; (239) rs12934476, rs2297437, rs11221332; (240) rs12934476, rs2297437, rs41309367; (241) rs12934476, rs2297437, rs6478109; (242) rs12934476, rs2070557, rs7278257; (243) rs12934476, rs2070557, rs11221332; (244) rs12934476, rs2070557, rs41309367; (245) rs12934476, rs2070557, rs6478109; (246) rs12934476, rs7278257, rs11221332; (247) rs12934476, rs7278257, rs41309367; (248) rs12934476, rs7278257, rs6478109; (249) rs12934476, rs11221332, rs41309367; (250) rs12934476, rs11221332, rs6478109; (251) rs12934476, rs41309367, rs6478109; (252) rs9806914, rs2297437, rs2070557; (253) rs9806914, rs2297437, rs7278257; (254) rs9806914, rs2297437, rs11221332; (255) rs9806914, rs2297437, rs41309367; (256) rs9806914, rs2297437, rs6478109; (257) rs9806914, rs2070557, rs7278257; (258) rs9806914, rs2070557, rs11221332; (259) rs9806914, rs2070557, rs41309367; (260) rs9806914, rs2070557, rs6478109; (261) rs9806914, rs7278257, rs11221332; (262) rs9806914, rs7278257, rs41309367; (263) rs9806914, rs7278257, rs6478109; (264) rs9806914, rs11221332, rs41309367; (265) rs9806914, rs11221332, rs6478109; (266) rs9806914, rs41309367, rs6478109; (267) rs2297437, rs2070557, rs7278257; (268) rs2297437, rs2070557, rs11221332; (269) rs2297437, rs2070557, rs41309367; (270) rs2297437, rs2070557, rs6478109; (271) rs2297437, rs7278257, rs11221332; (272) rs2297437, rs7278257, rs41309367; (273) rs2297437, rs7278257, rs6478109; (274) rs2297437, rs11221332, rs41309367; (275) rs2297437, rs11221332, rs6478109; (276) rs2297437, rs41309367, rs6478109; (277) rs2070557, rs7278257, rs11221332; (278) rs2070557, rs7278257, rs41309367; (279) rs2070557, rs7278257, rs6478109; (280) rs2070557, rs11221332, rs41309367; (281) rs2070557, rs11221332, rs6478109; (282) rs2070557, rs41309367, rs6478109; (283) rs7278257, rs11221332, rs41309367; (284) rs7278257, rs11221332, rs6478109; (285) rs7278257, rs41309367, rs6478109; or (286) rs11221332, rs41309367, rs6478109.

›DETAILED DESCRIPTION · 4 of 5

15. The genotype of embodiment 14, wherein the rs7278257 is replaced with rs56124762. 16. The genotype of embodiment 14, wherein the rs7278257 is replaced with rs2070558. 17. The genotype of embodiment 14, wherein the rs7278257 is replaced with rs2070561. 18. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from imm_9_116608587, imm_11_127948309, and rs1892231. 19. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from imm_9_116608587, imm_11_127948309, and rs9806914. 20. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from imm_9_116608587, imm_11_127948309, and imm_21_44478192. 21. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from imm_9_116608587, imm_11_127948309, and imm_21_44479552. 22. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from imm_9_116608587, rs1892231, and rs9806914. 23. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from imm_9_116608587, rs1892231, and imm_21_44478192. 24. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from imm_9_116608587, rs1892231, and imm_21_44479552. 25. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from imm_9_116608587, rs9806914, and imm_21_44478192. 26. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from imm_9_116608587, rs9806914, and imm_21_44479552. 27. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from imm_9_116608587, imm_21_44478192, and imm_21_44479552. 28. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from imm_11_127948309, rs1892231, and rs9806914. 29. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from imm_11_127948309, rs1892231, and imm_21_44478192. 30. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from imm_11_127948309, rs1892231, and imm_21_44479552. 31. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from imm_11_127948309, rs9806914, and imm_21_44478192. 32. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from imm_11_127948309, rs9806914, and imm_21_44479552. 33. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from imm_11_127948309, imm_21_44478192, and imm_21_44479552. 34. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from rs1892231, rs9806914, and imm_21_44478192. 35. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from rs1892231, rs9806914, and imm_21_44479552. 36. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from rs1892231, imm_21_44478192, and imm_21_44479552. 37. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from rs9806914, imm_21_44478192, and imm_21_44479552. 38. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from rs6478109, rs56124762, and rs1892231. 39. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from rs6478109, rs56124762, and rs16901748. 40. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from rs6478109, rs1892231, and rs16901748. 41. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from rs56124762, rs1892231, and rs16901748. 42. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from rs6478109, rs2070558, and rs1892231. 43. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from rs6478109, rs2070558, and rs16901748. 44. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from rs6478109, rs1892231, and rs16901748. 45. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from rs2070558, rs1892231, and rs16901748. 46. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from rs6478109, rs2070561, and rs1892231. 47. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from rs6478109, rs2070561, and rs16901748. 48. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from rs6478109, rs1892231, and rs16901748. 49. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from rs2070561, rs1892231, and rs16901748. 50. The genotype of embodiments 1-49, wherein the genotype comprises a minor allele provided in Table 1 for at least one polymorphism. 51. The genotype of embodiments 1-49, wherein the genotype comprises a major allele provided in Table 1 for at least one polymorphism. 52. The genotype of embodiments 1-51, wherein a presence of the genotype is predictive of a positive therapeutic response to a treatment with an inhibitor of TL1A activity of expression at a positive predictive value of at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%. 53. The genotype of embodiments 1-55, wherein a presence of the genotype is predictive of a positive therapeutic response to a treatment with an inhibitor of TL1A activity of expression with a specificity of at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%.

›DETAILED DESCRIPTION · 5 of 5

Aspects disclosed herein provide genotypes that are associated with, and therefore indicative of, a subject having or being susceptible to developing a particular disease or condition, or a subclinical phenotype thereof. In addition, the genotypes disclosed herein are associated with an increase TNFSF15 (TL1A) expression or activity. Thus, the genotypes are indicative that the subject will have a positive therapeutic response to an inhibitor of TL1A activity or expression. Table 1 provides exemplary polymorphisms associated with, and therefore predictive of, a positive therapeutic response to an inhibitor of TNFSF15 (TL1A) expression or activity. The term, “positive therapeutic response” refers to a reduction or an elimination of at least one symptom of the disease or the condition (e.g., Cohn's disease) after induction of a therapy (e.g., anti-TL1A antibody).

The instant disclosure provides models comprising 3 polymorphisms (e.g., “3-SNP Models”) that, when detected in a sample obtained from a subject, indicate a positive therapeutic response in the subject to a treatment, such as with an inhibitor of TL1A activity or expression. Non-limiting examples of models described herein include Model A (rs6478109, rs7278257, and rs1892231); Model B (rs6478109, rs2070557, and rs9806914); Model C (rs6478109, rs7935393, and rs1892231); Model D (rs6478109, rs7935393, and rs9806914); Model E (rs6478109, rs9806914, and rs16901748); Model F (rs6478109, rs16901748, and rs2297437); Model G (rs6478109, rs1892231, and rs16901748); Model H (rs6478109, rs2070557, and rs7935393); Model I (rs6478109, rs7278257, and rs7935393); Model J (rs6478109, rs9806914, and rs1892231); and Model K (rs6478109, rs7278257, and rs16901748).

›METHODS · 1 of 46

Methods of Detection

Methods disclosed herein for detecting a genotype in a sample from a subject comprise analyzing the genetic material in the sample to detect at least one of a presence, an absence, and a quantity of a nucleic acid sequence encompassing the genotype of interest. In some embodiments, the sample is assayed to measure a presence, absence or quantity of at least three polymorphisms. In some embodiments, the sample is assayed to measure a presence, absence, or quantity of at least four polymorphisms. In some embodiments, the sample is assayed to measure a presence, absence, or quantity of at least five polymorphisms. In some embodiments, at least three genotypes are detected, using the methods described herein.

In some cases, the nucleic acid sequence comprises DNA. In some instances, the nucleic acid sequence comprises a denatured DNA molecule or fragment thereof. In some instances, the nucleic acid sequence comprises DNA selected from: genomic DNA, viral DNA, mitochondrial DNA, plasmid DNA, amplified DNA, circular DNA, circulating DNA, cell-free DNA, or exosomal DNA. In some instances, the DNA is single-stranded DNA (ssDNA), double-stranded DNA, denaturing double-stranded DNA, synthetic DNA, and combinations thereof. The circular DNA may be cleaved or fragmented. In some instances, the nucleic acid sequence comprises RNA. In some instances, the nucleic acid sequence comprises fragmented RNA. In some instances, the nucleic acid sequence comprises partially degraded RNA. In some instances, the nucleic acid sequence comprises a microRNA or portion thereof. In some instances, the nucleic acid sequence comprises an RNA molecule or a fragmented RNA molecule (RNA fragments) selected from: a microRNA (miRNA), a pre-miRNA, a pri-miRNA, a mRNA, a pre-mRNA, a viral RNA, a viroid RNA, a virusoid RNA, circular RNA (circRNA), a ribosomal RNA (rRNA), a transfer RNA (tRNA), a pre-tRNA, a long non-coding RNA (lncRNA), a small nuclear RNA (snRNA), a circulating RNA, a cell-free RNA, an exosomal RNA, a vector-expressed RNA, an RNA transcript, a synthetic RNA, and combinations thereof.

Nucleic acid-based detection techniques that may be useful for the methods herein include quantitative polymerase chain reaction (qPCR), gel electrophoresis, immunochemistry, in situ hybridization such as fluorescent in situ hybridization (FISH), cytochemistry, and next generation sequencing. In some embodiments, the methods involve real-time (TaqMan™) qPCR, which involves a nucleic acid amplification reaction with a specific primer pair, and hybridization of the amplified nucleic acids with a hydrolysable probe specific to a target nucleic acid.

In some instances, the methods involve hybridization and/or amplification assays that include, but are not limited to, Southern or Northern analyses, polymerase chain reaction analyses, and probe arrays. Non-limiting amplification reactions include, but are not limited to, qPCR, self-sustained sequence replication, transcriptional amplification system, Q-Beta Replicase, rolling circle replication, or any other nucleic acid amplification known in the art. As discussed, reference to qPCR herein includes use of real-time PCR (TaqMan™) methods. An additional exemplary hybridization assay includes the use of nucleic acid probes conjugated or otherwise immobilized on a bead, multi-well plate, or other substrate, wherein the nucleic acid probes are configured to hybridize with a target nucleic acid sequence of a genotype provided herein. A non-limiting method is one employed in Anal Chem. 2013 Feb. 5; 85(3):1932-9.

In some embodiments, detecting the presence or absence of a genotype comprises sequencing genetic material from the subject. Sequencing can be performed with any appropriate sequencing technology, including but not limited to single-molecule real-time (SNRT) sequencing, Polony sequencing, sequencing by ligation, reversible terminator sequencing, proton detection sequencing, ion semiconductor sequencing, nanopore sequencing, electronic sequencing, pyrosequencing, Maxam-Gilbert sequencing, chain termination (e.g., Sanger™) sequencing, +S sequencing, or sequencing-by-synthesis. Sequencing methods also include next-generation sequencing, e.g., modern sequencing technologies such as sequencing-by-synthesis (Illumina®) sequencing (e.g., Solexa™), pyrosequencing (Roche 454™), ion semiconductor (Ion Torrent®) sequencing, and sequencing by oligonucleotide ligation and detection (SOLiD™) sequencing. In some cases, next-generation sequencing involves high-throughput sequencing methods. Additional sequencing methods available to one of skill in the art may also be employed.

In some instances, a number of nucleotides that are sequenced are at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 150, 200, 300, 400, 500, 2000, 4000, 6000, 8000, 10000, 20000, 50000, 100000, or more than 100000 nucleotides. In some instances, the number of nucleotides sequenced is in a range of about 1 to about 100000 nucleotides, about 1 to about 10000 nucleotides, about 1 to about 1000 nucleotides, about 1 to about 500 nucleotides, about 1 to about 300 nucleotides, about 1 to about 200 nucleotides, about 1 to about 100 nucleotides, about 5 to about 100000 nucleotides, about 5 to about 10000 nucleotides, about 5 to about 1000 nucleotides, about 5 to about 500 nucleotides, about 5 to about 300 nucleotides, about 5 to about 200 nucleotides, about 5 to about 100 nucleotides, about 10 to about 100000 nucleotides, about 10 to about 10000 nucleotides, about 10 to about 1000 nucleotides, about 10 to about 500 nucleotides, about 10 to about 300 nucleotides, about 10 to about 200 nucleotides, about 10 to about 100 nucleotides, about 20 to about 100000 nucleotides, about 20 to about 10000 nucleotides, about 20 to about 1000 nucleotides, about 20 to about 500 nucleotides, about 20 to about 300 nucleotides, about 20 to about 200 nucleotides, about 20 to about 100 nucleotides, about 30 to about 100000 nucleotides, about 30 to about 10000 nucleotides, about 30 to about 1000 nucleotides, about 30 to about 500 nucleotides, about 30 to about 300 nucleotides, about 30 to about 200 nucleotides, about 30 to about 100 nucleotides, about 50 to about 100000 nucleotides, about 50 to about 10000 nucleotides, about 50 to about 1000 nucleotides, about 50 to about 500 nucleotides, about 50 to about 300 nucleotides, about 50 to about 200 nucleotides, or about 50 to about 100 nucleotides.

›METHODS · 2 of 46

Exemplary probes comprise a nucleic acid sequence of at least 10 contiguous nucleic acids provided in any one of SEQ ID NOS: 1-48, or 57-59, including the nucleobase indicated with a non-nucleobase letter (e.g., R, N, S), or a reverse complement thereof. In some instances, the probes may be used to detect the polymorphisms provided in Table 1, wherein the probe comprises a nucleic acid sequence of at least 10 contiguous nucleic acids provided in a corresponding SEQ ID NO or reverse complement thereof, the 10 contiguous nucleic acids comprising the “risk allele” also provided in Table 1 at a nucleoposition indicated with the non-nucleobase letter, or reverse complement thereof. In some embodiments, the probe comprises at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to any one of SEQ ID NOS: 1-48, or 57-59, or its reverse complement. In some instances, forward and reverse primers are used to amplify the target nucleic acid sequence. Forward and reverse primers may comprise a nucleic acid sequence flanking the risk allele provided in Table 1 corresponding to the nucleic acid sequence provided in any one of SEQ ID NOS: 1-48, or 57-59, or a reverse complement thereof.

Examples of molecules that are utilized as probes include, but are not limited to, RNA and DNA. In some embodiments, the term “probe” with regards to nucleic acids, refers to any molecule that is capable of selectively binding to a specifically intended target nucleic acid sequence. In some instances, probes are specifically designed to be labeled, for example, with a radioactive label, a fluorescent label, an enzyme, a chemiluminescent tag, a colorimetric tag, or other labels or tags that are known in the art. In some instances, the fluorescent label comprises a fluorophore. In some instances, the fluorophore is an aromatic or heteroaromatic compound. In some instances, the fluorophore is a pyrene, anthracene, naphthalene, acridine, stilbene, benzoxazole, indole, benzindole, oxazole, thiazole, benzothiazole, canine, carbocyanine, salicylate, anthranilate, xanthenes dye, coumarin. Exemplary xanthene dyes include, e.g., fluorescein and rhodamine dyes. Fluorescein and rhodamine dyes include, but are not limited to 6-carboxyfluorescein (FAM), 2′7′-dimethoxy-4′5′-dichloro-6-carboxyfluorescein (JOE), tetrachlorofluorescein (TET), 6-carboxyrhodamine (R6G), N,N,N; N′-tetramethyl-6-carboxyrhodamine (TAMRA), 6-carboxy-X-rhodamine (ROX). Suitable fluorescent probes also include the naphthylamine dyes that have an amino group in the alpha or beta position. For example, naphthylamino compounds include 1-dimethylaminonaphthyl-5-sulfonate, 1-anilino-8-naphthalene sulfonate and 2-p-toluidinyl-6-naphthalene sulfonate, 5-(2′-aminoethyl)aminonaphthalene-1-sulfonic acid (EDANS). Exemplary coumarins include, e.g., 3-phenyl-7-isocyanatocoumarin; acridines, such as 9-isothiocyanatoacridine and acridine orange; N-(p-(2-b enzoxazolyl)phenyl) maleimide; cyanines, such as, e.g., indodicarbocyanine 3 (Cy3), indodicarbocyanine 5 (Cy5), indodicarbocyanine 5.5 (Cy5.5), 3-(-carboxy-pentyl)-3′-ethyl-5,5′-dimethyloxacarbocyanine (CyA); 1H, 5H, 11H, 15H-Xantheno[2,3, 4-ij: 5,6, 7-i′j′]diquinolizin-18-ium, 9-[2 (or 4)-[[[6-[2,5-dioxo-1-pyrrolidinyl)oxy]-6-oxohexyl]amino]sulfonyl]-4 (or 2)-sulfophenyl]-2,3, 6,7, 12,13, 16,17-octahydro-inner salt (TR or Texas Red); or BODIPY™ dyes. In some cases, the probe comprises FAM as the dye label.

In some instances, primers and/or probes described herein for detecting a target nucleic acid are used in an amplification reaction. In some instances, the amplification reaction is qPCR. An exemplary qPCR is a method employing a TaqMan™ assay. Non-limiting examples of primer pairs useful for detecting one or more polymorphisms described herein are provided in Table 6, below.

“Wt_Probe_Hex” and “Mut_Probe_FAM” mean “Wild type_probes_tagged with HEX reporter dye” and“Mut_probe_tagged with FAM reporter dye”, respectively. “+” stands for LNA bases (Locked nucleotides), which are analogues that are modified at 2′-O, 4′-C and form a bridge. This bridge results in restricted base pairing giving room to adjust the Tm as needed between the probes. Thus, +A, +T, +C or +G signify A, T, G or C bases are added on the modified backbone.

In some instances, qPCR comprises using an intercalating dye. Examples of intercalating dyes include SYBR green I, SYBR green II, SYBR gold, ethidium bromide, methylene blue, Pyronin Y, DAPI, acridine orange, Blue View or phycoerythrin. In some instances, the intercalating dye is SYBR.

In some instances, a number of amplification cycles for detecting a target nucleic acid in an amplification assay is about 5 to about 30 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is at least about 5 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is at most about 30 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is about 5 to about 10, about 5 to about 15, about 5 to about 20, about 5 to about 25, about 5 to about 30, about 10 to about 15, about 10 to about 20, about 10 to about 25, about 10 to about 30, about 15 to about 20, about 15 to about 25, about 15 to about 30, about 20 to about 25, about 20 to about 30, or about 25 to about 30 cycles.

In one aspect, the methods provided herein for determining the presence, absence, and/or quantity of a nucleic acid sequence from a particular genotype comprise an amplification reaction such as qPCR. In an exemplary method, genetic material is obtained from a sample of a subject, e.g., a sample of blood or serum. In certain embodiments where nucleic acids are extracted, the nucleic acids are extracted using any technique that does not interfere with subsequent analysis. In certain embodiments, this technique uses alcohol precipitation using ethanol, methanol, or isopropyl alcohol. In certain embodiments, this technique uses phenol, chloroform, or any combination thereof. In certain embodiments, this technique uses cesium chloride. In certain embodiments, this technique uses sodium, potassium or ammonium acetate or any other salt commonly used to precipitate DNA. In certain embodiments, this technique utilizes a column or resin based nucleic acid purification scheme such as those commonly sold commercially, one non-limiting example would be the GenElute Bacterial Genomic DNA Kit available from Sigma Aldrich. In certain embodiments, after extraction the nucleic acid is stored in water, Tris buffer, or Tris-EDTA buffer before subsequent analysis. In an exemplary embodiment, the nucleic acid material is extracted in water. In some cases, extraction does not comprise nucleic acid purification.

›METHODS · 3 of 46

In the exemplary qPCR assay, the nucleic acid sample is combined with primers and probes specific for a target nucleic acid that may or may not be present in the sample, and a DNA polymerase. An amplification reaction is performed with a thermal cycler that heats and cools the sample for nucleic acid amplification, and illuminates the sample at a specific wavelength to excite a fluorophore on the probe and detect the emitted fluorescence. For TaqMan™ methods, the probe may be a hydrolysable probe comprising a fluorophore and quencher that is hydrolyzed by DNA polymerase when hybridized to a target nucleic acid. In some cases, the presence of a target nucleic acid is determined when the number of amplification cycles to reach a threshold value is less than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or 20 cycles.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 1 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 1. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 1 comprising a “G” or an “A” allele at nucleoposition 501 within SEQ ID NO: 1. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising a “G” or an “A” allele at nucleoposition 501 within SEQ ID NO: 1 is sufficient to detect the polymorphism at rs11897732.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 2 comprising non-reference allele at nucleoposition 501 within SEQ ID NO: 2. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 2 comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 2. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 2 is sufficient to detect the polymorphism at rs6740739.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 3 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 3. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 3 comprising a “G” or a “C” allele at nucleoposition 501 within SEQ ID NO: 3. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising a “G” or a “C” allele at nucleoposition 501 within SEQ ID NO: 3 is sufficient to detect the polymorphism at rs17796285.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 4 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 4. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 4 comprising a “C” or an “A” allele at nucleoposition 501 within SEQ ID NO: 4. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising a “C” or an “A” allele at nucleoposition 501 within SEQ ID NO: 4 is sufficient to detect the polymorphism at rs7935393.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 5 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 5. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 5 comprising a “G” or an “A” allele at nucleoposition 501 within SEQ ID NO: 5. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising a “G” of an “A” allele at nucleoposition 501 within SEQ ID NO: 5 is sufficient to detect the polymorphism at rs12934476.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 6 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 6. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 6 comprising an “A” or a “C” allele at nucleoposition 501 within SEQ ID NO: 6. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising an “A” or a “C” allele at nucleoposition 501 within SEQ ID NO: 6 is sufficient to detect the polymorphism at rs12457255.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 7 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 7. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 7 comprising an “A” or a “T” allele at nucleoposition 501 within SEQ ID NO: 7. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising an “A” or a “T” allele at nucleoposition 501 within SEQ ID NO: 7 is sufficient to detect the polymorphism at rs2070557.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 8 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 8. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 8 comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 8. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising an “A” or “G” allele at nucleoposition 501 within SEQ ID NO: 8 is sufficient to detect the polymorphism at rs4246905.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 9 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 9. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 9 comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 9. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 9 is sufficient to detect the polymorphism at rs10974900.

›METHODS · 4 of 46

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 10 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 10. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 10 comprising a “C” or an “A” allele at nucleoposition 501 within SEQ ID NO: 10. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising a “C” or an “A” allele at nucleoposition 501 within SEQ ID NO: 10 is sufficient to detect the polymorphism at rs12434976.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 11 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 11. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 11 comprising an “A” or a “C” allele at nucleoposition 501 within SEQ ID NO: 11. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising an “A” or a “C” allele at nucleoposition 501 within SEQ ID NO: 11 is sufficient to detect the polymorphism at rs16901748.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 12 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 12. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 12 comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 12. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 12 is sufficient to detect the polymorphism at rs2815844.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 13 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 13. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 13 comprising a “G” or an “A” allele at nucleoposition 501 within SEQ ID NO: 13. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising a “G” or an “A” allele at nucleoposition 501 within SEQ ID NO: 13 is sufficient to detect the polymorphism at rs889702.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 14 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 14. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 14 comprising a “C” or an “A” allele at nucleoposition 501 within SEQ ID NO: 14. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising a “C” or an “A” allele at nucleoposition 501 within SEQ ID NO: 14 is sufficient to detect the polymorphism at rs2409750.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 15 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 15. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 15 comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 15. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising an “A” or “G” allele at nucleoposition 501 within SEQ ID NO: 15 is sufficient to detect the polymorphism at rs1541020.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 16 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 16. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 16 comprising a “T” or an “A” allele at nucleoposition 501 within SEQ ID NO: 16. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising a “T” or an “A” allele at nucleoposition 501 within SEQ ID NO: 16 is sufficient to detect the polymorphism at rs4942248.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 17 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 17. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 17 comprising a “G” or an “A” allele at nucleoposition 501 within SEQ ID NO: 17. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising a “G” or an “A” allele at nucleoposition 501 within SEQ ID NO: 17 is sufficient to detect the polymorphism at rs12934476.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 18 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 18. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 18 comprising an “A” or a “C” allele at nucleoposition 501 within SEQ ID NO: 18. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising an “A” or a “C” allele at nucleoposition 501 within SEQ ID NO: 18 is sufficient to detect the polymorphism at rs12457255.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 19 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 19. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 19 comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 19. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 19 is sufficient to detect the polymorphism at rs2297437.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 20 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 20. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 20 comprising a “G” or an “A” allele at nucleoposition 501 within SEQ ID NO: 20. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising a “G” or an “A” allele at nucleoposition 501 within SEQ ID NO: 20 is sufficient to detect the polymorphism at rs41309367.

›METHODS · 5 of 46

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 21 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 21. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 21 comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 21. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 21 is sufficient to detect the polymorphism at rs10733509.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 22 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 22. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 22 comprising a “G” or an “A” allele at nucleoposition 501 within SEQ ID NO: 22. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising a “G” or an “A” allele at nucleoposition 501 within SEQ ID NO: 22 is sufficient to detect the polymorphism at rs10750376.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 23 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 23. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 23 comprising a “G” or an “A” allele at nucleoposition 501 within SEQ ID NO: 23. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising a “G” or an “A” allele at nucleoposition 501 within SEQ ID NO: 23 is sufficient to detect the polymorphism at rs10932456.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 24 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 24. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 24 comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 24. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 24 is sufficient to detect the polymorphism at rs1326860.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 25 comprising a “G” or an “A” allele at nucleoposition 501 within SEQ ID NO: 25. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising a “G” or an “A” allele at nucleoposition 501 within SEQ ID NO: 25 is sufficient to detect the polymorphism at rs1528663.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 26 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 26. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 26 comprising a “C” or an “A” allele at nucleoposition 501 within SEQ ID NO: 26. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising a “C” or an “A” allele at nucleoposition 501 within SEQ ID NO: 26 is sufficient to detect the polymorphism at rs1892231.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 27 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 27. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 27 comprising a “G” or an “A” allele at nucleoposition 501 within SEQ ID NO: 27. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising a “G” or an “A” allele at nucleoposition 501 within SEQ ID NO: 27 is sufficient to detect the polymorphism at rs951279.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 28 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 28. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 28 comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 28. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 28 is sufficient to detect the polymorphism at rs9806914.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 29 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 29. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 29 comprising a “C” or an “A” allele at nucleoposition 501 within SEQ ID NO: 29. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising a “C” or an “A” allele at nucleoposition 501 within SEQ ID NO: 29 is sufficient to detect the polymorphism at rs7935393.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 30 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 30. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 30 comprising a “G” or a “C” allele at nucleoposition 501 within SEQ ID NO: 30. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising a “G” or a “C” allele at nucleoposition 501 within SEQ ID NO: 30 is sufficient to detect the polymorphism at rs1690492.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 31 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 31. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 31 comprising a “G” or an “A” allele at nucleoposition 501 within SEQ ID NO: 31. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising a “G” or an “A” allele at nucleoposition 501 within SEQ ID NO: 31 is sufficient to detect the polymorphism at rs420726.

›METHODS · 6 of 46

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 32 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 32. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 32 comprising a “T” or an “A” allele at nucleoposition 501 within SEQ ID NO: 32. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising a “T” of an “A” allele at nucleoposition 501 within SEQ ID NO: 32 is sufficient to detect the polymorphism at rs7759385.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 33 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 33. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 33 comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 33. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 33 is sufficient to detect the polymorphism at rs10974900.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 34 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 34. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 34 comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 34. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 34 is sufficient to detect the polymorphism at rs1326860.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 35 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 35. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 35 comprising a “C” or a “G” allele at nucleoposition 501 within SEQ ID NO: 35. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising a “C” or a “G” allele at nucleoposition 501 within SEQ ID NO: 35 is sufficient to detect the polymorphism at rs2548147.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 36 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 36. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 36 comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 36. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising an “A” of a “G” allele at nucleoposition 501 within SEQ ID NO: 36 is sufficient to detect the polymorphism at rs2815844.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 37 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 37. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 37 comprising a “G” or an “A” allele at nucleoposition 501 within SEQ ID NO: 37. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising a “G” or an “A” allele at nucleoposition 501 within SEQ ID NO: 37 is sufficient to detect the polymorphism at rs889702.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 38 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 38. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 38 comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 38. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 38 is sufficient to detect the polymorphism at rs9806914.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 39 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 39. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 39 comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 39. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 39 is sufficient to detect the polymorphism at rs6478109.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 40 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 40. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 40 comprising a “C” or a “G” allele at nucleoposition 501 within SEQ ID NO: 40. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising a “C” or a “G” allele at nucleoposition 501 within SEQ ID NO: 40 is sufficient to detect the polymorphism at rs7278257.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 41 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 41. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 41 comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 41. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 41 is sufficient to detect the polymorphism at rs11221332.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 57 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 57. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 57 comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 57. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 57 is sufficient to detect the polymorphism at rs56124762.

›METHODS · 7 of 46

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 58 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 58. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 58 comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 58. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising an “A” or a “G” allele at nucleoposition 501 within SEQ ID NO: 58 is sufficient to detect the polymorphism at rs2070558.

In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 59 comprising a non-reference allele at nucleoposition 501 within SEQ ID NO: 59. In some embodiments, the target nucleic acid is at least 10 contiguous nucleic acid molecules of SEQ ID NO: 59 comprising an “T” or a “C” allele at nucleoposition 501 within SEQ ID NO: 59. In some embodiments, detecting the at least 10 contiguous nucleic acid molecules comprising an “T” or a “C” allele at nucleoposition 501 within SEQ ID NO: 59 is sufficient to detect the polymorphism at rs2070561.

In some embodiments, one target nucleic acid (e.g., a polymorphism) is detected with the methods disclosed herein. In some embodiments, at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 target nucleic acids are detected. In some embodiments, the at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 target nucleic acids are detected in a single multiplexed assay. In some embodiments, when 4 target nucleic acids are detected in a sample from subject, 4 unique 3-polymorphism combinations are measured. In a non-limiting example, a sample (e.g., blood or plasma) obtained from a subject is contacted by 4 primer pairs, each primer pair individually adapted to amplify rs6487109, rs56124762, rs1892231, and rs16901748, respectively. A positive, negative, or indeterminate TNFSF15 profile may depend, at least in part, on which of the 3-polymorphism combinations is detected in the sample, and/or whether the genotype is heterozygous or homozygous for the polymorphism. In this example, assaying 4 polymorphism means a total of 4 unique 3-polymorphisms may be detected in the patient sample, which are rs6478109, rs56124762, rs1892231; rs6478109, rs56124762, rs16901748; r s6478109, rs1892231, rs16901748; and rs56124762, rs1892231, rs16901748. Each polymorphism detected may be heterozygous or homozygous.

To practice the methods and systems provided herein, genetic material may be extracted from a sample obtained from a subject, e.g., a sample of blood or serum. In certain embodiments where nucleic acids are extracted, the nucleic acids are extracted using any technique that does not interfere with subsequent analysis. In certain embodiments, this technique uses alcohol precipitation using ethanol, methanol or isopropyl alcohol. In certain embodiments, this technique uses phenol, chloroform, or any combination thereof. In certain embodiments, this technique uses cesium chloride. In certain embodiments, this technique uses sodium, potassium or ammonium acetate or any other salt commonly used to precipitate DNA. In certain embodiments, this technique utilizes a column or resin based nucleic acid purification scheme such as those commonly sold commercially, one non-limiting example would be the GenElute Bacterial Genomic DNA Kit available from Sigma Aldrich. In certain embodiments, after extraction the nucleic acid is stored in water, Tris buffer, or Tris-EDTA buffer before subsequent analysis. In an exemplary embodiment, the nucleic acid material is extracted in water. In some cases, extraction does not comprise nucleic acid purification. In certain embodiments, RNA may be extracted from cells using RNA extraction techniques including, for example, using acid phenol/guanidine isothiocyanate extraction (RNAzol B; Biogenesis), RNeasy RNA preparation kits (Qiagen) or PAXgene (PreAnalytix, Switzerland).

In some embodiments, methods of detecting a presence, absence, or level of a target protein (e.g., biomarker) in the sample obtained from the subject involve detecting protein activity or expression. In some embodiments, the target protein is TL1A, or a binding partner of TL1A such as Death Domain Receptor 3 (DcR3). A target protein may be detected by use of an antibody-based assay, where an antibody specific to the target protein is utilized. In some embodiments, antibody-based detection methods utilize an antibody that binds to any region of target protein. An exemplary method of analysis comprises performing an enzyme-linked immunosorbent assay (ELISA). The ELISA assay may be a sandwich ELISA or a direct ELISA. Another exemplary method of analysis comprises a single molecule array, e.g., Simoa. Other exemplary methods of detection include immunohistochemistry and lateral flow assay. Additional exemplary methods for detecting target protein include, but are not limited to, gel electrophoresis, capillary electrophoresis, high performance liquid chromatography (HPLC), thin layer chromatography (TLC), hyperdiffusion chromatography, and the like, or various immunological methods such as fluid or gel precipitation reactions, immunodiffusion (single or double), immunoelectrophoresis, radioimmunoassay (MA), immunofluorescent assays, and Western blotting. In some embodiments, antibodies, or antibody fragments, are used in methods such as Western blots or immunofluorescence techniques to detect the expressed proteins. The antibody or protein can be immobilized on a solid support for Western blots and immunofluorescence techniques. Suitable solid phase supports or carriers include any support capable of binding an antigen or an antibody. Exemplary supports or carriers include glass, polystyrene, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, polyacrylamides, gabbros, and magnetite.

In some cases, a target protein may be detected by detecting binding between the target protein and a binding partner of the target protein. Non-limiting examples of binding partners to TL1A include DcR3, and Tumor necrosis factor receptor superfamily member 25 (TNR25). Exemplary methods of analysis of protein-protein binding comprise performing an assay in vivo or in vitro, or ex vivo. In some instances, the method of analysis comprises an assay such as a co-immunoprecipitation (co-IP), pull-down, crosslinking protein interaction analysis, labeled transfer protein interaction analysis, or Far-western blot analysis, FRET based assay, including, for example FRET-FLIM, a yeast two-hybrid assay, BiFC, or split luciferase assay.

›METHODS · 8 of 46

Disclosed herein are methods of detecting a presence or a level of one or more serological markers in a sample obtained from a subject. In some embodiments, the one or more serological markers comprises anti- Saccharomyces cerevisiae antibody (ASCA), an anti-neutrophil cytoplasmic antibody (ANCA), antibody against E. coli outer membrane porin protein C (anti-OmpC), anti-chitin antibody, pANCA antibody, anti-I2 antibody, and anti-Cbir1 flagellin antibody. In some embodiments, the antibodies comprises immunoglobulin A (IgA), immunoglobulin G (IgG), immunoglobulin E (IgE), or immunoglobulin M (IgM), immunoglobulin D (IgD), or a combination thereof. Any suitable method for detecting a target protein or biomarker disclosed herein may be used to detect a presence, absence, or level of a serological marker. In some embodiments, the presence or the level of the one or more serological markers is detected using an enzyme-linked immunosorbent assay (ELISA), a single molecule array (Simoa Sensitivity®), immunohistochemistry, internal transcribed spacer (ITS) sequencing, or any combination thereof. In some embodiments, the ELISA is a fixed leukocyte ELISA. In some embodiments, the ELISA is a fixed neutrophil ELISA. A fixed leukocyte or neutrophil ELISA may be useful for the detection of certain serological markers, such as those described in Saxon et al., A distinct subset of antineutrophil cytoplasmic antibodies is associated with inflammatory bowel disease, J. Allergy Clin. Immuno. 86:2; 202-210 (August 1990). In some embodiments, ELISA units (EU) are used to measure positivity of a presence or level of a serological marker (e.g., seropositivity), which reflects a percentage of a standard or reference value. In some embodiments, the standard comprises pooled sera obtained from well-characterized patient population (e.g., diagnosed with the same disease or condition the subject has, or is suspected of having) reported as being seropositive for the serological marker of interest. In some embodiments, the control or reference value comprises 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 EU. In some instances, a quartile sum scores are calculated using, for example, the methods reported in Landers C J, Cohavy O, Misra R. et al., Selected loss of tolerance evidenced by Crohn's disease-associated immune responses to auto- and microbial antigens. Gastroenterology (2002)123:689-699.

Methods of Treatment

Disclosed herein are methods of treating a disease or condition, or a symptom of the disease or condition, in a subject, comprising administrating of therapeutic effective amount of one or more therapeutic agents to the subject. In some embodiments, the one or more therapeutic agents is administered to the subject alone (e.g., standalone therapy). In some embodiments, the one or more therapeutic agents is administered in combination with an additional agent. In some embodiments, the therapeutic agent is a first-line therapy for the disease or condition. In some embodiments, the therapeutic agent is a second-line, third-line, or fourth-line therapy, for the disease or condition.

Therapeutic Agents

Aspects provided herein are methods of treating an inflammatory, fibrostenotic, or fibrotic disease or condition in a subject by administering a therapeutically effective amount of an inhibitor of TNF Superfamily Member 15 (TL1A) activity or expression to the subject, provided a genotype is detected in a sample obtained from the subject. In some cases, the TL1A protein comprises an amino acid sequence provided in any one of SEQ ID NOS: 50-52. In some cases, the TL1A protein comprises an amino acid sequence that is at least or about 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%, 98%, or 99% identical to any one of SEQ ID NOS: 50-52. In some embodiments, the inhibitor of TL1A activity or expression is effective to inhibit TL1A-DR3 binding. In some embodiments, the inhibitor of TL1A activity or expression comprises an allosteric modulator of TL1A. An allosteric modulator of TL1A may indirectly influence the effects TL1A on DR3, or TR6/DcR3 on TL1A or DR3. The inhibitor of TL1A activity or expression may be a direct inhibitor or indirect inhibitor. Non-limiting examples of an inhibitor of TL1A expression include RNA to protein TL1A translation inhibitors, antisense oligonucleotides targeting the TNFSF15 mRNA (such as miRNAs, or siRNA), epigenetic editing (such as targeting the DNA-binding domain of TNFSF15, or post-translational modifications of histone tails and/or DNA molecules). Non-limiting examples of an inhibitor of TL1A activity include antagonists to the TL1A receptors, (DR3 and TR6/DcR3), antagonists to TL1A antigen, and antagonists to gene expression products involved in TL1A mediated disease. Antagonists as disclosed herein, may include, but are not limited to, an anti-TL1A antibody, an anti-TL1A-binding antibody fragment, or a small molecule. The small molecule may be a small molecule that binds to TL1A or DR3. The anti-TL1A antibody may be monoclonal or polyclonal. The anti-TL1A antibody may be humanized or chimeric. The anti-TL1A antibody may be a fusion protein. The anti-TL1A antibody may be a blocking anti-TL1A antibody. A blocking antibody blocks binding between two proteins, e.g., a ligand and its receptor. Therefore, a TL1A blocking antibody includes an antibody that prevents binding of TL1A to DR3 and/or TR6/DcR3 receptors. In a non-limiting example, the TL1A blocking antibody binds to DR3. In another example, the TL1A blocking antibody binds to DcR3. In some cases, the TL1A antibody is an anti-TL1A antibody that specifically binds to TL1A. In some cases, the TL1A antibody specifically binds to an epitope of the TL1A protein provided in any one of SEQ ID NOS: 50-52. In some cases, the TL1A protein comprises an amino acid sequence that is at least or about 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%, 98%, or 99% identical to any one of SEQ ID NOS: 50-52. The anti-TL1A antibody may comprise one or more of the antibody sequences of Table 2A or Table 2B. The anti-DR3 antibody may comprise an amino acid sequence that is at least 85% identical to any one of SEQ ID NOS: 258-270 and an amino acid sequence that is at least 85% identical to any one of SEQ ID NOS: 271-275. The anti-DR3 antibody may comprise an amino acid sequence comprising the HCDR1, HCDR2, HCDR3 domains of any one of SEQ ID NOS: 258-270 and the LCDR1, LCDR2, and LCDR3 domains of any one of SEQ ID NOS: 271-275.

›METHODS · 9 of 46

In some embodiments, an anti-TL1A antibody comprises a heavy chain comprising three complementarity-determining regions: HCDR1, HCDR2, and HCDR3; and a light chain comprising three complementarity-determining regions: LCDR1, LCDR2, and LCDR3. In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprising SEQ ID NO: 109, a HCDR2 comprising SEQ ID NO: 110, a HCDR3 comprising SEQ ID NO: 111, a LCDR1 comprising SEQ ID NO: 112, a LCDR2 comprising SEQ ID NO: 113, and a LCDR3 comprising SEQ ID NO: 114. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 115 and a light chain (LC) variable domain comprising SEQ ID NO: 116.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprising SEQ ID NO: 117, a HCDR2 comprising SEQ ID NO: 118, a HCDR3 comprising SEQ ID NO: 119, a LCDR1 comprising SEQ ID NO: 120, a LCDR2 comprising SEQ ID NO: 121, and a LCDR3 comprising SEQ ID NO: 122. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 123 and a light chain (LC) variable domain comprising SEQ ID NO: 124.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprising SEQ ID NO: 125, a HCDR2 comprising SEQ ID NO: 126, a HCDR3 comprising SEQ ID NO: 127, a LCDR1 comprising SEQ ID NO: 128, a LCDR2 comprising SEQ ID NO: 129, and a LCDR3 comprising SEQ ID NO: 130. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 131 and a light chain (LC) variable domain comprising SEQ ID NO: 132.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprising SEQ ID NO: 133, a HCDR2 comprising SEQ ID NO: 134, a HCDR3 comprising SEQ ID NO: 135, a LCDR1 comprising SEQ ID NO: 139, a LCDR2 comprising SEQ ID NO: 140, and a LCDR3 comprising SEQ ID NO: 141. In some cases, the anti-TL1A antibody comprises a HCDR1 comprising SEQ ID NO: 136, a HCDR2 comprising SEQ ID NO: 137, a HCDR3 comprising SEQ ID NO: 138, a LCDR1 comprising SEQ ID NO: 139, a LCDR2 comprising SEQ ID NO: 140, and a LCDR3 comprising SEQ ID NO: 141. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 142 and a light chain (LC) variable domain comprising SEQ ID NO: 143. In some cases, the anti-TL1A antibody comprises a heavy chain comprising SEQ ID NO: 144. In some cases, the anti-TL1A antibody comprises a light chain comprising SEQ ID NO: 145.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprising SEQ ID NO: 146, a HCDR2 comprising SEQ ID NO: 147, a HCDR3 comprising SEQ ID NO: 148, a LCDR1 comprising SEQ ID NO: 149, a LCDR2 comprising SEQ ID NO: 150, and a LCDR3 comprising SEQ ID NO: 151. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 152 and a light chain (LC) variable domain comprising SEQ ID NO: 153.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprising SEQ ID NO: 154, a HCDR2 comprising SEQ ID NO: 155, a HCDR3 comprising SEQ ID NO: 156, a LCDR1 comprising SEQ ID NO: 157, a LCDR2 comprising SEQ ID NO: 158, and a LCDR3 comprising SEQ ID NO: 159. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 160 and a light chain (LC) variable domain comprising SEQ ID NO: 161.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprising SEQ ID NO: 162, a HCDR2 comprising SEQ ID NO: 164, a HCDR3 comprising SEQ ID NO: 165, a LCDR1 comprising SEQ ID NO: 167, a LCDR2 comprising SEQ ID NO: 169, and a LCDR3 comprising SEQ ID NO: 170. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 171 and a light chain (LC) variable domain comprising SEQ ID NO: 175. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 171 and a light chain (LC) variable domain comprising SEQ ID NO: 176. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 171 and a light chain (LC) variable domain comprising SEQ ID NO: 177. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 171 and a light chain (LC) variable domain comprising SEQ ID NO: 178.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprising SEQ ID NO: 162, a HCDR2 comprising SEQ ID NO: 164, a HCDR3 comprising SEQ ID NO: 165, a LCDR1 comprising SEQ ID NO: 168, a LCDR2 comprising SEQ ID NO: 169, and a LCDR3 comprising SEQ ID NO: 170. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 171 and a light chain (LC) variable domain comprising SEQ ID NO: 179. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 171 and a light chain (LC) variable domain comprising SEQ ID NO: 180. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 171 and a light chain (LC) variable domain comprising SEQ ID NO: 181. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 171 and a light chain (LC) variable domain comprising SEQ ID NO: 182.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprising SEQ ID NO: 162, a HCDR2 comprising SEQ ID NO: 164, a HCDR3 comprising SEQ ID NO: 165, a LCDR1 comprising SEQ ID NO: 167, a LCDR2 comprising SEQ ID NO: 169, and a LCDR3 comprising SEQ ID NO: 170. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 172 and a light chain (LC) variable domain comprising SEQ ID NO: 175. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 172 and a light chain (LC) variable domain comprising SEQ ID NO: 176. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 172 and a light chain (LC) variable domain comprising SEQ ID NO: 177. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 172 and a light chain (LC) variable domain comprising SEQ ID NO: 178.

›METHODS · 10 of 46

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprising SEQ ID NO: 162, a HCDR2 comprising SEQ ID NO: 164, a HCDR3 comprising SEQ ID NO: 165, a LCDR1 comprising SEQ ID NO: 168, a LCDR2 comprising SEQ ID NO: 169, and a LCDR3 comprising SEQ ID NO: 170. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 172 and a light chain (LC) variable domain comprising SEQ ID NO: 179. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 172 and a light chain (LC) variable domain comprising SEQ ID NO: 180. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 172 and a light chain (LC) variable domain comprising SEQ ID NO: 181. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 172 and a light chain (LC) variable domain comprising SEQ ID NO: 182.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprising SEQ ID NO: 163, a HCDR2 comprising SEQ ID NO: 164, a HCDR3 comprising SEQ ID NO: 166, a LCDR1 comprising SEQ ID NO: 167, a LCDR2 comprising SEQ ID NO: 169, and a LCDR3 comprising SEQ ID NO: 170. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 173 and a light chain (LC) variable domain comprising SEQ ID NO: 175. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 173 and a light chain (LC) variable domain comprising SEQ ID NO: 176. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 173 and a light chain (LC) variable domain comprising SEQ ID NO: 177. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 173 and a light chain (LC) variable domain comprising SEQ ID NO: 178. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 173 and a light chain (LC) variable domain comprising SEQ ID NO: 179. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 173 and a light chain (LC) variable domain comprising SEQ ID NO: 180. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 173 and a light chain (LC) variable domain comprising SEQ ID NO: 181. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 173 and a light chain (LC) variable domain comprising SEQ ID NO: 182.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprising SEQ ID NO: 163, a HCDR2 comprising SEQ ID NO: 164, a HCDR3 comprising SEQ ID NO: 166, a LCDR1 comprising SEQ ID NO: 168, a LCDR2 comprising SEQ ID NO: 169, and a LCDR3 comprising SEQ ID NO: 170. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 174 and a light chain (LC) variable domain comprising SEQ ID NO: 179. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 174 and a light chain (LC) variable domain comprising SEQ ID NO: 180. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 174 and a light chain (LC) variable domain comprising SEQ ID NO: 181. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 174 and a light chain (LC) variable domain comprising SEQ ID NO: 182. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 174 and a light chain (LC) variable domain comprising SEQ ID NO: 175. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 174 and a light chain (LC) variable domain comprising SEQ ID NO: 176. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 174 and a light chain (LC) variable domain comprising SEQ ID NO: 177. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 174 and a light chain (LC) variable domain comprising SEQ ID NO: 178.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprising SEQ ID NO: 183, a HCDR2 comprising SEQ ID NO: 184, a HCDR3 comprising SEQ ID NO: 185, a LCDR1 comprising SEQ ID NO: 186, a LCDR2 comprising SEQ ID NO: 187, and a LCDR3 comprising SEQ ID NO: 188. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 189 and a light chain (LC) variable domain comprising SEQ ID NO: 194. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 189 and a light chain (LC) variable domain comprising SEQ ID NO: 195. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 189 and a light chain (LC) variable domain comprising SEQ ID NO: 196. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 189 and a light chain (LC) variable domain comprising SEQ ID NO: 197. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 190 and a light chain (LC) variable domain comprising SEQ ID NO: 194. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 190 and a light chain (LC) variable domain comprising SEQ ID NO: 195. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 190 and a light chain (LC) variable domain comprising SEQ ID NO: 196. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 190 and a light chain (LC) variable domain comprising SEQ ID NO: 197. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 191 and a light chain (LC) variable domain comprising SEQ ID NO: 194. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 191 and a light chain (LC) variable domain comprising SEQ ID NO: 195. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 191 and a light chain (LC) variable domain comprising SEQ ID NO: 196. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 191 and a light chain (LC) variable domain comprising SEQ ID NO: 197. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 192 and a light chain (LC) variable domain comprising SEQ ID NO: 194. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 192 and a light chain (LC) variable domain comprising SEQ ID NO: 195. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 192 and a light chain (LC) variable domain comprising SEQ ID NO: 196. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 192 and a light chain (LC) variable domain comprising SEQ ID NO: 197. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 193 and a light chain (LC) variable domain comprising SEQ ID NO: 194. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 193 and a light chain (LC) variable domain comprising SEQ ID NO: 195. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 193 and a light chain (LC) variable domain comprising SEQ ID NO: 196. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 193 and a light chain (LC) variable domain comprising SEQ ID NO: 197.

›METHODS · 11 of 46

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprising SEQ ID NO: 198, a HCDR2 comprising SEQ ID NO: 199, a HCDR3 comprising SEQ ID NO: 200, a LCDR1 comprising SEQ ID NO: 201, a LCDR2 comprising SEQ ID NO: 202, and a LCDR3 comprising SEQ ID NO: 203. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 204 and a light chain (LC) variable domain comprising SEQ ID NO: 205. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 206 and a light chain (LC) variable domain comprising SEQ ID NO: 207. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 208 and a light chain (LC) variable domain comprising SEQ ID NO: 209. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 210 and a light chain (LC) variable domain comprising SEQ ID NO: 211. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 212 and a light chain (LC) variable domain comprising SEQ ID NO: 213. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 214 and a light chain (LC) variable domain comprising SEQ ID NO: 215. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 216 and a light chain (LC) variable domain comprising SEQ ID NO: 217. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 218 and a light chain (LC) variable domain comprising SEQ ID NO: 219. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 220 and a light chain (LC) variable domain comprising SEQ ID NO: 221. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 222 and a light chain (LC) variable domain comprising SEQ ID NO: 223. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 224 and a light chain (LC) variable domain comprising SEQ ID NO: 225. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 226 and a light chain (LC) variable domain comprising SEQ ID NO: 227.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprising SEQ ID NO: 228, a HCDR2 comprising SEQ ID NO: 229, a HCDR3 comprising SEQ ID NO: 230, a LCDR1 comprising SEQ ID NO: 231, a LCDR2 comprising SEQ ID NO: 232, and a LCDR3 comprising SEQ ID NO: 233. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 234 and a light chain (LC) variable domain comprising SEQ ID NO: 235.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprising SEQ ID NO: 236, a HCDR2 comprising SEQ ID NO: 237, a HCDR3 comprising SEQ ID NO: 238, a LCDR1 comprising SEQ ID NO: 239, a LCDR2 comprising SEQ ID NO: 240, and a LCDR3 comprising SEQ ID NO: 241. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 242 and a light chain (LC) variable domain comprising SEQ ID NO: 243.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprising SEQ ID NO: 246, a HCDR2 comprising SEQ ID NO: 247, a HCDR3 comprising SEQ ID NO: 248, a LCDR1 comprising SEQ ID NO: 249, a LCDR2 comprising SEQ ID NO: 250, and a LCDR3 comprising SEQ ID NO: 251. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 244 and a light chain (LC) variable domain comprising SEQ ID NO: 245. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 252 and a light chain (LC) variable domain comprising SEQ ID NO: 253. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 254 and a light chain (LC) variable domain comprising SEQ ID NO: 255. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 256 and a light chain (LC) variable domain comprising SEQ ID NO: 257.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprising SEQ ID NO: 276, a HCDR2 comprising SEQ ID NO: 277, a HCDR3 comprising SEQ ID NO: 278, a LCDR1 comprising SEQ ID NO: 279, a LCDR2 comprising SEQ ID NO: 280, and a LCDR3 comprising SEQ ID NO: 281. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 282 and a light chain (LC) variable domain comprising SEQ ID NO: 283.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprising SEQ ID NO: 284, a HCDR2 comprising SEQ ID NO: 285, a HCDR3 comprising SEQ ID NO: 286, a LCDR1 comprising SEQ ID NO: 287, a LCDR2 comprising SEQ ID NO: 288, and a LCDR3 comprising SEQ ID NO: 299. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 290 and a light chain (LC) variable domain comprising SEQ ID NO: 291.

In some embodiments, the anti-TL1A antibody is A100. In some embodiments, the anti-TL1A antibody is A101. In some embodiments, the anti-TL1A antibody is A102. In some embodiments, the anti-TL1A antibody is A103. In some embodiments, the anti-TL1A antibody is A104. In some embodiments, the anti-TL1A antibody is A105. In some embodiments, the anti-TL1A antibody is A106. In some embodiments, the anti-TL1A antibody is A107. In some embodiments, the anti-TL1A antibody is A108. In some embodiments, the anti-TL1A antibody is A109. In some embodiments, the anti-TL1A antibody is A110. In some embodiments, the anti-TL1A antibody is A111. In some embodiments, the anti-TL1A antibody is A112. In some embodiments, the anti-TL1A antibody is A113. In some embodiments, the anti-TL1A antibody is A114. In some embodiments, the anti-TL1A antibody is A115. In some embodiments, the anti-TL1A antibody is A116. In some embodiments, the anti-TL1A antibody is A117. In some embodiments, the anti-TL1A antibody is A118. In some embodiments, the anti-TL1A antibody is A119. In some embodiments, the anti-TL1A antibody is A120. In some embodiments, the anti-TL1A antibody is A121. In some embodiments, the anti-TL1A antibody is A122. In some embodiments, the anti-TL1A antibody is A123. In some embodiments, the anti-TL1A antibody is A124. In some embodiments, the anti-TL1A antibody is A125. In some embodiments, the anti-TL1A antibody is A126. In some embodiments, the anti-TL1A antibody is A127. In some embodiments, the anti-TL1A antibody is A128. In some embodiments, the anti-TL1A antibody is A129. In some embodiments, the anti-TL1A antibody is A130. In some embodiments, the anti-TL1A antibody is A131. In some embodiments, the anti-TL1A antibody is A132. In some embodiments, the anti-TL1A antibody is A133. In some embodiments, the anti-TL1A antibody is A134. In some embodiments, the anti-TL1A antibody is A135. In some embodiments, the anti-TL1A antibody is A136. In some embodiments, the anti-TL1A antibody is A137. In some embodiments, the anti-TL1A antibody is A138. In some embodiments, the anti-TL1A antibody is A139. In some embodiments, the anti-TL1A antibody is A140. In some embodiments, the anti-TL1A antibody is A141. In some embodiments, the anti-TL1A antibody is A142. In some embodiments, the anti-TL1A antibody is A143. In some embodiments, the anti-TL1A antibody is A144. In some embodiments, the anti-TL1A antibody is A145. In some embodiments, the anti-TL1A antibody is A146. In some embodiments, the anti-TL1A antibody is A147. In some embodiments, the anti-TL1A antibody is A148. In some embodiments, the anti-TL1A antibody is A149. In some embodiments, the anti-TL1A antibody is A150. In some embodiments, the anti-TL1A antibody is A151. In some embodiments, the anti-TL1A antibody is A152. In some embodiments, the anti-TL1A antibody is A153. In some embodiments, the anti-TL1A antibody is A154. In some embodiments, the anti-TL1A antibody is A155. In some embodiments, the anti-TL1A antibody is A156. In some embodiments, the anti-TL1A antibody is A157. In some embodiments, the anti-TL1A antibody is A158. In some embodiments, the anti-TL1A antibody is A159. In some embodiments, the anti-TL1A antibody is A160. In some embodiments, the anti-TL1A antibody is A161. In some embodiments, the anti-TL1A antibody is A162. In some embodiments, the anti-TL1A antibody is A163. In some embodiments, the anti-TL1A antibody is A164. In some embodiments, the anti-TL1A antibody is A165. In some embodiments, the anti-TL1A antibody is A166. In some embodiments, the anti-TL1A antibody is A167. In some embodiments, the anti-TL1A antibody is A168. In some embodiments, the anti-TL1A antibody is A169. In some embodiments, the anti-TL1A antibody is A170. In some embodiments, the anti-TL1A antibody is A171. In some embodiments, the anti-TL1A antibody is A172. In some embodiments, the anti-TL1A antibody is A173. In some embodiments, the anti-TL1A antibody is A174. In some embodiments, the anti-TL1A antibody is A175. In some embodiments, the anti-TL1A antibody is A176. In some embodiments, the anti-TL1A antibody is A177. In some embodiments, the anti-DR3 is A178. In some embodiments, the anti-DR3 is A179. In some embodiments, the anti-DR3 is A180. In some embodiments, the anti-DR3 is A181. In some embodiments, the anti-DR3 is A182. In some embodiments, the anti-DR3 is A183. In some embodiments, the anti-DR3 is A184. In some embodiments, the anti-DR3 is A185. In some embodiments, the anti-DR3 is A186. In some embodiments, the anti-DR3 is A187. In some embodiments, the anti-DR3 is A188. In some embodiments, the anti-DR3 is A189. In some embodiments, the anti-DR3 is A190. In some embodiments, the anti-DR3 is A191. In some embodiments, the anti-DR3 is A192. In some embodiments, the anti-DR3 is A193. In some embodiments, the anti-DR3 is A194. In some embodiments, the anti-DR3 is A195. In some embodiments, the anti-DR3 is A196. In some embodiments, the anti-DR3 is A197. In some embodiments, the anti-DR3 is A198. In some embodiments, the anti-DR3 is A199. In some embodiments, the anti-DR3 is A200. In some embodiments, the anti-DR3 is A201. In some embodiments, the anti-DR3 is A202. In some embodiments, the anti-DR3 is A203. In some embodiments, the anti-DR3 is A204. In some embodiments, the anti-DR3 is A205. In some embodiments, the anti-DR3 is A206. In some embodiments, the anti-DR3 is A207. In some embodiments, the anti-DR3 is A208. In some embodiments, the anti-DR3 is A209. In some embodiments, the anti-DR3 is A210. In some embodiments, the anti-DR3 is A211. In some embodiments, the anti-DR3 is A212. In some embodiments, the anti-DR3 is A213. In some embodiments, the anti-DR3 is A214. In some embodiments, the anti-DR3 is A215. In some embodiments, the anti-DR3 is A216. In some embodiments, the anti-DR3 is A217. In some embodiments, the anti-DR3 is A218. In some embodiments, the anti-DR3 is A219. In some embodiments, the anti-DR3 is A220. In some embodiments, the anti-DR3 is A221. In some embodiments, the anti-DR3 is A222. In some embodiments, the anti-DR3 is A223. In some embodiments, the anti-DR3 is A224. In some embodiments, the anti-DR3 is A225. In some embodiments, the anti-DR3 is A226. In some embodiments, the anti-DR3 is A227. In some embodiments, the anti-DR3 is A228. In some embodiments, the anti-DR3 is A229. In some embodiments, the anti-DR3 is A230. In some embodiments, the anti-DR3 is A231. In some embodiments, the anti-DR3 is A232. In some embodiments, the anti-DR3 is A233. In some embodiments, the anti-DR3 is A234. In some embodiments, the anti-DR3 is A235. In some embodiments, the anti-DR3 is A236. In some embodiments, the anti-DR3 is A237. In some embodiments, the anti-DR3 is A238. In some embodiments, the anti-DR3 is A239. In some embodiments, the anti-DR3 is A240. In some embodiments, the anti-DR3 is A241. In some embodiments, the anti-DR3 is A242.

›METHODS · 12 of 46

In some cases, the anti-TL1A antibody binds to at least one or more of the same residues of human TL1A as an antibody described herein. For example, the anti-TL1A antibody binds to at least one or more of the same residues of human TL1A as an antibody selected from A100-A177. In some cases, the anti-TL1A antibody binds to the same epitope of human TL1A as an antibody selected from A100-A177. In some cases, the anti-TL1A antibody binds to the same region of human TL1A as an antibody selected from A100-A177.

In some embodiments, the anti-TL1A antibody comprises any one of the following embodiments 1-547 below.

1. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising: a heavy chain variable region comprising four heavy chain framework regions (HFR1, HFR2, HFR3, and HFR4), and three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3), the heavy chain variable region comprising:

(a) a HFR1 selected from: (i) a HFR1 comprising SEQ ID NO: 100100, (ii) a HFR1 comprising SEQ ID NO: 100108, and (iii) a HFR1 comprising an amino acid sequence that differs from a sequence selected from the group consisting of SEQ ID NOS: 100100 and 100108 by up to five, four, three, or two amino acids, (b) a HFR2 selected from: (i) a HFR2 comprising SEQ ID NO: 100101, and (ii) a HFR2 comprising an amino acid sequence that differs from SEQ ID NO: by up to five, four, three, or two amino acids, (c) a HFR3 selected from: (i) a HFR3 comprising SEQ ID NO: 100102, (ii) a HFR3 comprising SEQ ID NO: 100109, and (iii) a HFR3 comprising an amino acid sequence that differs from a sequence selected from the group consisting of SEQ ID NOS: 100102 and 100109 by up to five, four, three, or two amino acids, (d) a HFR4 selected from: (i) a HFR4 comprising SEQ ID NO: 100103, and (ii) a HFR4 comprising an amino acid sequence that differs from SEQ ID NO: 100103 by up to five, four, three, or two amino acids, (e) a HCDR1 selected from: (i) a HCDR1 comprising SEQ ID NO: 1009, (ii) a HCDR1 comprising SEQ ID NO: 100150, wherein X 1 is selected from D and E, X 2 is selected from I, P and V, X 3 is selected from G, Q, S, and V, X 4 is selected from F and Y, and X 5 is selected from I and M, (iii) a HCDR1 selected from SEQ ID NOS: 100200-100295, and (iv) a HCDR1 comprising an amino acid sequence that differs from a sequence selected from the group consisting of SEQ ID NOS: 1009, 100150 and 100200-100295 by up to five, four, three, or two amino acids, (f) a HCDR2 selected from: (i) a HCDR2 comprising SEQ ID NO: 10012, and (ii) a HCDR2 comprising an amino acid sequence that differs from SEQ ID NO: 10012 by up to five, four, three, or two amino acids, and (g) a HCDR3 selected from (i) a HCDR3 comprising SEQ ID NO: 10015, (ii) a HCDR3 comprising SEQ ID NO: 100152, wherein X 1 is selected from L and M, and X 2 is selected from E, I, K, L, M, Q, T, V, W, and Y, (iii) a HCDR3 selected from SEQ ID NOS: 100296-100314, and (iv) a HCDR3 comprising an amino acid sequence that differs from a sequence selected from the group consisting of SEQ ID NOS: 10015, 100152 and 100296-100314 by up to five, four, three, or two amino acids; and

a light chain variable region comprising four light chain framework regions (LFR1, LFR2, LFR3, and LFR4), and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3), the light chain variable region comprising:

(a) a LFR1 selected from: (i) a LFR1 comprising SEQ ID NO: 100104, and (ii) a LFR1 comprising an amino acid sequence that differs from SEQ ID NO: 100104 by up to five, four, three, or two amino acids, (b) a LFR2 selected from: (i) a LFR2 comprising SEQ ID NO: 100105, and (ii) a LFR2 comprising an amino acid sequence that differs from SEQ ID NO: 100105 by up to five, four, three, or two amino acids, (c) a LFR3 selected from: (i) a LFR3 comprising SEQ ID NO: 100106, (ii) a LFR3 comprising SEQ ID NO: 100110, and (iii) a LFR3 comprising an amino acid sequence that differs from a sequence selected from the group consisting of SEQ ID NOS: 100106 and 100110 by up to five, four, three, or two amino acids, (d) a LFR4 selected from: (i) a LFR4 comprising SEQ ID NO: 100107, and (ii) a LFR4 comprising an amino acid sequence that differs from SEQ ID NO: 100107 by up to five, four, three, or two amino acids, (e) a LCDR1 selected from: (i) a LCDR1 comprising SEQ ID NO: 10018, and (ii) a LCDR1 comprising an amino acid sequence that differs from SEQ ID NO: 10018 by up to five, four, three, or two amino acids, (f) a LCDR2 selected from: (i) a LCDR2 comprising SEQ ID NO: 10021, and (ii) a LCDR2 comprising an amino acid sequence that differs from SEQ ID NO: 10021 by up to five, four, three, or two amino acids, and (g) a LCDR3 selected from (i) a LCDR3 comprising SEQ ID NO: 10024, (ii) a LCDR3 comprising SEQ ID NO: 100155, wherein X 1 is selected from Q and N, X 2 is selected from D, E, H, N, Q, and S, X 3 is selected from A and G, and X 4 is selected from D, F, K, N, R, S, and T, (iii) a LCDR3 selected from SEQ ID NOS: 100315-100482, and (iv) a LCDR3 comprising an amino acid sequence that differs from a sequence selected from the group consisting of SEQ ID NOS: 10024, 100155, and 100315-100482 by up to five, four, three, or two amino acids.

2. The antibody or antigen-binding fragment of embodiment 1, provided that the HFR1 comprises SEQ ID NO: 100100. 3. The antibody or antigen-binding fragment of embodiment 1, provided that the HFR1 comprises SEQ ID NO: 100108. 4. The antibody or antigen-binding fragment of embodiment 1, provided that the HFR1 comprises an amino acid sequence that differs from SEQ ID NO: 100100 by up to five, four, three, or two amino acids. 5. The antibody or antigen-binding fragment of embodiment 1, provided that the HFR1 comprises an amino acid sequence that differs from SEQ ID NO: 100108 by up to five, four, three, or two amino acids. 6. The antibody or antigen-binding fragment of any of embodiments 1-5, provided that the HFR2 comprises SEQ ID NO: 100101. 7. The antibody or antigen-binding fragment of any of embodiments 1-5, provided that the HFR2 comprises an amino acid sequence that differs from SEQ ID NO: 100101 by up to five, four, three, or two amino acids. 8. The antibody or antigen-binding fragment of any of embodiments 1-7, provided that the HFR3 comprises SEQ ID NO: 100102. 9. The antibody or antigen-binding fragment of any of embodiments 1-7, provided that the HFR3 comprises SEQ ID NO: 100109. 10. The antibody or antigen-binding fragment of any of embodiments 1-7, provided that the HFR3 comprises an amino acid sequence that differs from SEQ ID NO: 100102 by up to five, four, three, or two amino acids. 11. The antibody or antigen-binding fragment of any of embodiments 1-7, provided that the HFR3 comprises an amino acid sequence that differs from SEQ ID NO: 100109 by up to five, four, three, or two amino acids. 12. The antibody or antigen-binding fragment of any of embodiments 1-11, provided that the HFR4 comprises SEQ ID NO: 100103. 13. The antibody or antigen-binding fragment of any of embodiments 1-11, provided that the HFR4 comprises an amino acid sequence that differs from SEQ ID NO: 100103 by up to five, four, three, or two amino acids. 14. The antibody or antigen-binding fragment of any of embodiments 1-13, provided that the HCDR1 comprises SEQ ID NO: 1009. 15. The antibody or antigen-binding fragment of any of embodiments 1-13, provided that the HCDR1 comprises SEQ ID NO: 100150. 16. The antibody or antigen-binding fragment of embodiment 15, provided that X 1 is E. 17. The antibody or antigen-binding fragment of embodiment 15 or embodiment 16, provided that X 2 is selected from P and V. 18. The antibody or antigen-binding fragment of any of embodiments 15-17, provided that X 3 is selected from G, S, and V. 19. The antibody or antigen-binding fragment of any of embodiments 15-18, provided that X 4 is F. 20. The antibody or antigen-binding fragment of any of embodiments 15-19, provided that X 5 is I. 21. The antibody or antigen-binding fragment of any of embodiments 1-13, provided that the HCDR1 comprises an amino acid sequence selected from SEQ ID NOS: 100200-100295. 22. The antibody or antigen-binding fragment of any of embodiments 1-21, provided that the HCDR2 comprises SEQ ID NO: 10012. 23. The antibody or antigen-binding fragment of any of embodiments 1-21, provided that the HCDR2 comprises an amino acid sequence that differs from SEQ ID NO: 10012 by up to five, four, three, or two amino acids. 24. The antibody or antigen-binding fragment of any of embodiments 1-23, provided that the HCDR3 comprises SEQ ID NO: 10015. 25. The antibody or antigen-binding fragment of any of embodiments 1-23, provided that the HCDR3 comprises SEQ ID NO: 100152. 26. The antibody or antigen-binding fragment of embodiment 25, provided that X 1 is M. 27. The antibody or antigen-binding fragment of embodiment 25 or embodiment 26, provided that X 2 is selected from E, I, K, L, M, Q, T, W, and Y. 28. The antibody or antigen-binding fragment of any of embodiments 1-23, provided that the HCDR3 comprises a sequence selected from SEQ ID NOS: 100296-100314. 29. The antibody or antigen-binding fragment of any of embodiments 1-28, provided that the LFR1 comprises SEQ ID NO: 100104. 30. The antibody or antigen-binding fragment of any of embodiments 1-28, provided that the LFR1 comprises an amino acid sequence that differs from SEQ ID NO: 100104 by up to five, four, three, or two amino acids. 31. The antibody or antigen-binding fragment of any of embodiments 1-30, provided that the LFR2 comprises SEQ ID NO: 100105. 32. The antibody or antigen-binding fragment of any of embodiments 1-30, provided that the LFR2 comprises an amino acid sequence that differs from SEQ ID NO: 100105 by up to five, four, three, or two amino acids. 33. The antibody or antigen-binding fragment of any of embodiments 1-32, provided that the LFR3 comprises SEQ ID NO: 100106. 34. The antibody or antigen-binding fragment of any of embodiments 1-32, provided that the LFR3 comprises SEQ ID NO: 100110. 35. The antibody or antigen-binding fragment of any of embodiments 1-32, provided that the LFR3 comprises an amino acid sequence that differs from SEQ ID NO: 100106 by up to five, four, three, or two amino acids. 36. The antibody or antigen-binding fragment of any of embodiments 1-32, provided that the LFR3 comprises an amino acid sequence that differs from SEQ ID NO: 100110 by up to five, four, three, or two amino acids. 37. The antibody or antigen-binding fragment of any of embodiments 1-36, provided that the LFR4 comprises SEQ ID NO: 100107. 38. The antibody or antigen-binding fragment of any of embodiments 1-36, provided that the LFR4 comprises an amino acid sequence that differs from SEQ ID NO: 100107 by up to five, four, three, or two amino acids. 39. The antibody or antigen-binding fragment of any of embodiments 1-38, provided that the LCDR1 comprises SEQ ID NO: 10018. 40. The antibody or antigen-binding fragment of any of embodiments 1-38, provided that the LCDR1 comprises an amino acid sequence that differs from SEQ ID NO: 10018 by up to five, four, three, or two amino acids. 41. The antibody or antigen-binding fragment of any of embodiments 1-40, provided that the LCDR2 comprises SEQ ID NO: 10021. 42. The antibody or antigen-binding fragment of any of embodiments 1-40, provided that the LCDR2 comprises an amino acid sequence that differs from SEQ ID NO: 10021 by up to five, four, three, or two amino acids. 43. The antibody or antigen-binding fragment of any of embodiments 1-42, provided that the LCDR3 comprises SEQ ID NO: 10024. 44. The antibody or antigen-binding fragment of any of embodiments 1-42, provided that the LCDR3 comprises SEQ ID NO: 100155. 45. The antibody or antigen-binding fragment of embodiment 44, provided that X 1 is N. 46. The antibody or antigen-binding fragment of embodiment 44 or embodiment 45, provided that X 2 is selected from D, E, H, N, and Q. 47. The antibody or antigen-binding fragment of any of embodiments 44-46, provided that X 3 is A. 48. The antibody or antigen-binding fragment of any of embodiments 44-47, provided that X 4 is selected from D, F, K, R, S, and T. 49. The antibody or antigen-binding fragment of any of embodiments 1-42, provided that the LCDR3 comprises an amino acid sequence selected from SEQ ID NOS: 100315-100482. 50. The antibody or antigen-binding fragment of embodiment 1, provided that the HFR1 comprises SEQ ID NO: 100100, the HFR2 comprises SEQ ID NO: 100101, the HFR3 comprises SEQ ID NO: 100102, the HFR4 comprises SEQ ID NO: 100103, the LFRI comprises SEQ ID NO: 100104, the LFR2 comprises SEQ ID NO: 100105, the LFR3 comprises SEQ ID NO: 100106, and the LFR4 comprises SEQ ID NO: 100107. 51. The antibody or antigen-binding fragment of embodiment 1, provided that the HFR1 comprises SEQ ID NO: 100108, the HFR2 comprises SEQ ID NO: 100101, the HFR3 comprises SEQ ID NO: 100109, the HFR4 comprises SEQ ID NO: 100103, the LFRI comprises SEQ ID NO: 100104, the LFR2 comprises SEQ ID NO: 100105, the LFR3 comprises SEQ ID NO: 100110, and the LFR4 comprises SEQ ID NO: 100107. 52. The antibody or antigen-binding fragment of embodiment 1, provided that the HFR1 comprises SEQ ID NO: 100108, the HFR2 comprises SEQ ID NO: 100101, the HFR3 comprises SEQ ID NO: 100109, the HFR4 comprises SEQ ID NO: 100103, the LFRI comprises SEQ ID NO: 100104, the LFR2 comprises SEQ ID NO: 100105, the LFR3 comprises SEQ ID NO: 100106, and the LFR4 comprises SEQ ID NO: 100107. 53. The antibody or antigen-binding fragment of any of embodiments 1 and 50-52, provided that the HCDR1 comprises SEQ ID NO: 1009, the HCDR2 comprises SEQ ID NO: 10012, the HCDR3 comprises SEQ ID NO: 10015, the LCDR1 comprises SEQ ID NO: 10018, the LCDR2 comprises SEQ ID NO: 10021, and the LCDR3 comprises SEQ ID NO: 10024. 54. The antibody or antigen-binding fragment of any of embodiments 1 and 50-52, provided that the HCDR1 comprises SEQ ID NO: 100150, the HCDR2 comprises SEQ ID NO: 10012, the HCDR3 comprises SEQ ID NO: 100152, the LCDR1 comprises SEQ ID NO: 10018, the LCDR2 comprises SEQ ID NO: 10021, and the LCDR3 comprises SEQ ID NO: 100155. 55. The antibody or antigen-binding fragment of embodiment 1, provided that the HFR1 comprises SEQ ID NO: 100100, the HFR2 comprises SEQ ID NO: 100101, the HFR3 comprises SEQ ID NO: 100102, the HFR4 comprises SEQ ID NO: 100103, the LFRI comprises SEQ ID NO: 100104, the LFR2 comprises SEQ ID NO: 100105, the LFR3 comprises SEQ ID NO: 100106, the LFR4 comprises SEQ ID NO: 100107, the HCDR1 comprises SEQ ID NO: 1009, the HCDR2 comprises SEQ ID NO: 10012, the HCDR3 comprises SEQ ID NO: 10015, the LCDR1 comprises SEQ ID NO: 10018, the LCDR2 comprises SEQ ID NO: 10021, and the LCDR3 comprises SEQ ID NO: 10024. 56. The antibody or antigen-binding fragment of embodiment 1, provided that the HFR1 comprises SEQ ID NO: 100100, the HFR2 comprises SEQ ID NO: 100101, the HFR3 comprises SEQ ID NO: 100102, the HFR4 comprises SEQ ID NO: 100103, the LFRI comprises SEQ ID NO: 100104, the LFR2 comprises SEQ ID NO: 100105, the LFR3 comprises SEQ ID NO: 100106, the LFR4 comprises SEQ ID NO: 100107, the HCDR1 comprises SEQ ID NO: 100150, the HCDR2 comprises SEQ ID NO: 10012, the HCDR3 comprises SEQ ID NO: 100152, the LCDR1 comprises SEQ ID NO: 10018, the LCDR2 comprises SEQ ID NO: 10021, and the LCDR3 comprises SEQ ID NO: 100155. 57. The antibody or antigen-binding fragment of embodiment 1, provided that the HFR1 comprises SEQ ID NO: 100108, the HFR2 comprises SEQ ID NO: 100101, the HFR3 comprises SEQ ID NO: 100109, the HFR4 comprises SEQ ID NO: 100103, the LFRI comprises SEQ ID NO: 100104, the LFR2 comprises SEQ ID NO: 100105, the LFR3 comprises SEQ ID NO: 100110, the LFR4 comprises SEQ ID NO: 100107, the HCDR1 comprises SEQ ID NO: 1009, the HCDR2 comprises SEQ ID NO: 10012, the HCDR3 comprises SEQ ID NO: 10015, the LCDR1 comprises SEQ ID NO: 10018, the LCDR2 comprises SEQ ID NO: 10021, and the LCDR3 comprises SEQ ID NO: 10024. 58. The antibody or antigen-binding fragment of embodiment 1, provided that the HFR1 comprises SEQ ID NO: 100108, the HFR2 comprises SEQ ID NO: 100101, the HFR3 comprises SEQ ID NO: 100109, the HFR4 comprises SEQ ID NO: 100103, the LFRI comprises SEQ ID NO: 100104, the LFR2 comprises SEQ ID NO: 100105, the LFR3 comprises SEQ ID NO: 100110, the LFR4 comprises SEQ ID NO: 100107, the HCDR1 comprises SEQ ID NO: 100150, the HCDR2 comprises SEQ ID NO: 10012, the HCDR3 comprises SEQ ID NO: 100152, the LCDR1 comprises SEQ ID NO: 10018, the LCDR2 comprises SEQ ID NO: 10021, and the LCDR3 comprises SEQ ID NO: 100155. 59. The antibody or antigen-binding fragment of embodiment 1, provided that the HFR1 comprises SEQ ID NO: 100108, the HFR2 comprises SEQ ID NO: 100101, the HFR3 comprises SEQ ID NO: 100109, the HFR4 comprises SEQ ID NO: 100103, the LFRI comprises SEQ ID NO: 100104, the LFR2 comprises SEQ ID NO: 100105, the LFR3 comprises SEQ ID NO: 100106, the LFR4 comprises SEQ ID NO: 100107, the HCDR1 comprises SEQ ID NO: 1009, the HCDR2 comprises SEQ ID NO: 10012, the HCDR3 comprises SEQ ID NO: 10015, the LCDR1 comprises SEQ ID NO: 10018, the LCDR2 comprises SEQ ID NO: 10021, and the LCDR3 comprises SEQ ID NO: 10024. 60. The antibody or antigen-binding fragment of embodiment 1, provided that the HFR1 comprises SEQ ID NO: 100108, the HFR2 comprises SEQ ID NO: 100101, the HFR3 comprises SEQ ID NO: 100109, the HFR4 comprises SEQ ID NO: 100103, the LFRI comprises SEQ ID NO: 100104, the LFR2 comprises SEQ ID NO: 100105, the LFR3 comprises SEQ ID NO: 100106, the LFR4 comprises SEQ ID NO: 100107, the HCDR1 comprises SEQ ID NO: 100150, the HCDR2 comprises SEQ ID NO: 10012, the HCDR3 comprises SEQ ID NO: 100152, the LCDR1 comprises SEQ ID NO: 10018, the LCDR2 comprises SEQ ID NO: 10021, and the LCDR3 comprises SEQ ID NO: 100155. 61. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60, provided that the X 1 of SEQ ID NO: 100150 is D. 62. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60, provided that the X 1 of SEQ ID NO: 100150 is E. 63. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-62, provided that the X 2 of SEQ ID NO: 100150 is I. 64. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-62, provided that the X 2 of SEQ ID NO: 100150 is P. 65. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-62, provided that the X 2 of SEQ ID NO: 100150 is V. 66. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-65, provided that the X 3 of SEQ ID NO: 100150 is G. 67. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-65, provided that the X 3 of SEQ ID NO: 100150 is Q. 68. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-65, provided that the X 3 of SEQ ID NO: 100150 is S. 69. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-65, provided that the X 3 of SEQ ID NO: 100150 is V. 70. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-69, provided that the X 4 of SEQ ID NO: 100150 is F. 71. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-69, provided that the X 4 of SEQ ID NO: 100150 is Y. 72. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-71, provided that the X 5 of SEQ ID NO: 100150 is I. 73. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-71, provided that the X 5 of SEQ ID NO: 100150 is M. 74. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-73, provided that the X 1 of SEQ ID NO: 100152 is L. 75. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-73, provided that the X 1 of SEQ ID NO: 100152 is M. 76. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-75, provided that the X 2 of SEQ ID NO: 100152 is E. 77. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-75, provided that the X 2 of SEQ ID NO: 100152 is I. 78. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-75, provided that the X 2 of SEQ ID NO: 100152 is K. 79. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-75, provided that the X 2 of SEQ ID NO: 100152 is L. 80. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-75, provided that the X 2 of SEQ ID NO: 100152 is M. 81. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-75, provided that the X 2 of SEQ ID NO: 100152 is Q. 82. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-75, provided that the X 2 of SEQ ID NO: 100152 is T. 83. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-75, provided that the X 2 of SEQ ID NO: 100152 is V. 84. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-75, provided that the X 2 of SEQ ID NO: 100152 is W. 85. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-75, provided that the X 2 of SEQ ID NO: 100152 is Y. 86. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-85, provided that the X 1 of SEQ ID NO: 100155 is Q. 87. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-85, provided that the X 1 of SEQ ID NO: 100155 is N. 88. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-87, provided that the X 2 of SEQ ID NO: 100155 is D. 89. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-87, provided that the X 2 of SEQ ID NO: 100155 is E. 90. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-87, provided that the X 2 of SEQ ID NO: 100155 is H. 91. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-87, provided that the X 2 of SEQ ID NO: 100155 is N. 92. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-87, provided that the X 2 of SEQ ID NO: 100155 is Q. 93. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-87, provided that the X 2 of SEQ ID NO: 100155 is S. 94. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-93, provided that the X 3 of SEQ ID NO: 100155 is A. 95. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-93, provided that the X 3 of SEQ ID NO: 100155 is G. 96. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-95, provided that the X 4 of SEQ ID NO: 100155 is D. 97. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-95, provided that the X 4 of SEQ ID NO: 100155 is F. 98. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-95, provided that the X 4 of SEQ ID NO: 100155 is K. 99. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-95, provided that the X 4 of SEQ ID NO: 100155 is N. 100. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-95, provided that the X 4 of SEQ ID NO: 100155 is R. 101. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-95, provided that the X 4 of SEQ ID NO: 100155 is S. 102. The antibody or antigen-binding fragment of any of embodiments 1, 54, 56, 58, and 60-95, provided that the X 4 of SEQ ID NO: 100155 is T. 103. The antibody or antigen-binding fragment of any of embodiments 1-102, provided that the antibody or antigen-binding fragment specifically binds to human TL1A. 104. The antibody or antigen-binding fragment of embodiment 103, provided that the antibody or antigen-binding fragment specifically binds to human TL1A with a K d of 1×10 −9 M or less. 105. The antibody or antigen-binding fragment of embodiment 104, provided that the K d is measured using a method selected from a standard ELISA assay and SPR. 106. The antibody or antigen-binding fragment of any of embodiments 1-105, provided that the antibody or antigen-binding fragment inhibits binding of DR3 to human TL1A. 107. The antibody or antigen-binding fragment of any of embodiments 1-106, provided that the antibody or antigen-binding fragment inhibits binding of DcR3 to human TL1A. 108. The antibody or antigen-binding fragment of any of embodiments 1-107, provided that the antibody or antigen-binding fragment is a humanized antibody, a CDR-grafted antibody, a chimeric antibody, a Fab, a ScFv, or a combination thereof 109. The antibody or antigen-binding fragment of any of embodiments 1-108, comprising a human CH1 domain. 110. The antibody or antigen-binding fragment of any of embodiments 1-109, comprising a human CH2 domain. 111. The antibody or antigen-binding fragment of embodiment 110, provided that that CH2 domain comprises at least one mutation selected from L234A, L235A, and G237A, as numbered using Kabat. 112. The antibody or antigen-binding fragment of any of embodiments 1-111, comprising a human CH3 domain. 113. A pharmaceutical composition comprising a therapeutically effective amount of the antibody or antigen-binding fragment of any of embodiments 1-112, and a pharmaceutically acceptable carrier. 114. A method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody or antigen-binding fragment of any of embodiments 1-113. 115. The method of embodiment 114, provided that the inflammatory disease is inflammatory bowel disease. 116. The method of embodiment 115, provided that the inflammatory bowel disease comprises Crohn's disease. 117. The method of embodiment 116, provided that the subject has been determined to be non-responsive to anti-TNF alpha therapy. 118. The method of embodiment 116 or embodiment 117, provided that the subject has been determined to comprise a disease phenotype comprising non-stricturing/non-penetrating, stricturing, stricturing and penetrating, or isolated internal penetrating. 119. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

›METHODS · 13 of 46

a heavy chain variable region comprising four heavy chain framework regions (HFR1, HFR2, HFR3, and HFR4) comprising SEQ ID NOS: 100100-100103, and three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) comprising:

(a) a HCDR1 selected from: (i) a HCDR1 comprising SEQ ID NO: 1009, (ii) a HCDR1 comprising SEQ ID NO: 100150, wherein X 1 is selected from D and E, X 2 is selected from I, P and V, X 3 is selected from G, Q, S, and V, X 4 is selected from F and Y, and X 5 is selected from I and M, (iii) a HCDR1 selected from SEQ ID NOS: 100200-100295, and (iv) a HCDR1 comprising an amino acid sequence that differs from a sequence selected from the group consisting of SEQ ID NOS: 1009, 100150 and 100200-100295 by up to five, four, three, or two amino acids, (b) a HCDR2 selected from: (i) a HCDR2 comprising SEQ ID NO: 10012, and (ii) a HCDR2 comprising an amino acid sequence that differs from SEQ ID NO: 10012 by up to five, four, three, or two amino acids, and (c) a HCDR3 selected from (i) a HCDR3 comprising SEQ ID NO: 10015, (ii) a HCDR3 comprising SEQ ID NO: 100152, wherein X 1 is selected from L and M, and X 2 is selected from E, I, K, L, M, Q, T, V, W, and Y, (iii) a HCDR3 selected from SEQ ID NOS: 100296-100314, and (iv) a HCDR3 comprising an amino acid sequence that differs from a sequence selected from the group consisting of SEQ ID NOS: 10015, 100152 and 100296-100314 by up to five, four, three, or two amino acids; and

a light chain variable region comprising four light chain framework regions (LFR1, LFR2, LFR3, and LFR4) comprising SEQ ID NOS: 100104-100107, and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) comprising:

(a) a LCDR1 selected from: (i) a LCDR1 comprising SEQ ID NO: 10018, and (ii) a LCDR1 comprising an amino acid sequence that differs from SEQ ID NO: 10018 by up to five, four, three, or two amino acids, (b) a LCDR2 selected from: (i) a LCDR2 comprising SEQ ID NO: 10021, and (ii) a LCDR2 comprising an amino acid sequence that differs from SEQ ID NO: 10021 by up to five, four, three, or two amino acids, and (c) a LCDR3 selected from (i) a LCDR3 comprising SEQ ID NO: 10024, (ii) a LCDR3 comprising SEQ ID NO: 100155, wherein X 1 is selected from Q and N, X 2 is selected from D, E, H, N, Q, and S, X 3 is selected from A and G, and X 4 is selected from D, F, K, N, R, S, and T, (iii) a LCDR3 selected from SEQ ID NOS: 100315-100482, and (iv) a LCDR3 comprising an amino acid sequence that differs from a sequence selected from the group consisting of SEQ ID NOS: 10024, 100155, and 100315-100482 by up to five, four, three, or two amino acids.

120. The antibody or antigen-binding fragment of embodiment 119, provided that the HCDR1 comprises SEQ ID NO: 1009. 121. The antibody or antigen-binding fragment of embodiment 119, provided that the HCDR1 comprises SEQ ID NO: 100150. 122. The antibody or antigen-binding fragment of embodiment 121, provided that X 1 is E. 123. The antibody or antigen-binding fragment of embodiment 121 or embodiment 122, provided that X 2 is selected from P and V. 124. The antibody or antigen-binding fragment of any of embodiments 121-123, provided that X 3 is selected from G, S, and V. 125. The antibody or antigen-binding fragment of any of embodiments 121-124, provided that X 4 is F. 126. The antibody or antigen-binding fragment of any of embodiments 121-125, provided that X 5 is I. 127. The antibody or antigen-binding fragment of embodiment 119, provided that the HCDR1 comprises an amino acid sequence selected from SEQ ID NOS: 100200-100295. 128. The antibody or antigen-binding fragment of any of embodiments 119-127, provided that the HCDR2 comprises SEQ ID NO: 10012. 129. The antibody or antigen-binding fragment of any of embodiments 119-127, provided that the HCDR2 comprises an amino acid sequence that differs from SEQ ID NO: 10012 by up to five, four, three, or two amino acids. 130. The antibody or antigen-binding fragment of any of embodiments 119-129, provided that the HCDR3 comprises SEQ ID NO: 10015. 131. The antibody or antigen-binding fragment of any of embodiments 119-129, provided that the HCDR3 comprises SEQ ID NO: 100152. 132. The antibody or antigen-binding fragment of embodiment 131, provided that X 1 is M. 133. The antibody or antigen-binding fragment of embodiment 131 or embodiment 132, provided that X 2 is selected from E, I, K, L, M, Q, T, W, and Y. 134. The antibody or antigen-binding fragment of any of embodiments 119-129, provided that the HCDR3 comprises a sequence selected from SEQ ID NOS: 100296-100314. 135. The antibody or antigen-binding fragment of any of embodiments 119-134, provided that the LCDR1 comprises SEQ ID NO: 10018. 136. The antibody or antigen-binding fragment of any of embodiments 119-134, provided that the LCDR1 comprises an amino acid sequence that differs from SEQ ID NO: 10018 by up to five, four, three, or two amino acids. 137. The antibody or antigen-binding fragment of any of embodiments 119-136, provided that the LCDR2 comprises SEQ ID NO: 10021. 138. The antibody or antigen-binding fragment of any of embodiments 119-136, provided that the LCDR2 comprises an amino acid sequence that differs from SEQ ID NO: 10021 by up to five, four, three, or two amino acids. 139. The antibody or antigen-binding fragment of any of embodiments 119-138, provided that the LCDR3 comprises SEQ ID NO: 10024. 140. The antibody or antigen-binding fragment of any of embodiments 119-138, provided that the LCDR3 comprises SEQ ID NO: 100155. 141. The antibody or antigen-binding fragment of embodiment 140, provided that X 1 is N. 142. The antibody or antigen-binding fragment of embodiment 140 or embodiment 141, provided that X 2 is selected from D, E, H, N, and Q. 143. The antibody or antigen-binding fragment of any of embodiments 140-142, provided that X 3 is A. 144. The antibody or antigen-binding fragment of any of embodiments 140-143, provided that X 4 is selected from D, F, K, R, S, and T. 145. The antibody or antigen-binding fragment of any of embodiments 119-138, provided that the LCDR3 comprises an amino acid sequence selected from SEQ ID NOS: 100315-100482. 146. The antibody or antigen-binding fragment of embodiment 119, provided that the HCDR1 comprises SEQ ID NO: 1009, the HCDR2 comprises SEQ ID NO: 10012, the HCDR3 comprises SEQ ID NO: 10015, the LCDR1 comprises SEQ ID NO: 10018, the LCDR2 comprises SEQ ID NO: 10021, and the LCDR3 comprises SEQ ID NO: 10024. 147. The antibody or antigen-binding fragment of embodiment 119, provided that the HCDR1 comprises SEQ ID NO: 100150, the HCDR2 comprises SEQ ID NO: 10012, the HCDR3 comprises SEQ ID NO: 100152, the LCDR1 comprises SEQ ID NO: 10018, the LCDR2 comprises SEQ ID NO: 10021, and the LCDR3 comprises SEQ ID NO: 100155. 148. The antibody or antigen-binding fragment of embodiment 119 or embodiment 147, provided that the X 1 of SEQ ID NO: 100150 is D. 149. The antibody or antigen-binding fragment of embodiment 119 or embodiment 147 provided that the X 1 of SEQ ID NO: 100150 is E. 150. The antibody or antigen-binding fragment of any of embodiments 119, 147-149, provided that the X 2 of SEQ ID NO: 100150 is I. 151. The antibody or antigen-binding fragment of any of embodiments 119, 147-149, provided that the X 2 of SEQ ID NO: 100150 is P. 152. The antibody or antigen-binding fragment of any of embodiments 119, 147-149, provided that the X 2 of SEQ ID NO: 100150 is V. 153. The antibody or antigen-binding fragment of any of embodiments 119, 147-152, provided that the X 3 of SEQ ID NO: 100150 is G. 154. The antibody or antigen-binding fragment of any of embodiments 119, 147-152, provided that the X 3 of SEQ ID NO: 100150 is Q. 155. The antibody or antigen-binding fragment of any of embodiments 119, 147-152, provided that the X 3 of SEQ ID NO: 100150 is S. 156. The antibody or antigen-binding fragment of any of embodiments 119, 147-152, provided that the X 3 of SEQ ID NO: 100150 is V. 157. The antibody or antigen-binding fragment of any of embodiments 119, 147-156, provided that the X 4 of SEQ ID NO: 100150 is F. 158. The antibody or antigen-binding fragment of any of embodiments 119, 147-156, provided that the X 4 of SEQ ID NO: 100150 is Y. 159. The antibody or antigen-binding fragment of any of embodiments 119, 147-158, provided that the X 5 of SEQ ID NO: 100150 is I. 160. The antibody or antigen-binding fragment of any of embodiments 119, 147-158, provided that the X 5 of SEQ ID NO: 100150 is M. 161. The antibody or antigen-binding fragment of any of embodiments 119, 147-160, provided that the X 1 of SEQ ID NO: 100152 is L. 162. The antibody or antigen-binding fragment of any of embodiments 119, 147-160, provided that the X 1 of SEQ ID NO: 100152 is M. 163. The antibody or antigen-binding fragment of any of embodiments 119, 147-162, provided that the X 2 of SEQ ID NO: 100152 is E. 164. The antibody or antigen-binding fragment of any of embodiments 119, 147-162, provided that the X 2 of SEQ ID NO: 100152 is I. 165. The antibody or antigen-binding fragment of any of embodiments 119, 147-162, provided that the X 2 of SEQ ID NO: 100152 is K. 166. The antibody or antigen-binding fragment of any of embodiments 119, 147-162, provided that the X 2 of SEQ ID NO: 100152 is L. 167. The antibody or antigen-binding fragment of any of embodiments 119, 147-162, provided that the X 2 of SEQ ID NO: 100152 is M. 168. The antibody or antigen-binding fragment of any of embodiments 119, 147-162, provided that the X 2 of SEQ ID NO: 100152 is Q. 169. The antibody or antigen-binding fragment of any of embodiments 119, 147-162, provided that the X 2 of SEQ ID NO: 100152 is T. 170. The antibody or antigen-binding fragment of any of embodiments 119, 147-162, provided that the X 2 of SEQ ID NO: 100152 is V. 171. The antibody or antigen-binding fragment of any of embodiments 119, 147-162, provided that the X 2 of SEQ ID NO: 100152 is W. 172. The antibody or antigen-binding fragment of any of embodiments 119, 147-162, provided that the X 2 of SEQ ID NO: 100152 is Y. 173. The antibody or antigen-binding fragment of any of embodiments 119, 147-172, provided that the X 1 of SEQ ID NO: 100155 is Q. 174. The antibody or antigen-binding fragment of any of embodiments 119, 147-172, provided that the X 1 of SEQ ID NO: 100155 is N. 175. The antibody or antigen-binding fragment of any of embodiments 119, 147-174, provided that the X 2 of SEQ ID NO: 100155 is D. 176. The antibody or antigen-binding fragment of any of embodiments 119, 147-174, provided that the X 2 of SEQ ID NO: 100155 is E. 177. The antibody or antigen-binding fragment of any of embodiments 119, 147-174, provided that the X 2 of SEQ ID NO: 100155 is H. 178. The antibody or antigen-binding fragment of any of embodiments 119, 147-174, provided that the X 2 of SEQ ID NO: 100155 is N. 179. The antibody or antigen-binding fragment of any of embodiments 119, 147-174, provided that the X 2 of SEQ ID NO: 100155 is Q. 180. The antibody or antigen-binding fragment of any of embodiments 119, 147-174, provided that the X 2 of SEQ ID NO: 100155 is S. 181. The antibody or antigen-binding fragment of any of embodiments 119, 147-180, provided that the X 3 of SEQ ID NO: 100155 is A. 182. The antibody or antigen-binding fragment of any of embodiments 119, 147-180, provided that the X 3 of SEQ ID NO: 100155 is G. 183. The antibody or antigen-binding fragment of any of embodiments 119, 147-182, provided that the X 4 of SEQ ID NO: 100155 is D. 184. The antibody or antigen-binding fragment of any of embodiments 119, 147-182, provided that the X 4 of SEQ ID NO: 100155 is F. 185. The antibody or antigen-binding fragment of any of embodiments 119, 147-182, provided that the X 4 of SEQ ID NO: 100155 is K. 186. The antibody or antigen-binding fragment of any of embodiments 119, 147-182, provided that the X 4 of SEQ ID NO: 100155 is N. 187. The antibody or antigen-binding fragment of any of embodiments 119, 147-182, provided that the X 4 of SEQ ID NO: 100155 is R. 188. The antibody or antigen-binding fragment of any of embodiments 119, 147-182, provided that the X 4 of SEQ ID NO: 100155 is S. 189. The antibody or antigen-binding fragment of any of embodiments 119, 147-182, provided that the X 4 of SEQ ID NO: 100155 is T. 190. The antibody or antigen-binding fragment of any of embodiments 119-189, provided that the antibody or antigen-binding fragment specifically binds to human TL1A. 191. The antibody or antigen-binding fragment of embodiment 190, provided that the antibody or antigen-binding fragment specifically binds to human TL1A with a K d of 1×10 −9 M or less. 192. The antibody or antigen-binding fragment of embodiment 191, provided that the K d is measured using a method selected from a standard ELISA assay and SPR. 193. The antibody or antigen-binding fragment of any of embodiments 119-192, provided that the antibody or antigen-binding fragment inhibits binding of DR3 to human TL1A. 194. The antibody or antigen-binding fragment of any of embodiments 119-193, provided that the antibody or antigen-binding fragment inhibits binding of DcR3 to human TL1A. 195. The antibody or antigen-binding fragment of any of embodiments 119-194, provided that the antibody or antigen-binding fragment is a humanized antibody, a CDR-grafted antibody, a chimeric antibody, a Fab, a ScFv, or a combination thereof 196. The antibody or antigen-binding fragment of any of embodiments 119-195, comprising a human CH1 domain. 197. The antibody or antigen-binding fragment of any of embodiments 119-196, comprising a human CH2 domain. 198. The antibody or antigen-binding fragment of embodiment 197, provided that that CH2 domain comprises at least one mutation selected from L234A, L235A, and G237A, as numbered using Kabat. 199. The antibody or antigen-binding fragment of any of embodiments 119-198, comprising a human CH3 domain. 200. A pharmaceutical composition comprising a therapeutically effective amount of the antibody or antigen-binding fragment of any of embodiments 119-199, and a pharmaceutically acceptable carrier. 201. A method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody or antigen-binding fragment of any of embodiments 119-199. 202. The method of embodiment 201, provided that the inflammatory disease is inflammatory bowel disease. 203. The method of embodiment 202, provided that the inflammatory bowel disease comprises Crohn's disease. 204. The method of embodiment 203, provided that the subject has been determined to be non-responsive to anti-TNF alpha therapy. 205. The method of embodiment 203 or embodiment 204, provided that the subject has been determined to comprise a disease phenotype comprising non-stricturing/non-penetrating, stricturing, stricturing and penetrating, or isolated internal penetrating. 206. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

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a heavy chain variable region comprising four heavy chain framework regions (HFR1, HFR2, HFR3, and HFR4) comprising SEQ ID NOS: 100108, 100101, 100109, and 100103, respectively, and three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) comprising:

a light chain variable region comprising four light chain framework regions (LFR1, LFR2, LFR3, and LFR4) comprising SEQ ID NOS: 100104, 100105, 100110, and 100107, respectively, and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) comprising:

207. The antibody or antigen-binding fragment of embodiment 206, provided that the HCDR1 comprises SEQ ID NO: 1009. 208. The antibody or antigen-binding fragment of embodiment 206, provided that the HCDR1 comprises SEQ ID NO: 100150. 209. The antibody or antigen-binding fragment of embodiment 208, provided that X 1 is E. 210. The antibody or antigen-binding fragment of embodiment 208 or embodiment 209, provided that X 2 is selected from P and V. 211. The antibody or antigen-binding fragment of any of embodiments 208-210, provided that X 3 is selected from G, S, and V. 212. The antibody or antigen-binding fragment of any of embodiments 208-211, provided that X 4 is F. 213. The antibody or antigen-binding fragment of any of embodiments 208-212, provided that X 5 is I. 214. The antibody or antigen-binding fragment of embodiment 206, provided that the HCDR1 comprises an amino acid sequence selected from SEQ ID NOS: 100200-100295. 215. The antibody or antigen-binding fragment of any of embodiments 206-214, provided that the HCDR2 comprises SEQ ID NO: 10012. 216. The antibody or antigen-binding fragment of any of embodiments 206-214, provided that the HCDR2 comprises an amino acid sequence that differs from SEQ ID NO: 10012 by up to five, four, three, or two amino acids. 217. The antibody or antigen-binding fragment of any of embodiments 206-216, provided that the HCDR3 comprises SEQ ID NO: 10015. 218. The antibody or antigen-binding fragment of any of embodiments 206-216, provided that the HCDR3 comprises SEQ ID NO: 100152. 219. The antibody or antigen-binding fragment of embodiment 218, provided that X 1 is M. 220. The antibody or antigen-binding fragment of embodiment 218 or embodiment 219, provided that X 2 is selected from E, I, K, L, M, Q, T, W, and Y. 221. The antibody or antigen-binding fragment of any of embodiments 206-220, provided that the HCDR3 comprises a sequence selected from SEQ ID NOS: 100296-100314. 222. The antibody or antigen-binding fragment of any of embodiments 206-221, provided that the LCDR1 comprises SEQ ID NO: 10018. 223. The antibody or antigen-binding fragment of any of embodiments 206-221, provided that the LCDR1 comprises an amino acid sequence that differs from SEQ ID NO: 10018 by up to five, four, three, or two amino acids. 224. The antibody or antigen-binding fragment of any of embodiments 206-223, provided that the LCDR2 comprises SEQ ID NO: 10021. 225. The antibody or antigen-binding fragment of any of embodiments 206-223, provided that the LCDR2 comprises an amino acid sequence that differs from SEQ ID NO: 10021 by up to five, four, three, or two amino acids. 226. The antibody or antigen-binding fragment of any of embodiments 206-225, provided that the LCDR3 comprises SEQ ID NO: 10024. 227. The antibody or antigen-binding fragment of any of embodiments 206-225, provided that the LCDR3 comprises SEQ ID NO: 100155. 228. The antibody or antigen-binding fragment of embodiment 227, provided that X 1 is N. 229. The antibody or antigen-binding fragment of embodiment 227 or embodiment 228, provided that X 2 is selected from D, E, H, N, and Q. 230. The antibody or antigen-binding fragment of any of embodiments 227-229, provided that X 3 is A. 231. The antibody or antigen-binding fragment of any of embodiments 227-230, provided that X 4 is selected from D, F, K, R, S, and T. 232. The antibody or antigen-binding fragment of any of embodiments 227-231, provided that the LCDR3 comprises an amino acid sequence selected from SEQ ID NOS: 100315-100482. 233. The antibody or antigen-binding fragment of embodiment 206, provided that the HCDR1 comprises SEQ ID NO: 1009, the HCDR2 comprises SEQ ID NO: 10012, the HCDR3 comprises SEQ ID NO: 10015, the LCDR1 comprises SEQ ID NO: 10018, the LCDR2 comprises SEQ ID NO: 10021, and the LCDR3 comprises SEQ ID NO: 10024. 234. The antibody or antigen-binding fragment of embodiment 206, provided that the HCDR1 comprises SEQ ID NO: 100150, the HCDR2 comprises SEQ ID NO: 10012, the HCDR3 comprises SEQ ID NO: 100152, the LCDR1 comprises SEQ ID NO: 10018, the LCDR2 comprises SEQ ID NO: 10021, and the LCDR3 comprises SEQ ID NO: 100155. 235. The antibody or antigen-binding fragment of embodiment 206 or embodiment 234, provided that the X 1 of SEQ ID NO: 100150 is D. 236. The antibody or antigen-binding fragment of embodiment 206 or embodiment 234 provided that the X 1 of SEQ ID NO: 100150 is E. 237. The antibody or antigen-binding fragment of any of embodiments 206, 234-236, provided that the X 2 of SEQ ID NO: 100150 is I. 238. The antibody or antigen-binding fragment of any of embodiments 206, 234-236, provided that the X 2 of SEQ ID NO: 100150 is P. 239. The antibody or antigen-binding fragment of any of embodiments 206, 234-236, provided that the X 2 of SEQ ID NO: 100150 is V. 240. The antibody or antigen-binding fragment of any of embodiments 206, 234-239, provided that the X 3 of SEQ ID NO: 100150 is G. 241. The antibody or antigen-binding fragment of any of embodiments 206, 234-239, provided that the X 3 of SEQ ID NO: 100150 is Q. 242. The antibody or antigen-binding fragment of any of embodiments 206, 234-239, provided that the X 3 of SEQ ID NO: 100150 is S. 243. The antibody or antigen-binding fragment of any of embodiments 206, 234-239, provided that the X 3 of SEQ ID NO: 100150 is V. 244. The antibody or antigen-binding fragment of any of embodiments 206, 234-243, provided that the X 4 of SEQ ID NO: 100150 is F. 245. The antibody or antigen-binding fragment of any of embodiments 206, 234-243, provided that the X 4 of SEQ ID NO: 100150 is Y. 246. The antibody or antigen-binding fragment of any of embodiments 206, 234-245, provided that the X 5 of SEQ ID NO: 100150 is I. 247. The antibody or antigen-binding fragment of any of embodiments 206, 234-245, provided that the X 5 of SEQ ID NO: 100150 is M. 248. The antibody or antigen-binding fragment of any of embodiments 206, 234-247, provided that the X 1 of SEQ ID NO: 100152 is L. 249. The antibody or antigen-binding fragment of any of embodiments 206, 234-247, provided that the X 1 of SEQ ID NO: 100152 is M. 250. The antibody or antigen-binding fragment of any of embodiments 206, 234-249, provided that the X 2 of SEQ ID NO: 100152 is E. 251. The antibody or antigen-binding fragment of any of embodiments 206, 234-249, provided that the X 2 of SEQ ID NO: 100152 is I. 252. The antibody or antigen-binding fragment of any of embodiments 206, 234-249, provided that the X 2 of SEQ ID NO: 100152 is K. 253. The antibody or antigen-binding fragment of any of embodiments 206, 234-249, provided that the X 2 of SEQ ID NO: 100152 is L. 254. The antibody or antigen-binding fragment of any of embodiments 206, 234-249, provided that the X 2 of SEQ ID NO: 100152 is M. 255. The antibody or antigen-binding fragment of any of embodiments 206, 234-249, provided that the X 2 of SEQ ID NO: 100152 is Q. 256. The antibody or antigen-binding fragment of any of embodiments 206, 234-249, provided that the X 2 of SEQ ID NO: 100152 is T. 257. The antibody or antigen-binding fragment of any of embodiments 206, 234-249, provided that the X 2 of SEQ ID NO: 100152 is V. 258. The antibody or antigen-binding fragment of any of embodiments 206, 234-249, provided that the X 2 of SEQ ID NO: 100152 is W. 259. The antibody or antigen-binding fragment of any of embodiments 206, 234-249, provided that the X 2 of SEQ ID NO: 100152 is Y. 260. The antibody or antigen-binding fragment of any of embodiments 206, 234-259, provided that the X 1 of SEQ ID NO: 100155 is Q. 261. The antibody or antigen-binding fragment of any of embodiments 206, 234-259, provided that the X 1 of SEQ ID NO: 100155 is N. 262. The antibody or antigen-binding fragment of any of embodiments 206, 234-261, provided that the X 2 of SEQ ID NO: 100155 is D. 263. The antibody or antigen-binding fragment of any of embodiments 206, 234-261, provided that the X 2 of SEQ ID NO: 100155 is E. 264. The antibody or antigen-binding fragment of any of embodiments 206, 234-261, provided that the X 2 of SEQ ID NO: 100155 is H. 265. The antibody or antigen-binding fragment of any of embodiments 206, 234-261, provided that the X 2 of SEQ ID NO: 100155 is N. 266. The antibody or antigen-binding fragment of any of embodiments 206, 234-261, provided that the X 2 of SEQ ID NO: 100155 is Q. 267. The antibody or antigen-binding fragment of any of embodiments 206, 234-261, provided that the X 2 of SEQ ID NO: 100155 is S. 268. The antibody or antigen-binding fragment of any of embodiments 206, 234-267, provided that the X 3 of SEQ ID NO: 100155 is A. 269. The antibody or antigen-binding fragment of any of embodiments 206, 234-267, provided that the X 3 of SEQ ID NO: 100155 is G. 270. The antibody or antigen-binding fragment of any of embodiments 206, 234-269, provided that the X 4 of SEQ ID NO: 100155 is D. 271. The antibody or antigen-binding fragment of any of embodiments 206, 234-269, provided that the X 4 of SEQ ID NO: 100155 is F. 272. The antibody or antigen-binding fragment of any of embodiments 206, 234-269, provided that the X 4 of SEQ ID NO: 100155 is K. 273. The antibody or antigen-binding fragment of any of embodiments 206, 234-269, provided that the X 4 of SEQ ID NO: 100155 is N. 274. The antibody or antigen-binding fragment of any of embodiments 206, 234-269, provided that the X 4 of SEQ ID NO: 100155 is R. 275. The antibody or antigen-binding fragment of any of embodiments 206, 234-269, provided that the X 4 of SEQ ID NO: 100155 is S. 276. The antibody or antigen-binding fragment of any of embodiments 206, 234-269, provided that the X 4 of SEQ ID NO: 100155 is T. 277. The antibody or antigen-binding fragment of any of embodiments 206-276, provided that the antibody or antigen-binding fragment specifically binds to human TL1A. 278. The antibody or antigen-binding fragment of embodiment 277, provided that the antibody or antigen-binding fragment specifically binds to human TL1A with a K d of 1×10 −9 M or less. 279. The antibody or antigen-binding fragment of embodiment 278, provided that the K d is measured using a method selected from a standard ELISA assay and SPR. 280. The antibody or antigen-binding fragment of any of embodiments 206-279, provided that the antibody or antigen-binding fragment inhibits binding of DR3 to human TL1A. 281. The antibody or antigen-binding fragment of any of embodiments 206-280, provided that the antibody or antigen-binding fragment inhibits binding of DcR3 to human TL1A. 282. The antibody or antigen-binding fragment of any of embodiments 206-281, provided that the antibody or antigen-binding fragment is a humanized antibody, a CDR-grafted antibody, a chimeric antibody, a Fab, a ScFv, or a combination thereof. 283. The antibody or antigen-binding fragment of any of embodiments 206-282, comprising a human CH1 domain. 284. The antibody or antigen-binding fragment of any of embodiments 206-283, comprising a human CH2 domain. 285. The antibody or antigen-binding fragment of embodiment 284, provided that that CH2 domain comprises at least one mutation selected from L234A, L235A, and G237A, as numbered using Kabat. 286. The antibody or antigen-binding fragment of any of embodiments 206-285, comprising a human CH3 domain. 287. A pharmaceutical composition comprising a therapeutically effective amount of the antibody or antigen-binding fragment of any of embodiments 206-286, and a pharmaceutically acceptable carrier. 288. A method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody or antigen-binding fragment of any of embodiments 206-287. 289. The method of embodiment 288, provided that the inflammatory disease is inflammatory bowel disease. 290. The method of embodiment 289, provided that the inflammatory bowel disease comprises Crohn's disease. 291. The method of embodiment 290, provided that the subject has been determined to be non-responsive to anti-TNF alpha therapy. 292. The method of embodiment 290 or embodiment 291, provided that the subject has been determined to comprise a disease phenotype comprising non-stricturing/non-penetrating, stricturing, stricturing and penetrating, or isolated internal penetrating. 293. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

›METHODS · 15 of 46

294. The antibody or antigen-binding fragment of embodiment 293, provided that the HCDR1 comprises SEQ ID NO: 1009. 295. The antibody or antigen-binding fragment of embodiment 293, provided that the HCDR1 comprises SEQ ID NO: 100150. 296. The antibody or antigen-binding fragment of embodiment 295, provided that X 1 is E. 297. The antibody or antigen-binding fragment of embodiment 295 or embodiment 296, provided that X 2 is selected from P and V. 298. The antibody or antigen-binding fragment of any of embodiments 295-297, provided that X 3 is selected from G, S, and V. 299. The antibody or antigen-binding fragment of any of embodiments 295-298, provided that X 4 is F. 300. The antibody or antigen-binding fragment of any of embodiments 295-299, provided that X 5 is I. 301. The antibody or antigen-binding fragment of embodiment 293, provided that the HCDR1 comprises an amino acid sequence selected from SEQ ID NOS: 100200-100295. 302. The antibody or antigen-binding fragment of any of embodiments 293-301, provided that the HCDR2 comprises SEQ ID NO: 10012. 303. The antibody or antigen-binding fragment of any of embodiments 293-301 provided that the HCDR2 comprises an amino acid sequence that differs from SEQ ID NO: 10012 by up to five, four, three, or two amino acids. 304. The antibody or antigen-binding fragment of any of embodiments 293-303, provided that the HCDR3 comprises SEQ ID NO: 10015. 305. The antibody or antigen-binding fragment of any of embodiments 293-303, provided that the HCDR3 comprises SEQ ID NO: 100152. 306. The antibody or antigen-binding fragment of embodiment 305, provided that X 1 is M. 307. The antibody or antigen-binding fragment of embodiment 305 or embodiment 306, provided that X 2 is selected from E, I, K, L, M, Q, T, W, and Y. 308. The antibody or antigen-binding fragment of any of embodiments 293-303, provided that the HCDR3 comprises a sequence selected from SEQ ID NOS: 100296-100314. 309. The antibody or antigen-binding fragment of any of embodiments 293-308, provided that the LCDR1 comprises SEQ ID NO: 10018. 310. The antibody or antigen-binding fragment of any of embodiments 293-308, provided that the LCDR1 comprises an amino acid sequence that differs from SEQ ID NO: 10018 by up to five, four, three, or two amino acids. 311. The antibody or antigen-binding fragment of any of embodiments 293-310, provided that the LCDR2 comprises SEQ ID NO: 10021. 312. The antibody or antigen-binding fragment of any of embodiments 293-310, provided that the LCDR2 comprises an amino acid sequence that differs from SEQ ID NO: 10021 by up to five, four, three, or two amino acids. 313. The antibody or antigen-binding fragment of any of embodiments 293-312, provided that the LCDR3 comprises SEQ ID NO: 10024. 314. The antibody or antigen-binding fragment of any of embodiments 293-312, provided that the LCDR3 comprises SEQ ID NO: 100155. 315. The antibody or antigen-binding fragment of embodiment 314, provided that X 1 is N. 316. The antibody or antigen-binding fragment of embodiment 314 or embodiment 315, provided that X 2 is selected from D, E, H, N, and Q. 317. The antibody or antigen-binding fragment of any of embodiments 314-316, provided that X 3 is A. 318. The antibody or antigen-binding fragment of any of embodiments 314-317, provided that X 4 is selected from D, F, K, R, S, and T. 319. The antibody or antigen-binding fragment of any of embodiments 314-312, provided that the LCDR3 comprises an amino acid sequence selected from SEQ ID NOS: 100315-100482. 320. The antibody or antigen-binding fragment of embodiment 293, provided that the HCDR1 comprises SEQ ID NO: 1009, the HCDR2 comprises SEQ ID NO: 10012, the HCDR3 comprises SEQ ID NO: 10015, the LCDR1 comprises SEQ ID NO: 10018, the LCDR2 comprises SEQ ID NO: 10021, and the LCDR3 comprises SEQ ID NO: 10024. 321. The antibody or antigen-binding fragment of embodiment 293, provided that the HCDR1 comprises SEQ ID NO: 100150, the HCDR2 comprises SEQ ID NO: 10012, the HCDR3 comprises SEQ ID NO: 100152, the LCDR1 comprises SEQ ID NO: 10018, the LCDR2 comprises SEQ ID NO: 10021, and the LCDR3 comprises SEQ ID NO: 100155. 322. The antibody or antigen-binding fragment of embodiment 293 or embodiment 321, provided that the X 1 of SEQ ID NO: 100150 is D. 323. The antibody or antigen-binding fragment of embodiment 293 or embodiment 321 provided that the X 1 of SEQ ID NO: 100150 is E. 324. The antibody or antigen-binding fragment of any of embodiments 293, 321-323, provided that the X 2 of SEQ ID NO: 100150 is I. 325. The antibody or antigen-binding fragment of any of embodiments 293, 321-323, provided that the X 2 of SEQ ID NO: 100150 is P. 326. The antibody or antigen-binding fragment of any of embodiments 293, 321-323, provided that the X 2 of SEQ ID NO: 100150 is V. 327. The antibody or antigen-binding fragment of any of embodiments 293, 321-326, provided that the X 3 of SEQ ID NO: 100150 is G. 328. The antibody or antigen-binding fragment of any of embodiments 293, 321-326, provided that the X 3 of SEQ ID NO: 100150 is Q. 329. The antibody or antigen-binding fragment of any of embodiments 293, 321-326, provided that the X 3 of SEQ ID NO: 100150 is S. 330. The antibody or antigen-binding fragment of any of embodiments 293, 321-326, provided that the X 3 of SEQ ID NO: 100150 is V. 331. The antibody or antigen-binding fragment of any of embodiments 293, 321-330, provided that the X 4 of SEQ ID NO: 100150 is F. 332. The antibody or antigen-binding fragment of any of embodiments 293, 321-330, provided that the X 4 of SEQ ID NO: 100150 is Y. 333. The antibody or antigen-binding fragment of any of embodiments 293, 321-332, provided that the X 5 of SEQ ID NO: 100150 is I. 334. The antibody or antigen-binding fragment of any of embodiments 293, 321-332, provided that the X 5 of SEQ ID NO: 100150 is M. 335. The antibody or antigen-binding fragment of any of embodiments 293, 321-334, provided that the X 1 of SEQ ID NO: 100152 is L. 336. The antibody or antigen-binding fragment of any of embodiments 293, 321-334, provided that the X 1 of SEQ ID NO: 100152 is M. 337. The antibody or antigen-binding fragment of any of embodiments 293, 321-336, provided that the X 2 of SEQ ID NO: 100152 is E. 338. The antibody or antigen-binding fragment of any of embodiments 293, 321-336, provided that the X 2 of SEQ ID NO: 100152 is I. 339. The antibody or antigen-binding fragment of any of embodiments 293, 321-336, provided that the X 2 of SEQ ID NO: 100152 is K. 340. The antibody or antigen-binding fragment of any of embodiments 293, 321-336, provided that the X 2 of SEQ ID NO: 100152 is L. 341. The antibody or antigen-binding fragment of any of embodiments 293, 321-336, provided that the X 2 of SEQ ID NO: 100152 is M. 342. The antibody or antigen-binding fragment of any of embodiments 293, 321-336, provided that the X 2 of SEQ ID NO: 100152 is Q. 343. The antibody or antigen-binding fragment of any of embodiments 293, 321-336, provided that the X 2 of SEQ ID NO: 100152 is T. 344. The antibody or antigen-binding fragment of any of embodiments 293, 321-336, provided that the X 2 of SEQ ID NO: 100152 is V. 345. The antibody or antigen-binding fragment of any of embodiments 293, 321-336, provided that the X 2 of SEQ ID NO: 100152 is W. 346. The antibody or antigen-binding fragment of any of embodiments 293, 321-336, provided that the X 2 of SEQ ID NO: 100152 is Y. 347. The antibody or antigen-binding fragment of any of embodiments 293, 321-346, provided that the X 1 of SEQ ID NO: 100155 is Q. 348. The antibody or antigen-binding fragment of any of embodiments 293, 321-346, provided that the X 1 of SEQ ID NO: 100155 is N. 349. The antibody or antigen-binding fragment of any of embodiments 293, 321-348, provided that the X 2 of SEQ ID NO: 100155 is D. 350. The antibody or antigen-binding fragment of any of embodiments 293, 321-348, provided that the X 2 of SEQ ID NO: 100155 is E. 351. The antibody or antigen-binding fragment of any of embodiments 293, 321-348, provided that the X 2 of SEQ ID NO: 100155 is H. 352. The antibody or antigen-binding fragment of any of embodiments 293, 321-348, provided that the X 2 of SEQ ID NO: 100155 is N. 353. The antibody or antigen-binding fragment of any of embodiments 293, 321-348, provided that the X 2 of SEQ ID NO: 100155 is Q. 354. The antibody or antigen-binding fragment of any of embodiments 293, 321-348, provided that the X 2 of SEQ ID NO: 100155 is S. 355. The antibody or antigen-binding fragment of any of embodiments 293, 321-354, provided that the X 3 of SEQ ID NO: 100155 is A. 356. The antibody or antigen-binding fragment of any of embodiments 293, 321-354, provided that the X 3 of SEQ ID NO: 100155 is G. 357. The antibody or antigen-binding fragment of any of embodiments 293, 321-356, provided that the X 4 of SEQ ID NO: 100155 is D. 358. The antibody or antigen-binding fragment of any of embodiments 293, 321-356, provided that the X 4 of SEQ ID NO: 100155 is F. 359. The antibody or antigen-binding fragment of any of embodiments 293, 321-356, provided that the X 4 of SEQ ID NO: 100155 is K. 360. The antibody or antigen-binding fragment of any of embodiments 293, 321-356, provided that the X 4 of SEQ ID NO: 100155 is N. 361. The antibody or antigen-binding fragment of any of embodiments 293, 321-356, provided that the X 4 of SEQ ID NO: 100155 is R. 362. The antibody or antigen-binding fragment of any of embodiments 293, 321-356, provided that the X 4 of SEQ ID NO: 100155 is S. 363. The antibody or antigen-binding fragment of any of embodiments 293, 321-356, provided that the X 4 of SEQ ID NO: 100155 is T. 364. The antibody or antigen-binding fragment of any of embodiments 293-363, provided that the antibody or antigen-binding fragment specifically binds to human TL1A. 365. The antibody or antigen-binding fragment of embodiment 364, provided that the antibody or antigen-binding fragment specifically binds to human TL1A with a K d of 1×10 −9 M or less. 366. The antibody or antigen-binding fragment of embodiment 365, provided that the K d is measured using a method selected from a standard ELISA assay and SPR. 367. The antibody or antigen-binding fragment of any of embodiments 293-366, provided that the antibody or antigen-binding fragment inhibits binding of DR3 to human TL1A. 368. The antibody or antigen-binding fragment of any of embodiments 293-367, provided that the antibody or antigen-binding fragment inhibits binding of DcR3 to human TL1A. 369. The antibody or antigen-binding fragment of any of embodiments 293-368, provided that the antibody or antigen-binding fragment is a humanized antibody, a CDR-grafted antibody, a chimeric antibody, a Fab, a ScFv, or a combination thereof 370. The antibody or antigen-binding fragment of any of embodiments 293-369, comprising a human CH1 domain. 371. The antibody or antigen-binding fragment of any of embodiments 293-370, comprising a human CH2 domain. 372. The antibody or antigen-binding fragment of embodiment 371, provided that that CH2 domain comprises at least one mutation selected from L234A, L235A, and G237A, as numbered using Kabat. 373. The antibody or antigen-binding fragment of any of embodiments 293-372, comprising a human CH3 domain. 374. A pharmaceutical composition comprising a therapeutically effective amount of the antibody or antigen-binding fragment of any of embodiments 293-373, and a pharmaceutically acceptable carrier. 375. A method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody or antigen-binding fragment of any of embodiments 293-373. 376. The method of embodiment 375, provided that the inflammatory disease is inflammatory bowel disease. 377. The method of embodiment 376, provided that the inflammatory bowel disease comprises Crohn's disease. 378. The method of embodiment 377, provided that the subject has been determined to be non-responsive to anti-TNF alpha therapy. 379. The method of embodiment 377 or embodiment 378, provided that the subject has been determined to comprise a disease phenotype comprising non-stricturing/non-penetrating, stricturing, stricturing and penetrating, or isolated internal penetrating. 380. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

›METHODS · 16 of 46

a heavy chain variable region comprising three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) comprising

a light chain variable region comprising three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) comprising:

381. The antibody or antigen-binding fragment of embodiment 380, provided that the HCDR1 comprises SEQ ID NO: 100150, the HCDR2 comprises SEQ ID NO: 10012, the HCDR3 comprises SEQ ID NO: 100152, the LCDR1 comprises SEQ ID NO: 10018, the LCDR2 comprises SEQ ID NO: 10021, and the LCDR3 comprises SEQ ID NO: 100155. 382. The antibody or antigen-binding fragment of embodiment 380 or embodiment 381, provided that the X 1 of SEQ ID NO: 100150 is D. 383. The antibody or antigen-binding fragment of embodiment 380 or embodiment 381 provided that the X 1 of SEQ ID NO: 100150 is E. 384. The antibody or antigen-binding fragment of any of embodiments 380-383, provided that the X 2 of SEQ ID NO: 100150 is I. 385. The antibody or antigen-binding fragment of any of embodiments 380-383, provided that the X 2 of SEQ ID NO: 100150 is P. 386. The antibody or antigen-binding fragment of any of embodiments 380-383, provided that the X 2 of SEQ ID NO: 100150 is V. 387. The antibody or antigen-binding fragment of any of embodiments 380-386, provided that the X 3 of SEQ ID NO: 100150 is G. 388. The antibody or antigen-binding fragment of any of embodiments 380-386, provided that the X 3 of SEQ ID NO: 100150 is Q. 389. The antibody or antigen-binding fragment of any of embodiments 380-386, provided that the X 3 of SEQ ID NO: 100150 is S. 390. The antibody or antigen-binding fragment of any of embodiments 380-386, provided that the X 3 of SEQ ID NO: 100150 is V. 391. The antibody or antigen-binding fragment of any of embodiments 380-390, provided that the X 4 of SEQ ID NO: 100150 is F. 392. The antibody or antigen-binding fragment of any of embodiments 380-390, provided that the X 4 of SEQ ID NO: 100150 is Y. 393. The antibody or antigen-binding fragment of any of embodiments 380-392, provided that the X 5 of SEQ ID NO: 100150 is I. 394. The antibody or antigen-binding fragment of any of embodiments 380-392, provided that the X 5 of SEQ ID NO: 100150 is M. 395. The antibody or antigen-binding fragment of any of embodiments 380-394, provided that the X 1 of SEQ ID NO: 100152 is L. 396. The antibody or antigen-binding fragment of any of embodiments 380-394, provided that the X 1 of SEQ ID NO: 100152 is M. 397. The antibody or antigen-binding fragment of any of embodiments 380-396, provided that the X 2 of SEQ ID NO: 100152 is E. 398. The antibody or antigen-binding fragment of any of embodiments 380-396, provided that the X 2 of SEQ ID NO: 100152 is I. 399. The antibody or antigen-binding fragment of any of embodiments 380-396, provided that the X 2 of SEQ ID NO: 100152 is K. 400. The antibody or antigen-binding fragment of any of embodiments 380-396, provided that the X 2 of SEQ ID NO: 100152 is L. 401. The antibody or antigen-binding fragment of any of embodiments 380-396, provided that the X 2 of SEQ ID NO: 100152 is M. 402. The antibody or antigen-binding fragment of any of embodiments 380-396, provided that the X 2 of SEQ ID NO: 100152 is Q. 403. The antibody or antigen-binding fragment of any of embodiments 380-396, provided that the X 2 of SEQ ID NO: 100152 is T. 404. The antibody or antigen-binding fragment of any of embodiments 380-396, provided that the X 2 of SEQ ID NO: 100152 is V. 405. The antibody or antigen-binding fragment of any of embodiments 380-396, provided that the X 2 of SEQ ID NO: 100152 is W. 406. The antibody or antigen-binding fragment of any of embodiments 380-396, provided that the X 2 of SEQ ID NO: 100152 is Y. 407. The antibody or antigen-binding fragment of any of embodiments 380-406, provided that the X 1 of SEQ ID NO: 100155 is Q. 408. The antibody or antigen-binding fragment of any of embodiments 380-406, provided that the X 1 of SEQ ID NO: 100155 is N. 409. The antibody or antigen-binding fragment of any of embodiments 380-408, provided that the X 2 of SEQ ID NO: 100155 is D. 410. The antibody or antigen-binding fragment of any of embodiments 380-408, provided that the X 2 of SEQ ID NO: 100155 is E. 411. The antibody or antigen-binding fragment of any of embodiments 380-408, provided that the X 2 of SEQ ID NO: 100155 is H. 412. The antibody or antigen-binding fragment of any of embodiments 380-408, provided that the X 2 of SEQ ID NO: 100155 is N. 413. The antibody or antigen-binding fragment of any of embodiments 380-408, provided that the X 2 of SEQ ID NO: 100155 is Q. 414. The antibody or antigen-binding fragment of any of embodiments 380-408, provided that the X 2 of SEQ ID NO: 100155 is S. 415. The antibody or antigen-binding fragment of any of embodiments 380-414, provided that the X 3 of SEQ ID NO: 100155 is A. 416. The antibody or antigen-binding fragment of any of embodiments 380-414, provided that the X 3 of SEQ ID NO: 100155 is G. 417. The antibody or antigen-binding fragment of any of embodiments 380-416, provided that the X 4 of SEQ ID NO: 100155 is D. 418. The antibody or antigen-binding fragment of any of embodiments 380-416, provided that the X 4 of SEQ ID NO: 100155 is F. 419. The antibody or antigen-binding fragment of any of embodiments 380-416, provided that the X 4 of SEQ ID NO: 100155 is K. 420. The antibody or antigen-binding fragment of any of embodiments 380-416, provided that the X 4 of SEQ ID NO: 100155 is N. 421. The antibody or antigen-binding fragment of any of embodiments 380-416, provided that the X 4 of SEQ ID NO: 100155 is R. 422. The antibody or antigen-binding fragment of any of embodiments 380-416, provided that the X 4 of SEQ ID NO: 100155 is S. 423. The antibody or antigen-binding fragment of any of embodiments 380-416, provided that the X 4 of SEQ ID NO: 100155 is T. 424. The antibody or antigen-binding fragment of any of embodiments 380-423, provided that the antibody or antigen-binding fragment specifically binds to human TL1A. 425. The antibody or antigen-binding fragment of embodiment 424, provided that the antibody or antigen-binding fragment specifically binds to human TL1A with a K d of 1×10 −9 M or less. 426. The antibody or antigen-binding fragment of embodiment 425, provided that the K d is measured using a method selected from a standard ELISA assay and SPR. 427. The antibody or antigen-binding fragment of any of embodiments 380-426, provided that the antibody or antigen-binding fragment inhibits binding of DR3 to human TL1A. 428. The antibody or antigen-binding fragment of any of embodiments 380-427, provided that the antibody or antigen-binding fragment inhibits binding of DcR3 to human TL1A. 429. The antibody or antigen-binding fragment of any of embodiments 380-428, provided that the antibody or antigen-binding fragment is a humanized antibody, a CDR-grafted antibody, a chimeric antibody, a Fab, a ScFv, or a combination thereof 430. The antibody or antigen-binding fragment of any of embodiments 380-429, comprising a human CH1 domain. 431. The antibody or antigen-binding fragment of any of embodiments 380-430, comprising a human CH2 domain. 432. The antibody or antigen-binding fragment of embodiment 431, provided that that CH2 domain comprises at least one mutation selected from L234A, L235A, and G237A, as numbered using Kabat. 433. The antibody or antigen-binding fragment of any of embodiments 380-432, comprising a human CH3 domain. 434. A pharmaceutical composition comprising a therapeutically effective amount of the antibody or antigen-binding fragment of any of embodiments 380-433, and a pharmaceutically acceptable carrier. 435. A method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody or antigen-binding fragment of any of embodiments 380-433. 436. The method of embodiment 435, provided that the inflammatory disease is inflammatory bowel disease. 437. The method of embodiment 436, provided that the inflammatory bowel disease comprises Crohn's disease. 438. The method of embodiment 437, provided that the subject has been determined to be non-responsive to anti-TNF alpha therapy. 439. The method of embodiment 437 or embodiment 438, provided that the subject has been determined to comprise a disease phenotype comprising non-stricturing/non-penetrating, stricturing, stricturing and penetrating, or isolated internal penetrating. 440. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising: a heavy chain variable region comprising SEQ ID NO: 10052 or SEQ ID NO: 10054, and a light chain variable region comprising SEQ ID NO: 10053. 441. The antibody or antigen-binding fragment of embodiment 440, provided that the heavy chain variable region comprises SEQ ID NO: 10052. 442. The antibody or antigen-binding fragment of embodiment 440, provided that the heavy chain variable region comprises SEQ ID NO: 10054. 443. The antibody or antigen-binding fragment of any of embodiments 440-442, provided that the X 1 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is D. 444. The antibody or antigen-binding fragment of any of embodiments 440-442 provided that the X 1 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is E. 445. The antibody or antigen-binding fragment of any of embodiments 440-444, provided that the X 2 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is I. 446. The antibody or antigen-binding fragment of any of embodiments 440-444, provided that the X 2 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is P. 447. The antibody or antigen-binding fragment of any of embodiments 440-444, provided that the X 2 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is V. 448. The antibody or antigen-binding fragment of any of embodiments 440-447, provided that the X 3 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is G. 449. The antibody or antigen-binding fragment of any of embodiments 440-447, provided that the X 3 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is Q. 450. The antibody or antigen-binding fragment of any of embodiments 440-447, provided that the X 3 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is S. 451. The antibody or antigen-binding fragment of any of embodiments 440-447, provided that the X 3 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is V. 452. The antibody or antigen-binding fragment of any of embodiments 440-451, provided that the X 4 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is F. 453. The antibody or antigen-binding fragment of any of embodiments 440-451, provided that the X 4 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is Y. 454. The antibody or antigen-binding fragment of any of embodiments 440-453, provided that the X 5 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is I. 455. The antibody or antigen-binding fragment of any of embodiments 440-453, provided that the X 5 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is M. 456. The antibody or antigen-binding fragment of any of embodiments 440-455, provided that the X 6 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is L. 457. The antibody or antigen-binding fragment of any of embodiments 440-455, provided that the X 6 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is M. 458. The antibody or antigen-binding fragment of any of embodiments 440-457, provided that the X 7 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is E. 459. The antibody or antigen-binding fragment of any of embodiments 440-457, provided that the X 7 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is I. 460. The antibody or antigen-binding fragment of any of embodiments 440-457, provided that the X 7 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is K. 461. The antibody or antigen-binding fragment of any of embodiments 440-457, provided that the X 7 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is L. 462. The antibody or antigen-binding fragment of any of embodiments 440-457, provided that the X 7 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is M. 463. The antibody or antigen-binding fragment of any of embodiments 440-457, provided that the X 7 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is Q. 464. The antibody or antigen-binding fragment of any of embodiments 440-457, provided that the X 7 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is T. 465. The antibody or antigen-binding fragment of any of embodiments 440-457, provided that the X 7 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is V. 466. The antibody or antigen-binding fragment of any of embodiments 440-457, provided that the X 7 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is W. 467. The antibody or antigen-binding fragment of any of embodiments 440-457, provided that the X 7 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is Y. 468. The antibody or antigen-binding fragment of any of embodiments 440-467, provided that the X 1 of SEQ ID NO: 10053 is Q. 469. The antibody or antigen-binding fragment of any of embodiments 440-467, provided that the X 1 of SEQ ID NO: 10053 is N. 470. The antibody or antigen-binding fragment of any of embodiments 440-469, provided that the X 2 of SEQ ID NO: 10053 is D. 471. The antibody or antigen-binding fragment of any of embodiments 440-469, provided that the X 2 of SEQ ID NO: 10053 is E. 472. The antibody or antigen-binding fragment of any of embodiments 440-469, provided that the X 2 of SEQ ID NO: 10053 is H. 473. The antibody or antigen-binding fragment of any of embodiments 440-469, provided that the X 2 of SEQ ID NO: 10053 is N. 474. The antibody or antigen-binding fragment of any of embodiments 440-469, provided that the X 2 of SEQ ID NO: 10053 is Q. 475. The antibody or antigen-binding fragment of any of embodiments 440-469, provided that the X 2 of SEQ ID NO: 10053 is S. 476. The antibody or antigen-binding fragment of any of embodiments 440-475, provided that the X 3 of SEQ ID NO: 10053 is A. 477. The antibody or antigen-binding fragment of any of embodiments 440-475, provided that the X 3 of SEQ ID NO: 10053 is G. 478. The antibody or antigen-binding fragment of any of embodiments 440-477, provided that the X 4 of SEQ ID NO: 10053 is D. 479. The antibody or antigen-binding fragment of any of embodiments 440-477, provided that the X 4 of SEQ ID NO: 10053 is F. 480. The antibody or antigen-binding fragment of any of embodiments 440-477, provided that the X 4 of SEQ ID NO: 10053 is K. 481. The antibody or antigen-binding fragment of any of embodiments 440-477, provided that the X 4 of SEQ ID NO: 10053 is N. 482. The antibody or antigen-binding fragment of any of embodiments 440-477, provided that the X 4 of SEQ ID NO: 10053 is R. 483. The antibody or antigen-binding fragment of any of embodiments 440-477, provided that the X 4 of SEQ ID NO: 10053 is S. 484. The antibody or antigen-binding fragment of any of embodiments 440-477, provided that the X 4 of SEQ ID NO: 10053 is T. 485. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising: a heavy chain variable region of SEQ ID NO: 10036, and a light chain variable region of SEQ ID NO: 10038. 486. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising: a heavy chain variable region of SEQ ID NO: 10040, and a light chain variable region of SEQ ID NO: 10042. 487. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising: a heavy chain variable region of SEQ ID NO: 10040, and a light chain variable region of SEQ ID NO: 10038. 488. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising: a heavy chain variable region of SEQ ID NO: 10044, and a light chain variable region of SEQ ID NO: 10038. 489. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising: a heavy chain variable region of SEQ ID NO: 10043, and a light chain variable region of SEQ ID NO: 10038. 490. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising: a heavy chain variable region of SEQ ID NO: 10045, and a light chain variable region of SEQ ID NO: 10038. 491. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising: a heavy chain variable region of SEQ ID NO: 10046, and a light chain variable region of SEQ ID NO: 10038. 492. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising: a heavy chain variable region of SEQ ID NO: 10040, and a light chain variable region of SEQ ID NO: 10047. 493. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising: a heavy chain variable region of SEQ ID NO: 10040, and a light chain variable region of SEQ ID NO: 10048. 494. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising: a heavy chain variable region of SEQ ID NO: 10040, and a light chain variable region of SEQ ID NO: 10049. 495. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising: a heavy chain variable region of SEQ ID NO: 10040, and a light chain variable region of SEQ ID NO: 10050. 496. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising: a heavy chain variable region of SEQ ID NO: 10040, and a light chain variable region of SEQ ID NO: 10051. 497. The antibody or antigen-binding fragment of any of embodiments 440-496, provided that the antibody or antigen-binding fragment specifically binds to human TL1A. 498. The antibody or antigen-binding fragment of embodiment 497, provided that the antibody or antigen-binding fragment specifically binds to human TL1A with a K d of 1×10 −9 M or less. 499. The antibody or antigen-binding fragment of embodiment 498, provided that the K d is measured using a method selected from a standard ELISA assay and SPR. 500. The antibody or antigen-binding fragment of any of embodiments 440-499, provided that the antibody or antigen-binding fragment inhibits binding of DR3 to human TL1A. 501. The antibody or antigen-binding fragment of any of embodiments 440-500, provided that the antibody or antigen-binding fragment inhibits binding of DcR3 to human TL1A. 502. The antibody or antigen-binding fragment of any of embodiments 440-501, provided that the antibody or antigen-binding fragment is a humanized antibody, a CDR-grafted antibody, a chimeric antibody, a Fab, a ScFv, or a combination thereof 503. The antibody or antigen-binding fragment of any of embodiments 440-502, comprising a human CH1 domain. 504. The antibody or antigen-binding fragment of any of embodiments 440-503, comprising a human CH2 domain. 505. The antibody or antigen-binding fragment of embodiment 504, provided that that CH2 domain comprises at least one mutation selected from L234A, L235A, and G237A, as numbered using Kabat. 506. The antibody or antigen-binding fragment of any of embodiments 440-505, comprising a human CH3 domain. 507. A pharmaceutical composition comprising a therapeutically effective amount of the antibody or antigen-binding fragment of any of embodiments 440-506, and a pharmaceutically acceptable carrier. 508. A method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody or antigen-binding fragment of any of embodiments 440-506. 509. The method of embodiment 508, provided that the inflammatory disease is inflammatory bowel disease. 510. The method of embodiment 509, provided that the inflammatory bowel disease comprises Crohn's disease. 511. The method of embodiment 510, provided that the subject has been determined to be non-responsive to anti-TNF alpha therapy. 512. The method of embodiment 510 or embodiment 511, provided that the subject has been determined to comprise a disease phenotype comprising non-stricturing/non-penetrating, stricturing, stricturing and penetrating, or isolated internal penetrating. 513. An antibody or antigen binding fragment that binds to the same region of human TL1A as a reference antibody of any of embodiments 1-112, 119-199, 206-286, 293-373, 380-433, and 440-506. 514. An antibody or antigen binding fragment that binds to the same region of human TL1A as a reference antibody comprising a heavy chain variable region of SEQ ID NO: 10036, and a light chain variable region of SEQ ID NO: 10038. 515. An antibody or antigen binding fragment that binds to the same region of human TL1A as a reference antibody comprising a heavy chain variable region of SEQ ID NO: 10040, and a light chain variable region of SEQ ID NO: 10042. 516. An antibody or antigen binding fragment that binds to the same region of human TL1A as a reference antibody comprising a heavy chain variable region of SEQ ID NO: 10040, and a light chain variable region of SEQ ID NO: 10038. 517. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

›METHODS · 17 of 46

a heavy chain variable region comprising:

(a) an HCDR1 comprising an amino acid sequence set forth by SEQ ID NO: 553; (b) an HCDR2 comprising an amino acid sequence set forth by any one of SEQ ID NOs: 554 to 564 or 574 to 577; and (c) an HCDR3 comprising an amino acid sequence set forth by any one of SEQ ID NOs: 565 to 568 or 578 to 581; and

a light chain variable region comprising:

(d) an LCDR1 comprising an amino acid sequence set forth by any one of SEQ ID NOs: 569 or 570; (e) an LCDR2 comprising an amino acid sequence set forth by SEQ ID NO: 488; and (f) an LCDR3 comprising an amino acid sequence set forth by any one of SEQ ID NOs: 571 to 573 or 582 to 585.

518. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

a heavy chain variable region comprising:

(a) an HCDR1 comprising an amino acid sequence set forth by SEQ ID NO: 553; (b) an HCDR2 comprising an amino acid sequence set forth by SEQ ID NO: 559; and (c) an HCDR3 comprising an amino acid sequence set forth by SEQ ID NO: 567; and

a light chain variable region comprising:

(d) an LCDR1 comprising an amino acid sequence set forth by SEQ ID NO: 569; (e) an LCDR2 comprising an amino acid sequence set forth by SEQ ID NO: 488; and (f) an LCDR3 comprising an amino acid sequence set forth by any one of SEQ ID NO: 573.

519. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

a heavy chain variable region comprising:

(a) an HCDR1 comprising an amino acid sequence set forth by SEQ ID NO: 553; (b) an HCDR2 comprising an amino acid sequence set forth by SEQ ID NO: 563; and (c) an HCDR3 comprising an amino acid sequence set forth by SEQ ID NO: 568; and

a light chain variable region comprising:

520. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

a heavy chain variable region comprising:

(a) an HCDR1 comprising an amino acid sequence set forth by SEQ ID NO: 553; (b) an HCDR2 comprising an amino acid sequence set forth by SEQ ID NO: 555; and (c) an HCDR3 comprising an amino acid sequence set forth by SEQ ID NO: 566; and

a light chain variable region comprising:

521. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

a heavy chain variable region comprising:

(a) an HCDR1 comprising an amino acid sequence set forth by SEQ ID NO: 553; (b) an HCDR2 comprising an amino acid sequence set forth by SEQ ID NO: 558; and (c) an HCDR3 comprising an amino acid sequence set forth by SEQ ID NO: 566; and

a light chain variable region comprising:

522. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

a heavy chain variable region comprising:

(a) an HCDR1 comprising an amino acid sequence set forth by SEQ ID NO: 553; (b) an HCDR2 comprising an amino acid sequence set forth by SEQ ID NO: 564; and (c) an HCDR3 comprising an amino acid sequence set forth by SEQ ID NO: 568; and

a light chain variable region comprising:

523. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

(a) a heavy chain variable region comprising an HCDR1, an HCDR2, and an HCDR3 from any one of SEQ ID NOs: 491, 493, 495, 497, 499, 501, 503, 505, 507, 509, 511, 513, 515, 517, 519, 521, 523, 525, 527, 529, 531, 533, 535, 537, 539, or 541; and (b) a light chain variable region comprising an LCDR1, an LCDR2, and an LCDR3 from any one of SEQ ID NOs: 490, 492, 494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, or 540;

wherein the CDRs are defined by the Kabat, Chothia, or IMGT method or a combination thereof.

524. The antibody or antigen-binding fragment of any one of embodiments 517 to 523, comprising a human heavy chain framework region 1 that is at least 90%, 95%, 96%, 97%, 98%, 99% identical to that set forth is SEQ ID NO: 545. 525. The antibody or antigen-binding fragment of any one of embodiments 517 to 524, comprising a human heavy chain framework region 2 that is at least 90%, 95%, 96%, 97%, 98%, 99% identical to that set forth is SEQ ID NO: 546. 526. The antibody or antigen-binding fragment of any one of embodiments 517 to 525, comprising a human heavy chain framework region 3 that is at least 90%, 95%, 96%, 97%, 98%, 99% identical to that set forth is SEQ ID NO: 547 or 586 to 588. 527. The antibody or antigen-binding fragment of any one of embodiments 517 to 526, comprising a human heavy chain framework region 4 that is at least 90%, 95%, 96%, 97%, 98%, 99% identical to that set forth is SEQ ID NO: 548. 528. The antibody or antigen-binding fragment of any one of embodiments 517 to 527, comprising a human light chain framework region 1 that is at least 90%, 95%, 96%, 97%, 98%, 99% identical to that set forth is SEQ ID NO: 549. 529. The antibody or antigen-binding fragment of any one of embodiments 517 to 528, comprising a human light chain framework region 2 that is at least 90%, 95%, 96%, 97%, 98%, 99% identical to that set forth is SEQ ID NO: 550. 530. The antibody or antigen-binding fragment of any one of embodiments 517 to 529, comprising a human light chain framework region 3 that is at least 90%, 95%, 96%, 97%, 98%, 99% identical to that set forth is SEQ ID NO: 551. 531. The antibody or antigen-binding fragment of any one of embodiments 517 to 530, comprising a human light chain framework region 4 that is at least 90%, 95%, 96%, 97%, 98%, 99% identical to that set forth is SEQ ID NO: 552. 532. The antibody or antigen-binding fragment of any one of embodiments 517 to 531, comprising:

›METHODS · 18 of 46

(a) a human heavy chain framework region 1 that is at least 90% identical to that set forth is SEQ ID NO: 545; (b) a human heavy chain framework region 2 that is at least 90% identical to that set forth is SEQ ID NO: 546; (c) a human heavy chain framework region 3 that is at least 90% identical to that set forth is SEQ ID NO: 547 or 586 to 588; (d) a human heavy chain framework region 4 that is at least 90% identical to that set forth is SEQ ID NO: 548; (e) a human light chain framework region 1 that is at least 90% identical to that set forth is SEQ ID NO: 549; (f) a human light chain framework region 2 that is at least 90% identical to that set forth is SEQ ID NO: 550; (g) a human light chain framework region 3 that is at least 90% identical to that set forth is SEQ ID NO: 551; and (h) a human light chain framework region 4 that is at least 90% identical to that set forth is SEQ ID NO: 552.

533. The antibody or antigen-binding fragment of embodiment 532, comprising:

(a) a human heavy chain framework region 1 that is at least 95% identical to that set forth is SEQ ID NO: 545; (b) a human heavy chain framework region 2 that is at least 95% identical to that set forth is SEQ ID NO: 546; (c) a human heavy chain framework region 3 that is at least 95% identical to that set forth is SEQ ID NO: 547 or 586 to 588; (d) a human heavy chain framework region 4 that is at least 95% identical to that set forth is SEQ ID NO: 548; (e) a human light chain framework region 1 that is at least 95% identical to that set forth is SEQ ID NO: 549; (f) a human light chain framework region 2 that is at least 95% identical to that set forth is SEQ ID NO: 550; (g) a human light chain framework region 3 that is at least 95% identical to that set forth is SEQ ID NO: 551; and (h) a human light chain framework region 4 that is at least 95% identical to that set forth is SEQ ID NO: 552.

534. The antibody or antigen-binding fragment of embodiments 532, comprising:

(a) a human heavy chain framework region 1 that is at least 97% identical to that set forth is SEQ ID NO: 545; (b) a human heavy chain framework region 2 that is at least 97% identical to that set forth is SEQ ID NO: 546; (c) a human heavy chain framework region 3 that is at least 97% identical to that set forth is SEQ ID NO: 547 or 586 to 588; (d) a human heavy chain framework region 4 that is at least 97% identical to that set forth is SEQ ID NO: 548; (e) a human light chain framework region 1 that is at least 97% identical to that set forth is SEQ ID NO: 549; (f) a human light chain framework region 2 that is at least 97% identical to that set forth is SEQ ID NO: 550; (g) a human light chain framework region 3 that is at least 97% identical to that set forth is SEQ ID NO: 551; and (h) a human light chain framework region 4 that is at least 97% identical to that set forth is SEQ ID NO: 552.

535. The antibody or antigen-binding fragment of embodiment 532, comprising:

(a) a human heavy chain framework region 1 that is at least 98% identical to that set forth is SEQ ID NO: 545; (b) a human heavy chain framework region 2 that is at least 98% identical to that set forth is SEQ ID NO: 546; (c) a human heavy chain framework region 3 that is at least 98% identical to that set forth is SEQ ID NO: 547 or 586 to 588; (d) a human heavy chain framework region 4 that is at least 98% identical to that set forth is SEQ ID NO: 548; (e) a human light chain framework region 1 that is at least 98% identical to that set forth is SEQ ID NO: 549; (f) a human light chain framework region 2 that is at least 98% identical to that set forth is SEQ ID NO: 550; (g) a human light chain framework region 3 that is at least 98% identical to that set forth is SEQ ID NO: 551; and (h) a human light chain framework region 4 that is at least 98% identical to that set forth is SEQ ID NO: 552.

536. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

(a) a heavy chain variable region comprising an amino acid sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID NOs: 491, 493, 495, 497, 499, 501, 503, 505, 507, 509, 511, 513, 515, 517, 519, 521, 523, 525, 527, 529, 531, 533, 535, 537, 539, or 541; and (b) a light chain variable region comprising an amino acid sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID NOs: 490, 492, 494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, or 540.

537. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

(a) a heavy chain variable region comprising an amino acid sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 503; and (b) a light chain variable region comprising an amino acid sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 502.

538. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

(a) a heavy chain variable region comprising an amino acid sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 511; and (b) a light chain variable region comprising an amino acid sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 510.

539. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

(a) a heavy chain variable region comprising an amino acid sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 493; and (b) a light chain variable region comprising an amino acid sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 492.

540. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

(a) a heavy chain variable region comprising an amino acid sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 501; and (b) a light chain variable region comprising an amino acid sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 500.

›METHODS · 19 of 46

541. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

(a) a heavy chain variable region comprising an amino acid sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 515; and (b) a light chain variable region comprising an amino acid sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 514.

542. The antibody or antigen-binding fragment of any one of embodiments 517 to 541, wherein the antibody or antigen-binding fragment is chimeric or humanized. 543. The antibody or antigen-binding fragment of any one of embodiments 517 to 541, wherein the antibody or antigen-binding fragment is an IgG antibody. 544. The antibody or antigen-binding fragment of any one of embodiments 517 to 541, wherein the antibody or antigen-binding fragment comprises a Fab, F(ab) 2 , a single-domain antibody, a single chain variable fragment (scFv), or a nanobody. 545. The antibody or antigen-binding fragment of any one of embodiments 517 to 544, comprising a heavy chain constant region comprising an amino acid sequence as set forth by SEQ ID NO: 542 or 543. 546. The antibody or antigen-binding fragment of any one of embodiments 517 to 544, comprising a heavy chain constant region comprising an amino acid sequence as set forth by SEQ ID NO: 542. 547. The antibody or antigen-binding fragment of any one of embodiments 517 to 544, comprising a light chain constant region comprising an amino acid sequence as set forth by SEQ ID NO: 544.

In certain embodiments, the antibody or antigen binding fragment comprises (a) a heavy chain variable region comprising an amino acid sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID NOs: 491, 493, 495, 497, 499, 501, 503, 505, 507, 509, 511, 513, 515, 517, 519, 521, 523, 525, 527, 529, 531, 533, 535, 537, 539, or 541; and (b) a light chain variable region comprising an amino acid sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID NOs: 490, 492, 494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, or 540.

Non-limiting methods for determining whether an anti-TL1A antibody binds to the same region of a reference antibody are known in the art. An exemplary method comprises a competition assay. For instance, the method comprises determining whether a reference antibody can compete with binding between the reference antibody and the TL1A protein or portion thereof, or determining whether the reference antibody can compete with binding between the reference antibody and the TL1A protein or portion thereof. Exemplary methods include use of surface plasmon resonance to evaluate whether an anti-TL1A antibody can compete with the binding between TL1A and another anti-TL1A antibody. In some cases, surface plasmon resonance is utilized in the competition assay.

Dosages and Routes of Administration

In general, methods disclosed herein comprise administering a therapeutic agent by oral administration. However, in some instances, methods comprise administering a therapeutic agent by intraperitoneal injection. In some instances, methods comprise administering a therapeutic agent in the form of an anal suppository. In some instances, methods comprise administering a therapeutic agent by intravenous (“i.v.”) administration. It is conceivable that one may also administer therapeutic agents disclosed herein by other routes, such as subcutaneous injection, intramuscular injection, intradermal injection, transdermal injection percutaneous administration, intranasal administration, intralymphatic injection, rectal administration intragastric administration, or any other suitable parenteral administration. In some embodiments, routes for local delivery closer to site of injury or inflammation are preferred over systemic routes. Routes, dosage, time points, and duration of administrating therapeutics may be adjusted. In some embodiments, administration of therapeutics is prior to, or after, onset of either, or both, acute and chronic symptoms of the disease or condition.

An effective dose and dosage of therapeutics to prevent or treat the disease or condition disclosed herein is defined by an observed beneficial response related to the disease or condition, or symptom of the disease or condition. Beneficial response comprises preventing, alleviating, arresting, or curing the disease or condition, or symptom of the disease or condition (e.g., reduced instances of diarrhea, rectal bleeding, weight loss, and size or number of intestinal lesions or strictures, reduced fibrosis or fibrogenesis, reduced fibrostenosis, reduced inflammation). In some embodiments, the beneficial response may be measured by detecting a measurable improvement in the presence, level, or activity, of biomarkers, transcriptomic risk profile, or intestinal microbiome in the subject. An “improvement,” as used herein refers to shift in the presence, level, or activity towards a presence, level, or activity, observed in normal individuals (e.g. individuals who do not suffer from the disease or condition). In instances wherein the therapeutic agent is not therapeutically effective or is not providing a sufficient alleviation of the disease or condition, or symptom of the disease or condition, then the dosage amount and/or route of administration may be changed, or an additional agent may be administered to the subject, along with the therapeutic agent. In some embodiments, as a patient is started on a regimen of a therapeutic agent, the patient is also weaned off (e.g., step-wise decrease in dose) a second treatment regimen.

Suitable dose and dosage administrated to a subject is determined by factors including, but no limited to, the particular therapeutic agent, disease condition and its severity, the identity (e.g., weight, sex, age) of the subject in need of treatment, and can be determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In one aspect, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day. Non-limiting examples of effective dosages of for oral delivery of a therapeutic agent include between about 0.1 mg/kg and about 100 mg/kg of body weight per day, and preferably between about 0.5 mg/kg and about 50 mg/kg of body weight per day. In other instances, the oral delivery dosage of effective amount is about 1 mg/kg and about 10 mg/kg of body weight per day of active material. Non-limiting examples of effective dosages for intravenous administration of the therapeutic agent include at a rate between about 0.01 to 100 pmol/kg body weight/min. In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the therapeutic agent used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

›METHODS · 20 of 46

In some embodiments, the administration of the therapeutic agent is hourly, once every 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours 22 hours, 23 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, or 5 years, or 10 years. The effective dosage ranges may be adjusted based on subject's response to the treatment. Some routes of administration will require higher concentrations of effective amount of therapeutics than other routes.

In certain embodiments wherein the patient's condition does not improve, upon the doctor's discretion the administration of therapeutic agent is administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition. In certain embodiments wherein a patient's status does improve, the dose of therapeutic agent being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%. In certain embodiments, the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug diversion”). In specific embodiments, the length of the drug diversion is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during a drug diversion is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%. After a suitable length of time, the normal dosing schedule is optionally reinstated.

In some embodiments, once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.

Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 and the ED50. The dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50. In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans. In some embodiments, the daily dosage amount of the therapeutic agent described herein lies within a range of circulating concentrations that include the ED50 with minimal toxicity. In certain embodiments, the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.

Additional Therapeutic Agent

A therapeutic agent may be used alone or in combination with an additional therapeutic agent. The therapeutic agents may be administered together or sequentially. The combination therapies may be administered within the same day, or may be administered one or more days, weeks, months, or years apart. In some cases, a therapeutic agent provided herein is administered if the subject is determined to be non-responsive to a first line of therapy, e.g., such as TNF inhibitor. Such determination may be made by treatment with the first line therapy and monitoring of disease state and/or diagnostic determination that the subject would be non-responsive to the first line therapy.

In some embodiments, the additional therapeutic agent comprises an anti-TNF therapy, e.g., an anti-TNFα therapy. In some embodiments, the additional therapeutic agent comprises a second-line treatment to an anti-TNF therapy. In some embodiments, the additional therapeutic agent comprises an immunosuppressant, or a class of drugs that suppress, or reduce, the strength of the immune system. In some embodiments, the immunosuppressant is an antibody. Non-limiting examples of immunosuppressant therapeutic agents include STELARA® (ustekinumab) azathioprine (AZA), 6-mercaptopurine ( 6 -MP), methotrexate, cyclosporin A. (CsA).

In some embodiments, the additional therapeutic agent comprises a selective anti-inflammatory drug, or a class of drugs that specifically target pro-inflammatory molecules in the body. In some embodiments, the anti-inflammatory drug comprises an antibody. In some embodiments, the anti-inflammatory drug comprises a small molecule. Non-limiting examples of anti-inflammatory drugs include vedolizumab (ENTYVIO®), corticosteroids, aminosalicylates, mesalamine, balsalazide (Colazal®) and olsalazine (Dipentum®).

In some embodiments, the additional therapeutic agent comprises a stem cell therapy. The stem cell therapy may be embryonic or somatic stem cells. The stem cells may be isolated from a donor (allogeneic) or isolated from the subject (autologous). The stem cells may be expanded adipose-derived stem cells (eASCs), hematopoietic stem cells (HSCs), mesenchymal stem (stromal) cells (MSCs), or induced pluripotent stem cells (iPSCs) derived from the cells of the subject. In some embodiments, the therapeutic agent comprises Cx601/Alofisel® (darvadstrocel).

›METHODS · 21 of 46

In some embodiments, the additional therapeutic agent comprises a small molecule. The small molecule may be used to treat inflammatory diseases or conditions, or fibrostenonic or fibrotic disease. Non-limiting examples of small molecules include Otezla® (apremilast), alicaforsen, or ozanimod (RPC-1063).

The additional therapeutic agent may comprise an antimycotic agent. In some instances, the antimycotic agent comprises an active agent that inhibits growth of a fungus. In some instances, the antimycotic agent comprises an active agent that kills a fungus. In some embodiments, the antimycotic agent comprises polyene, an azole, an echinocandin, an flucytosine, an allylamine, a tolnaftate, or griseofulvin, or a combination thereof. In other embodiments, the azole comprises triazole, imidazole, clotrimazole, ketoconazole, itraconazole, terconazole, oxiconazole, miconazole, econazole, tioconazole, voriconazole, fluconazole, isavuconazole, itraconazole, pramiconazole, ravuconazole, or posaconazole. In some other embodiments, the polyene comprises amphotericin B, nystatin, or natamycin. In yet other embodiments, the echinocandin comprises caspofungin, anidulafungin, or micafungin. In various other embodiments, the allylamine comprises naftifine or terbinafine.

The additional therapeutic agent may comprise an agonist or an antagonist of therapeutic target. Non-limiting therapeutic targets include Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4), Prostaglandin E Receptor 4 (PTGER4), Interleukin 18 Receptor 1 (IL18R1), Interleukin 18 Receptor Accessory Protein (IL18RAP), Adenylate Cyclase 7 (ADCY7), B Lymphoid Tyrosine Kinase (BLK), G Protein-Coupled Receptor 65 (GPR65), Sprouty Related EVH1 Domain Containing 2 (SPRED2), and Src Kinase Associated Phosphoprotein 2 (SKAP2). Non-limiting examples of MAP4K4 modulators include GNE-220 and PF-6260933. Non-limiting examples of PTGER4 modulators include grapiprant (CJ-023,423), ONO-AE3-208, GW627368X, AH23848, ONO-AE2-227, ONO-AE1-734, AGN205203, rivenprost (ONO-4819), CJ-023,423, and BGC20-1531. Exemplary modulators of PFKFB3 include, but are not limited to 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3P0), 1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PFK15), 5-triazolo-2-arylpyridazinone,125 1-(3-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PQP), 126 5, 6, 7, 8-tetrahydroxy-2-(4-hydroxyphenyl) chrome-4-one (N4A), and 7, 8-dihydroxy-3-(4-hydroxyphenyl) chromen-4-one (YN1). Non-limiting modulators of ADCY7 include forskolin and colforsin daropate. Non-limiting examples of GPR65 modulators include BTB09089 (3-[(2,4-dichlorophenyl)methylsulfanyl]-1,6-dimethylpyridazino[4,5-e][1,3,4]thiadiazin-5-one), and ZINC62678696.

In some embodiments, the therapeutic agent comprises an agonist of Janus Kinase 1 (JAK1). Non-limiting examples of JAK1 inhibitors include Ruxolitinib (INCB018424), S-Ruxolitinib (INCB018424), Baricitinib (LY3009104, INCB028050), Filgotinib (GLPG0634), Momelotinib (CYT387), Cerdulatinib (PRT062070, PRT2070), LY2784544, NVP-BSK805, 2HC1, Tofacitinib (CP-690550,Tasocitinib), XL019, Pacritinib (SB1518), or ZM 39923 HCl.

The therapeutic agent targeting the above genes or gene expression products may be an antibody or antigen binding fragment thereof. The therapeutic agent may be a small molecule. The therapeutic agent may be a peptide or a protein. The therapeutic agent may be an agonist, or partial agonist. The therapeutic agent may be an allosteric modulator, such as a positive allosteric modulator (PAM). The therapeutic agent may be an antagonist, or partial antagonist. The therapeutic agent may be an inverse agonist. The therapeutic agent may be a negative allosteric modulator (NAM).

Disclosed herein are additional therapeutic agents comprising modulators of Receptor Interacting Serine/Threonine Kinase 2 (RIPK2) (Entrez Gene ID: 8767) activity or expression that are useful for the treatment of an inflammatory, fibrotic, and/or fibrostenotic disease or condition. In some embodiments, the inflammatory disease comprises inflammatory bowel disease (IBD), Crohn's disease (CD), and/or ulcerative colitis (UC). In some embodiments, a modulator of RIPK2 activity or expression comprises an antagonist or a partial antagonist of RIPK2. In some embodiments, the RIPK2 antagonist or partial antagonist comprises an antibody or antigen-binding fragment, or a small molecule.

In some embodiments, the RIPK2 antagonist or partial antagonist comprises a type I RIPK2 inhibitor effective to bind to the ATP binding pocket of an active conformation of the RIPK2 kinase domain. In some embodiments, the RIPK2 antagonist or partial antagonist comprises a type I½ RIPK2 inhibitor effective to bind to the ATP binding pocket of an inactive conformation of the RIPK2 kinase domain without displacing the RIPK2 kinase activation segment. In some embodiments, the RIPK2 antagonist or partial antagonist comprises a type II RIPK2 inhibitor effective to displace a RIPK2 kinase activation segment. In some embodiments, the RIPK2 antagonist or partial antagonist comprises a type III RIPK2 inhibitor effective to bind an allosteric site of RIPK2 located in the cleft between the small and large lobes adjacent to the ATP binding pocket. In some embodiments, the RIPK2 antagonist or partial antagonist comprises a type IV RIPK2 inhibitor effective to bind an allosteric site of RIPK2 located outside of the cleft and the phosphoacceptor region. In some embodiments, the RIPK2 antagonist or partial antagonist comprises a type V RIPK2 inhibitor effective to span two regions of the RIPK2 kinase domain. In some embodiments, the RIPK2 antagonist or partial antagonist comprises a type VI RIPK2 inhibitor effective to form a covalent adduct with RIPK2. In some embodiments, the RIPK2 antagonist or partial antagonist comprises a RIPK2 inhibitor effective to inhibit RIPK2 ubiquitination. In some embodiments, the RIPK2 antagonist or partial antagonist comprises a RIPK2 inhibitor effective to inhibit RIPK2 autophosphorylation. In some embodiments, the RIPK2 antagonist or partial antagonist comprises a RIPK2 inhibitor effective to block NOD-dependent tumor necrosis factor production without affecting lipopolysaccharide-dependent pathways. In some embodiments, the RIPK2 antagonist or partial antagonist comprises ponatinib, sorafenib, regorafenib, gefitinib, or erlotinib. In some embodiments, the RIPK2 antagonist or partial antagonist comprises GSK2983559, GSK583, Inhibitor 7, Biaryl Urea, CSR35, CSLP37, CSLP43, RIPK2 inhibitor 1, CS6, PP2, WEHI-345, SB203580, OD36, OD38, RIPK2-IN-1, or RIPK2-IN-2, or any combination thereof.

›METHODS · 22 of 46

Disclosed herein, are antagonists or partial antagonists of RIPK2 having a structure of Formula (I) or a pharmaceutically acceptable salt or isotopic variant thereof:

wherein

Ring A is C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, or 6- to 10-membered aryl; X is N or CR 4 ; R 1 and R 2 are independently —H, halogen, —OH, —OR 5 , —CN, —N(R 6 ) 2 , —NR 6 C(O)R 5 , —C(O)OR 5 , —C(O)N(R 6 ) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 5 , —C 1-6 alkyl-N(R 6 ) 2 , —O—C 1-6 alkyl, —O—C 1-6 alkyl-OH, —O—C 1-6 alkyl-OR 5 , —O—C 1-6 alkyl-N(R 6 ) 2 , or —S(═O) 2 R 5 ; each R 3 is independently —H, halogen, —NO 2 , —CN, —OH, —OR 5 , —SR 5 , —N(R 6 ) 2 , —S(O)R 5 , —S(═O) 2 R 5 , —NR 6 S(═O) 2 R 5 , —S(═O) 2 N(R 6 ) 2 , —C(O)R 5 , —C(O)OR 5 , —OC(O)R 5 , —C(O)N(R 6 ) 2 , —OC(O)N(R 6 ) 2 , —NR 6 C(O)N(R 6 ) 2 , —NR 6 C(O)R 5 , —NR 6 C(O)OR 5 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, —O—C 1-6 alkyl, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, 6- to 10-membered aryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 7 ; R 4 is —H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, or —C 1-6 alkyl-C 2-9 heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, phenyl, heteroaryl, and heterocycloalkyl are optionally substituted; each R 5 is independently —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, or —C 1-6 alkyl-C 2-9 heteroaryl; each R 6 is independently —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, or C 2-9 heteroaryl; or

two R 6 substituents are taken together with the nitrogen atom to which they are attached to form a 5- or 6-membered heterocycle; and

R 7 is —H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, or —C 1-6 alkyl-C 2-9 heteroaryl; and n is 0, 1, 2, 3, 4, or 5.

In some embodiments of a compound of Formula (I), Ring A is C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, or 6- to 10-membered aryl. In some embodiments of a compound of Formula (I), Ring A is C 3-7 heteroaryl or 6-membered aryl. In some embodiments of a compound of Formula (I), Ring A is pyrrazolyl. In some embodiments of a compound of Formula (I), Ring A is C 7 heteroaryl. In some embodiments of a compound of Formula (I), Ring A is phenyl.

In some embodiments, for a compound of Formula (I), X is N or CR 4 . In some embodiments, for a compound of Formula (I), X is N or CH. In some embodiments, for a compound of Formula (I), X is N. In some embodiments, for a compound of Formula (I), X is CH.

In some embodiments, for a compound of Formula (I), R 1 is —H, halogen, —OH, —CN, —N(R 6 ) 2 , —NR 6 C(O)R 5 , —C(O)OR 5 , —C(O)N(R 6 ) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 5 , —C 1-6 alkyl-N(R 6 ) 2 , —O—C 1-6 alkyl, —O—C 1-6 alkyl-OH, —O—C 1-6 alkyl-OR 5 , —O—C 1-6 alkyl-N(R 6 ) 2 , or —S(═O) 2 R 5 . In some embodiments, for a compound of Formula (I), R 1 is C 1-6 alkyl, C 2-6 alkenyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 5 , —C 1-6 alkyl-N(R 6 ) 2 , —O—C 1-6 alkyl, —O—C 1-6 alkyl-OH, —O—C 1-6 alkyl-OR 5 , —O—C 1-6 alkyl-N(R 6 ) 2 , or —S(═O) 2 R 5 . In some embodiments, for a compound of Formula (I), R 1 is —O—C 1-6 alkyl, —O—C 1-6 alkyl-OR 5 , —O—C 1-6 alkyl-N(R 6 ) 2 , or —S(═O) 2 R 5 . In some embodiments, for a compound of Formula (I), R 1 is —O—C 1-6 alkyl. In some embodiments, for a compound of Formula (I), R 1 is —OCH 3 . In some embodiments, for a compound of Formula (I), R 1 is —O—C 1-6 alkyl-OR 5 . In some embodiments, for a compound of Formula (I), R 1 is —OCH 2 CH 2 OCH 3 . In some embodiments, for a compound of Formula (I), R 1 is —O—C 1-6 alkyl-N(R 6 ) 2 . In some embodiments, for a compound of Formula (I), R 1 is —O CH 2 CH 2 CH 2 morpholine. In some embodiments, for a compound of Formula (I), R 1 is —S(═O) 2 R 5 . In some embodiments, for a compound of Formula (I), R 1 is —S(═O) 2 tert-butyl.

In some embodiments, for a compound of Formula (I), R 2 is —H, halogen, —OH, —CN, —N(R 6 ) 2 , —NR 6 C(O)R 5 , —C(O)OR 5 , —C(O)N(R 6 ) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 5 , —C 1-6 alkyl-N(R 6 ) 2 , —O—C 1-6 alkyl, —O—C 1-6 alkyl-OH, —O—C 1-6 alkyl-OR 5 , —O—C 1-6 alkyl-N(R 6 ) 2 , or —S(═O) 2 R 5 . In some embodiments, for a compound of Formula (I), R 2 is —H, —O—C 1-6 alkyl, —O—C 1-6 alkyl-OR 5 , or —O—C 1-6 alkyl-OH. In some embodiments, for a compound of Formula (I), R 2 is —H. In some embodiments, for a compound of Formula (I), R 2 is —O—C 1-6 alkyl. In some embodiments, for a compound of Formula (I), R 2 is —OCH 3 . In some embodiments, for a compound of Formula (I), R 2 is —O—C 1-6 alkyl-OR 5 . In some embodiments, for a compound of Formula (I), R 2 is —OCH 2 CH 2 OCH 3 . In some embodiments, for a compound of Formula (I), R 2 is —O—C 1-6 alkyl-OH. In some embodiments, for a compound of Formula (I), R 2 is —OCH 2 CH 2 OH.

In some embodiments, for a compound of Formula (I), R 3 is —H, halogen, —NO 2 , —CN, —OH, —OR 5 , —SR 5 , —N(R 6 ) 2 , —S(O)R 5 , —S(═O) 2 R 5 , —NR 6 S(═O) 2 R 5 , —S(═O) 2 N(R 6 ) 2 , —C(O)R 5 , —C(O)OR 5 , —OC(O)R 5 , —C(O)N(R 6 ) 2 , —OC(O)N(R 6 ) 2 , —NR 6 C(O)N(R 6 ) 2 , —NR 6 C(O)R 5 , —NR 6 C(O)OR 5 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, —O—C 1-6 alkyl, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, 6- to 10-membered aryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 7 . In some embodiments, for a compound of Formula (I), R 3 is —H, halogen, C 1-6 alkyl, C 2-6 alkynyl, or —O-phenyl. In some embodiments, for a compound of Formula (I), R 3 is —H. In some embodiments, for a compound of Formula (I), R 3 is —Cl. In some embodiments, for a compound of Formula (I), R 3 is —F. In some embodiments, for a compound of Formula (I), R 3 is —CH 3 . In some embodiments, for a compound of Formula (I), R 3 is —CCH. In some embodiments, for a compound of Formula (I), R 3 is —O-phenyl.

›METHODS · 23 of 46

In some embodiments, for a compound of Formula (I), n is 0, 1, 2, or 3. In some embodiments, for a compound of Formula (I), n is 1, 2, or 3. In some embodiments, for a compound of Formula (I), n is 1 or 2. In some embodiments, for a compound of Formula (I), n is 0. In some embodiments, for a compound of Formula (I), n is 1. In some embodiments, for a compound of Formula (I), n is 2. In some embodiments, for a compound of Formula (I), n is 3.

Disclosed herein, are antagonists or partial antagonists of RIPK2 having a structure of Formula (Ia) or a pharmaceutically acceptable salt or isotopic variant thereof:

wherein;

each R 3 is independently —H, halogen, —C≡CH, or —O-aryl; and

each R 5 is independently C 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl, or —C 1-6 alkyl-heterocycloalkyl.

Disclosed herein, are antagonists or partial antagonists of RIPK2 having a structure of Formula (Ia) or a pharmaceutically acceptable salt or isotopic variant thereof:

wherein;

each R 3 is independently —H, —Cl, —F, —C≡CH, or —O-phenyl; and

each R 5 is independently —CH 3 , —CH 2 CH 2 OCH 3 , or —CH 2 CH 2 CH 2 morpholine.

Disclosed herein, are antagonists or partial antagonists of RIPK2 having a structure of Formula (Ib) or a pharmaceutically acceptable salt or isotopic variant thereof:

wherein;

Ring A is C 3-7 heteroaryl;

X is N or CH;

R 2 is —H, —OC 1-6 alkyl, or —O—C 1-6 alkyl-OH;

each R 3 is independently —H, —C 1-6 alkyl, or halogen; and

n is 0, 1, or 2.

Disclosed herein, are antagonists or partial antagonists of RIPK2 having a structure of Formula (Ib) or a pharmaceutically acceptable salt or isotopic variant thereof:

wherein;

Ring A is C 3-7 heteroaryl;

X is N or CH;

R 2 is —H, —OCH 3 , or —OCH 2 CH 2 OH;

each R 3 is independently —H, —CH 3 , or —F; and

n is 0, 1, or 2.

In some embodiments a compound of Formula (I) or a pharmaceutically acceptable salt or isotopic variant thereof has the structure of:

Disclosed herein, are antagonists or partial antagonists of RIPK2 having a structure of Formula (II) or a pharmaceutically acceptable salt or isotopic variant thereof:

wherein

Rings A and B are independently C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, or 6- to 10-membered aryl; X 1 , X 2 , and X 3 are independently N or CR 4 ; Y 1 and Y 2 are independently a bond, —O—, —S—, —C(R 5 ) 2 , —NR 6 C(O)—, —C(O)NR 6 —, or —NR 6 C(O)NR 6 —; each R 1 and R 2 is independently —H, halogen, —NO 2 , —CN, —OH, —OR 5 , —SR 5 , —N(R 6 ) 2 , —S(O)R 5 , —S(═O) 2 R 5 , —NR 6 S(═O) 2 R 5 , —S(═O) 2 N(R 6 ) 2 , —SCH 2 C(O)OR 5 , —C(O)R 5 , —C(O)OR 5 , —OC(O)R 5 , —C(O)N(R 6 ) 2 , —OC(O)N(R 6 ) 2 , —NR 6 C(O)N(R 6 ) 2 , —NR 6 C(O)R 5 , —NR 6 C(O)OR 5 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, —O—C 1-6 alkyl, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, 6- to 10-membered aryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 7 ; each R 4 is independently —H, halogen, —N(R 6 ) 2 , —NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, or —C 1-6 alkyl-C 2-9 heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, phenyl, heteroaryl, and heterocycloalkyl are optionally substituted; each R 5 is independently —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, or —C 1-6 alkyl-C 2-9 heteroaryl; each R 6 is independently —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, or C 2-9 heteroaryl; or

two R 6 are taken together with the nitrogen atom to which they are attached to form a 5- or 6-membered heterocycle; and

In some embodiments, for a compound of Formula (II), Rings A and B are independently C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, or 6- to 10-membered aryl. In some embodiments, for a compound of Formula (II), Rings A and B are independently C 2-9 heteroaryl or 6- to 10-membered aryl. In some embodiments, for a compound of Formula (II), Ring A is phenyl. In some embodiments, for a compound of Formula (II), Ring A is pyridyl. In some embodiments, for a compound of Formula (II), Ring A is furanyl. In some embodiments, for a compound of Formula (II), Ring B is phenyl. In some embodiments, for a compound of Formula (II), Ring B is pyrrazolyl. In some embodiments, for a compound of Formula (II), Ring B is pyridyl. In some embodiments, for a compound of Formula (II), Ring B is isoxazolyl. In some embodiments, for a compound of Formula (II), Ring A is phenyl and Ring B is pyrrazolyl. In some embodiments, for a compound of Formula (II), Ring A is phenyl and Ring B is phenyl. In some embodiments, for a compound of Formula (II), Ring A is phenyl and Ring B is pyridyl. In some embodiments, for a compound of Formula (II), Ring A is pyridyl and Ring B is phenyl. In some embodiments, for a compound of Formula (II), Ring A is pyridyl and Ring B is isoxazolyl. In some embodiments, for a compound of Formula (II), Ring A is isoxazoylyl and Ring B is pyridyl. In some embodiments, for a compound of Formula (II), Ring A is furanyl and Ring B is phenyl.

In some embodiments, for a compound of Formula (II), X 1 , X 2 , and X 3 are independently N or CR 4 . In some embodiments, for a compound of Formula (II), X 1 is CH. In some embodiments, for a compound of Formula (II), X 1 is CF. In some embodiments, for a compound of Formula (II), X 1 is CCH 3 . In some embodiments, for a compound of Formula (II), X 1 is CNH 2 . In some embodiments, for a compound of Formula (II), X 1 is N. In some embodiments, for a compound of Formula (II), X 2 is CH. In some embodiments, for a compound of Formula (II), X 2 is CF. In some embodiments, for a compound of Formula (II), X 2 is N. In some embodiments, for a compound of Formula (II), X 2 is C—N-methylpyrazine. In some embodiments, for a compound of Formula (II), X 3 is CH. In some embodiments, for a compound of Formula (II), X 3 is N. In some embodiments, for a compound of Formula (II), X 1 is CF and X 2 and X 3 are CH. In some embodiments, for a compound of Formula (II), X 2 is CF and X 1 and X 3 are CH. In some embodiments, for a compound of Formula (II), X 1 , X 2 , and X 3 are CH. In some embodiments, for a compound of Formula (II), X 1 is CCH 3 and X 2 and X 3 are CH. In some embodiments, for a compound of Formula (II), X 1 is CNH 2 , X 2 is N, and X 3 is CH. In some embodiments, for a compound of Formula (II), X 2 is C—N-methylpyrazine and X 1 and X 3 are N.

›METHODS · 24 of 46

In some embodiments, for a compound of Formula (II), Y 1 and Y 2 are independently a bond, —O—, —S—, —C(R 5 ) 2 , —NR 6 —, —NR 6 C(O)—, —C(O)NR 6 —, or —NR 6 C(O)NR 6 —. In some embodiments, for a compound of Formula (II), Y 1 is —NR 6 C(O)—. In some embodiments, for a compound of Formula (II), Y 1 is —O—. In some embodiments, for a compound of Formula (II), Y 1 is —NR 6 C(O)NR 6 —. In some embodiments, for a compound of Formula (II), Y 1 is a bond. In some embodiments, for a compound of Formula (II), Y 1 is —NR 6 —. In some embodiments, for a compound of Formula (II), Y 2 is —NR 6 C(O)—. In some embodiments, for a compound of Formula (II), Y 2 is —O—. In some embodiments, for a compound of Formula (II), Y 2 is —NR 6 C(O)NR 6 —. In some embodiments, for a compound of Formula (II), Y 2 is a bond. In some embodiments, for a compound of Formula (II), Y 1 is —S—. In some embodiments, for a compound of Formula (II), Y 1 and Y 2 are —NHC(O)—. In some embodiments, for a compound of Formula (II), Y 1 is —O— and Y 2 is —NHC(O)NH—. In some embodiments, for a compound of Formula (II), Y 1 is —NHC(O)NH— and Y 2 is —O—. In some embodiments, for a compound of Formula (II), Y 1 and Y 2 are bonds. In some embodiments, for a compound of Formula (II), Y 1 is —NH— and Y 2 is —S—.

In some embodiments, for a compound of Formula (II), R 1 is —H, halogen, —NO 2 , —CN, —OH, —OR 5 , —SR 5 , —N(R 6 ) 2 , —S(O)R 5 , —S(═O) 2 R 5 , —NR 6 S(═O) 2 R 5 , —S(═O) 2 N(R 6 ) 2 , —C(O)R 5 , —C(O)OR 5 , —OC(O)R 5 , —C(O)N(R 6 ) 2 , —OC(O)N(R 6 ) 2 , —NR 6 C(O)N(R 6 ) 2 , —NR 6 C(O)R 5 , —NR 6 C(O)OR 5 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, —O—C 1-6 alkyl, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, 6- to 10-membered aryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 7 . In some embodiments, for a compound of Formula (II), R 1 is —Cl. In some embodiments, for a compound of Formula (II), R 1 is —F. In some embodiments, for a compound of Formula (II), R 1 is —C(O)NHCH 3 . In some embodiments, for a compound of Formula (II), R 1 is 2-methylpyrrazolyl. In some embodiments, for a compound of Formula (II), R 1 is N-methylimidazolyl. In some embodiments, for a compound of Formula (II), R 1 is tert-butyl. In some embodiments, for a compound of Formula (II), R 1 is —NHC(O)cyclopropyl. In some embodiments, for a compound of Formula (II), R 1 is —SCH 2 C(O)OH. In some embodiments, for a compound of Formula (II), R 1 is —OCH 3 . In some embodiments, for a compound of Formula (II), R 1 is —NHS(═O) 2 CH 2 CH 2 CH 3 .

In some embodiments, for a compound of Formula (II), R 2 is —H, halogen, —NO 2 , —CN, —OH, —OR 5 , —SR 5 ,—N(R 6 ) 2 , —S(O)R 5 , —S(═O) 2 R 5 ,—NR 6 S(═O) 2 R 5 , —S(═O) 2 N(R 6 ) 2 , —C(O)R 5 , —C(O)OR 5 , —OC(O)R 5 , —C(O)N(R 6 ) 2 , —OC(O)N(R 6 ) 2 , —NR 6 C(O)N(R 6 ) 2 , —NR 6 C(O)N(R 6 ) 2 , —NR 6 C(O)R 5 , —NR 6 C(O)OR 5 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, —O—C 1-6 alkyl, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, 6- to 10-membered aryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 7 . In some embodiments, for a compound of Formula (II), R 2 is —Cl. In some embodiments, for a compound of Formula (II), R 2 is —F. In some embodiments, for a compound of Formula (II), R 2 is —C(O)NHCH 3 . In some embodiments, for a compound of Formula (II), R 1 is 2-methylpyrrazolyl. In some embodiments, for a compound of Formula (II), R 1 is N-methylimidazolyl. In some embodiments, for a compound of Formula (II), R 2 is —CH 2 -(2-iso-propylimidazole). In some embodiments, for a compound of Formula (II), R 2 is tert-butyl. In some embodiments, for a compound of Formula (II), R 2 is —CH 3 . In some embodiments, for a compound of Formula (II), R 2 is —C(O)NHCH 3 . In some embodiments, for a compound of Formula (II), R 2 is pyrazinyl.

In some embodiments, for a compound of Formula (II), m is 1 or 2. In some embodiments, for a compound of Formula (II), m is 1. In some embodiments, for a compound of Formula (II), m is 2. In some embodiments, for a compound of Formula (II), n is 1 or 2. In some embodiments, for a compound of Formula (II), n is 1. In some embodiments, for a compound of Formula (II), n is 2.

Disclosed herein, are antagonists or partial antagonists of RIPK2 having a structure of Formula (IIa) or a pharmaceutically acceptable salt or isotopic variant thereof:

wherein

Ring A is phenyl or isoxazolyl;

each R 1 is independently C 1-6 alkyl, halogen, —C 1-6 fluoroalkyl, or —S—C 1-6 alkyl-C(O)OH;

R 2 is —H or —C(O)NHCH 3 ;

R 4 is —H or halogen; and

m is 1 or 2.

Disclosed herein, are antagonists or partial antagonists of RIPK2 having a structure of Formula (IIa) or a pharmaceutically acceptable salt or isotopic variant thereof:

wherein

Ring A is phenyl or isoxazolyl;

each R 1 is independently tert-butyl, —Cl, —F, —CF 3 , or —SCH 2 C(O)OH;

R 2 is —H or —C(O)NHCH 3 ;

R 4 is —H or halogen; and

m is 1 or 2.

Disclosed herein, are antagonists or partial antagonists of RIPK2 having a structure of Formula (IIb) or a pharmaceutically acceptable salt or isotopic variant thereof:

wherein

R 1 is halogen or —OR 5 .

In some embodiments a compound of Formula (II) or a pharmaceutically acceptable salt or isotopic variant thereof has the structure of:

Disclosed herein, are antagonists or partial antagonists of RIPK2 having a structure of Formula (III) or a pharmaceutically acceptable salt or isotopic variant thereof:

wherein

X is N or CR 4 ; Y is a bond, —O—, —S—, —C(R 5 ) 2 , —NR 6 —, —NR 6 C(O)—, —C(O)NR 6 —, or —NR 6 C(O)NR 6 —; R 1 is —H, halogen, —OH, —CN, —N(R 6 ) 2 , —NR 6 C(O)R 5 , —C(O)OR 5 , —C(O)N(R 6 ) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 5 , —C 1-6 alkyl-N(R 6 ) 2 , —O—C 1-6 alkyl, —O—C 1-6 alkyl-OH, —O—C 1-6 alkyl-OR 5 , —O—C 1-6 alkyl-N(R 6 ) 2 , or —S(═O) 2 R 5 ; R 2 and R 3 are independently —H, halogen, —NO 2 , —CN, —OH, —OR 5 , —SR 5 , —N(R 6 ) 2 , —S(O)R 5 , —S(═O) 2 R 5 , —NR 6 S(═O) 2 R 5 , —S(═O) 2 N(R 6 ) 2 , —C(O)R 5 , —C(O)OR 5 , —OC(O)R 5 , —C(O)N(R 6 ) 2 , —OC(O)N(R 6 ) 2 , —NR 6 C(O)N(R 6 ) 2 , —NR 6 C(O)R 5 , —NR 6 C(O)OR 5 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, —O—C 1-6 alkyl, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, 6- to 10-membered aryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 7 ; or

›METHODS · 25 of 46

R 2 and R 3 are taken together with the atoms to which they are attached to form an optionally substituted C 3-8 cycloalkyl; and

R 4 is hydrogen, halogen, —N(R 6 ) 2 , —NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, or —C 1-6 alkyl-C 2-9 heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, phenyl, heteroaryl, and heterocycloalkyl are optionally substituted; R 5 is —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, or —C 1-6 alkyl-C 2-9 heteroaryl; each R 6 is independently —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, or C 2-9 heteroaryl; or

two R 6 substituents are taken together with the nitrogen atom to which they are attached to form a 5- or 6-membered heterocycle; and

In some embodiments, for a compound of Formula (III), X is N or CR 4 . In some embodiments, for a compound of Formula (III), X is N and CH. In some embodiments, for a compound of Formula (III), X is N. In some embodiments, for a compound of Formula (III), X is CH.

In some embodiments, for a compound of Formula (III), Y is a bond, —O—, —S—, —C(R 5 ) 2 —NR 6 —, —NR 6 C(O)—, —C(O)NR 6 —, or —NR 6 C(O)NR 6 —. In some embodiments, for a compound of Formula (III), Y is —NR 6 C(O)— or —C(O)NR 6 —. In some embodiments, for a compound of Formula (III), Y is —NHC(O)—. In some embodiments, for a compound of Formula (III), Y is —C(O)NH—.

In some embodiments, for a compound of Formula (III), R 1 is —H, halogen, —OH, —CN, —N(R 6 ) 2 , —NR 6 C(O)R 5 , —C(O)OR 5 , —C(O)N(R 6 ) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 5 , —C 1-6 alkyl-N(R 6 ) 2 , —O—C 1-6 alkyl, —O—C 1-6 alkyl-OH, —O—C 1-6 alkyl-OR 5 , —O—C 1-6 alkyl-N(R 6 ) 2 , or —S(═O) 2 R 5 . In some embodiments, for a compound of Formula (III), R 1 is —H, halogen, —OH, —CN, —N(R 6 ) 2 , C 1-6 alkyl, C 2-6 alkynyl, or C 3-8 cycloalkyl. In some embodiments, for a compound of Formula (III), R 1 is C 1-6 alkyl. In some embodiments, for a compound of Formula (III), R 1 is —CH 3 . In some embodiments, for a compound of Formula (III), R 1 is tert-butyl.

In some embodiments, for a compound of Formula (III), R 2 is —H, halogen, —NO 2 , —CN, —OH, —OR 5 , —SR 5 , —N(R 6 ) 2 , —S(O)R 5 , —S(═O) 2 R 5 , —NR 6 S(═O) 2 R 5 , —S(═O) 2 N(R 6 ) 2 , —C(O)R 5 , —C(O)OR 5 , —OC(O)R 5 , —C(O)N(R 6 ) 2 , —OC(O)N(R 6 ) 2 , —NR 6 C(O)N(R 6 ) 2 , —NR 6 C(O)R 5 , —NR 6 C(O)OR 5 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, —O—C 1-6 alkyl, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, 6- to 10-membered aryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 7 , or R 2 and R 3 are taken together with the atoms to which they are attached to form an optionally substituted C 3-8 cycloalkyl. In some embodiments, for a compound of Formula (III), R 2 is —H, halogen, —NO 2 , —CN, —OH, —OR 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, or 6- to 10-membered aryl, or R 2 and R 3 are taken together with the atoms to which they are attached to form an optionally substituted C 3-8 cycloalkyl. In some embodiments, for a compound of Formula (III), R 2 is C 1-6 alkyl, C 1-6 haloalkyl, or C 3-8 cycloalkyl, or R 2 and R 3 are taken together with the atoms to which they are attached to form an optionally substituted C 3-8 cycloalkyl. In some embodiments, for a compound of Formula (III), R 2 is —CH 3 , —CF 3 , or cyclopropyl, or R 2 and R 3 are taken together with the atoms to which they are attached to form an optionally substituted C 3-8 cycloalkyl. In some embodiments, for a compound of Formula (III), R 2 is —CH 3 , —CF 3 , or cyclopropyl. In some embodiments, for a compound of Formula (III), R 2 is —CH 3 . In some embodiments, for a compound of Formula (III), R 2 is —CF 3 . In some embodiments, for a compound of Formula (III), R 2 is cyclopropyl. In some embodiments, for a compound of Formula (III), R 2 and R 3 are taken together with the atoms to which they are attached to form a C 5 cycloalkyl. In some embodiments, for a compound of Formula (III), R 2 and R 3 are taken together with the atoms to which they are attached to form a CS cycloalkyl substituted with an N-methylpiperazine.

In some embodiments, for a compound of Formula (III), R 3 is —H, halogen, —NO 2 , —CN, —OH, —OR 5 , —SR 5 , —N(R 6 ) 2 , —S(O)R 5 , —S(═O) 2 R 5 , —NR 6 S(═O) 2 R 5 , —S(═O) 2 N(R 6 ) 2 , —C(O)R 5 , —C(O)OR 5 , —OC(O)R 5 , —C(O)N(R 6 ) 2 , —OC(O)N(R 6 ) 2 , —NR 6 C(O)N(R 6 ) 2 , —NR 6 C(O)R 5 , —NR 6 C(O)OR 5 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, —O—C 1-6 alkyl, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, 6- to 10-membered aryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 7 , or R 2 and R 3 are taken together with the atoms to which they are attached to form an optionally substituted C 3-8 cycloalkyl. In some embodiments, for a compound of Formula (III), R 3 is —H, halogen, —CN, —OR 5 , —N(R 6 ) 2 , —S(═O) 2 R 5 , —C(O)R 5 , —C(O)OR 5 , —NR 6 C(O)N(R 6 ) 2 , —NR 6 C(O)R 5 , —NR 6 C(O)OR 5 , C 1-6 alkyl, C 1-6 heteroalkyl, C 2-9 heterocycloalkyl, or C 2-9 heteroaryl, wherein each alkyl, heteroalkyl, heterocycloalkyl, and heteroaryl is optionally substituted with one or more R 7 , or R 2 and R 3 are taken together with the atoms to which they are attached to form an optionally substituted C 3-8 cycloalkyl. In some embodiments, for a compound of Formula (III), R 3 is C 1-6 alkyl substituted with C 2-9 heterocycloalkyl. In some embodiments, for a compound of Formula (III), R 3 is CH 2 —N-methylpiperazine. In some embodiments, for a compound of Formula (III), R 2 and R 3 are taken together with the atoms to which they are attached to form a C 5 cycloalkyl. In some embodiments, for a compound of Formula (III), R 2 and R 3 are taken together with the atoms to which they are attached to form a C 5 cycloalkyl substituted with an N-methylpiperazine.

›METHODS · 26 of 46

Disclosed herein, are antagonists or partial antagonists of RIPK2 having a structure of Formula (III) or a pharmaceutically acceptable salt or isotopic variant thereof:

wherein

R 1 is C 1-6 alkyl.

In some embodiments a compound of Formula (III) or a pharmaceutically acceptable salt or isotopic variant thereof has the structure of:

Disclosed herein, are antagonists or partial antagonists of RIPK2 having a structure of Formula (IV) or a pharmaceutically acceptable salt or isotopic variant thereof:

wherein

Ring A is C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, or 6- to 10-membered aryl; Y is a bond, —O—, —S—, —C(R 5 ) 2 —, —NR 6 —, —NR 6 C(O)—, —C(O)NR 6 —, or —NR 6 C(O)NR 6 —; R 1 is —H, halogen, —OH, —CN, —N(R 6 ) 2 , —NR 6 C(O)R 5 , —C(O)OR 5 , —C(O)N(R 6 ) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 5 , —C 1-6 alkyl-N(R 6 ) 2 , —O—C 1-6 alkyl, —O—C 1-6 alkyl-OH, —O—C 1-6 alkyl-OR 5 , —O—C 1-6 alkyl-N(R 6 ) 2 , or —S(═O) 2 R 5 ; R 2 is —H, halogen, —NO 2 , —CN, —OH, —OR 5 , —SR 5 , —N(R 6 ) 2 , —S(O)R 5 , —S(═O) 2 R 5 , —NR 6 S(═O) 2 R 5 , —S(═O) 2 N(R 6 ) 2 , —C(O)R 5 , —C(O)OR 5 , —OC(O)R 5 , —C(O)N(R 6 ) 2 , —OC(O)N(R 6 ) 2 , —NR 6 C(O)N(R 6 ) 2 , —NR 6 C(O)R 5 , —NR 6 C(O)OR 5 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, —O—C 1-6 alkyl, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, 6- to 10-membered aryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 7 ; R 5 is —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, or —C 1-6 alkyl-C 2-9 heteroaryl; each R 6 is independently —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, or C 2-9 heteroaryl; or

two R 6 substituents are taken together with the nitrogen atom to which they are attached to form a 5- or 6-membered heterocycle;

In some embodiments, for a compound of Formula (IV), Ring A is C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, or 6- to 10-membered aryl. In some embodiments, for a compound of Formula (IV), Ring A is 6- to 10-membered aryl. In some embodiments, for a compound of Formula (IV), Ring A is phenyl. In some embodiments, for a compound of Formula (IV), Ring A is naphthyl.

In some embodiments, for a compound of Formula (IV), Y is a bond, —O—, —S—, —C(R 5 ) 2 —, —NR 6 —, —NR 6 C(O)—, —C(O)NR 6 —, or —NR 6 C(O)NR 6 —. In some embodiments, for a compound of Formula (IV), Y is a bond or —C(R 5 ) 2 —. In some embodiments, for a compound of Formula (IV), Y is a bond. In some embodiments, for a compound of Formula (IV), Y is —CH 2 —.

In some embodiments, for a compound of Formula (IV), R 1 is —H, halogen, —OH, —CN, —N(R 6 ) 2 , —NR 6 C(O)R 5 , —C(O)OR 5 , —C(O)N(R 6 ) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 5 , —C 1-6 alkyl-N(R 6 ) 2 , —O—C 1-6 alkyl-OH, —O—C 1-6 alkyl-OR 5 , —O—C 1-6 alkyl-N(R 6 ) 2 , or —S(═O) 2 R 5 . In some embodiments, for a compound of Formula (IV), R 1 is —H, halogen, or C 1-6 alkyl. In some embodiments, for a compound of Formula (IV), R 1 is —H, —Cl, or CH 3 . In some embodiments, for a compound of Formula (IV), R 1 is —H. In some embodiments, for a compound of Formula (IV), R 1 is In some embodiments, for a compound of Formula (IV), R 1 is —CH 3 .

In some embodiments, for a compound of Formula (IV), R 2 is —H, halogen, —NO 2 , —CN, —OH, —OR 5 , —SR 5 , —N(R 6 ) 2 , —S(O)R 5 , —S(═O) 2 R 5 , —NR 6 S(═O) 2 R 5 , —S(═O) 2 N(R 6 ) 2 , —C(O)R 5 , —C(O)OR 5 , —OC(O)R 5 , —C(O)N(R 6 ) 2 , —OC(O)N(R 6 ) 2 , —NR 6 C(O)N(R 6 ) 2 , —NR 6 C(O)R 5 , —NR 6 C(O)OR 5 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, —O—C 1-6 alkyl, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, 6- to 10-membered aryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 7 . In some embodiments, for a compound of Formula (IV), R 2 is —H or —NR 6 C(O)R 5 . In some embodiments, for a compound of Formula (IV), R 2 is —H or —NR 6 C(O)C 2-9 heteroaryl. In some embodiments, for a compound of Formula (IV), R 2 is —H. In some embodiments, for a compound of Formula (IV), R 2 is —NHC(O)pyridyl.

In some embodiments, for a compound of Formula (IV), n is 1, 2, or 3. In some embodiments, for a compound of Formula (IV), n is 1 or 2. In some embodiments, for a compound of Formula (IV), n is 1. In some embodiments, for a compound of Formula (IV), n is 2. In some embodiments, for a compound of Formula (IV), n is 3.

Disclosed herein, are antagonists or partial antagonists of RIPK2 having a structure of Formula (IVa) or a pharmaceutically acceptable salt or isotopic variant thereof:

wherein

R 1 is halogen or C 1-6 alkyl.

Disclosed herein, are antagonists or partial antagonists of RIPK2 having a structure of Formula (IVb) or a pharmaceutically acceptable salt or isotopic variant thereof:

wherein Y is a bond or —C 1-3 alkyl-.

Disclosed herein, are antagonists or partial antagonists of RIPK2 having a structure of Formula (IVb) or a pharmaceutically acceptable salt or isotopic variant thereof:

wherein

Y is a bond or —CH 2 —.

In some embodiments a compound of Formula (IV) or a pharmaceutically acceptable salt or isotopic variant thereof has the structure of:

Disclosed herein, are antagonists or partial antagonists of RIPK2 having a structure of Formula (V) or a pharmaceutically acceptable salt or isotopic variant thereof:

›METHODS · 27 of 46

wherein

X 1 and X 2 are independently N or CR 4 ; Y is S, O, or NR 1 ; R 1 is —H, —S(═O) 2 R 5 , —S(═O) 2 N(R 6 ) 2 , —C(O)R 5 , —C(O)OR 5 , —C(O)N(R 6 ) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, or 6- to 10-membered aryl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 7 ; R 2 is —H, halogen, —NO 2 , —CN, —OH, —OR 5 , —SR 5 , —N(R 6 ) 2 , —S(O)R 5 , —S(═O) 2 R 5 , —NR 6 S(═O) 2 R 5 , —S(═O) 2 N(R 6 ) 2 , —C(O)R 5 , —C(O)OR 5 , —OC(O)R 5 , —C(O)N(R 6 ) 2 , —OC(O)N(R 6 ) 2 , —NR 6 C(O)N(R 6 ) 2 , —NR 6 C(O)R 5 , —NR 6 C(O)OR 5 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, —O—C 1-6 alkyl, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, 6- to 10-membered aryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 7 ; or

R 1 and R 2 are taken together with the atoms to which they are attached to form an optionally substituted C 3-8 heterocycloalkyl; and

R 3 and R 4 are independently —H, halogen, —NO 2 , —CN, —OH, —OR 5 , —SR 5 , —N(R 6 ) 2 , —S(O)R 5 , —S(═O) 2 R 5 , —NR 6 S(═O) 2 R 5 , —S(═O) 2 N(R 6 ) 2 , —C(O)R 5 , —C(O)OR 5 , —OC(O)R 5 , —C(O)N(R 6 ) 2 , —OC(O)N(R 6 ) 2 , —NR 6 C(O)N(R 6 ) 2 , —NR 6 C(O)R 5 , —NR 6 C(O)OR 5 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, —O—C 1-6 alkyl, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, 6- to 10-membered aryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 7 ; R 5 is —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, or —C 1-6 alkyl-C 2-9 heteroaryl; each R 6 is independently —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, or C 2-9 heteroaryl; or

two R 6 substituents are taken together with the nitrogen atom to which they are attached to form a 5- or 6-membered heterocycle; and

R 7 is —H, halogen, —S(═O)CH 3 , —N(R 6 ) 2 , —C(O)N(R 6 ) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, or —C 1-6 alkyl-C 2-9 heteroaryl.

In some embodiments, for a compound of Formula (V), X 1 and X 2 are independently N or CR 4 . In some embodiments, for a compound of Formula (V), X 1 is N. In some embodiments, for a compound of Formula (V), X 1 is CR 4 . In some embodiments, for a compound of Formula (V), X 2 is N. In some embodiments, for a compound of Formula (V), X 2 is CR 4 . In some embodiments, for a compound of Formula (V), X 1 is N and X 2 is CR 4 . In some embodiments, for a compound of Formula (V), X 1 is CR 4 and X 2 is N.

In some embodiments, for a compound of Formula (V), Y is S, O, or NR 1 . In some embodiments, for a compound of Formula (V), Y is S. In some embodiments, for a compound of Formula (V), Y is NH. In some embodiments, for a compound of Formula (V), Y is NR′.

In some embodiments, for a compound of Formula (V), R 1 is —H, —S(═O) 2 R 5 , —S(═O) 2 N(R 6 ) 2 , —C(O)R 5 , —C(O)OR 5 , —C(O)N(R 6 ) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, or 6- to 10-membered aryl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 7 . In some embodiments, for a compound of Formula (V), R 1 is —H, C 1-6 alkyl, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, or 6- to 10-membered aryl, wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 7 . In some embodiments, for a compound of Formula (V), R 1 is aryl optionally substituted with one or more R 7 . In some embodiments, for a compound of Formula (V), R 1 is 2,4-dichlorophenyl.

In some embodiments, for a compound of Formula (V), R 2 is —H, halogen, —NO 2 , —CN, —OH, —OR 5 , —SR 5 , —N(R 6 ) 2 , —S(O)R 5 , —S(═O) 2 R 5 , —NR 6 S(═O) 2 R 5 , —S(═O) 2 N(R 6 ) 2 , —C(O)R 5 , —C(O)OR 5 , —OC(O)R 5 , —C(O)N(R 6 ) 2 , —OC(O)N(R 6 ) 2 , —NR 6 C(O)N(R 6 ) 2 , —NR 6 C(O)R 5 , —NR 6 C(O)OR 5 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, —O—C 1-6 alkyl, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, 6- to 10-membered aryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 7 , or R 1 and R 2 are taken together with the atoms to which they are attached to form an optionally substituted C 3-8 heterocycloalkyl. In some embodiments, for a compound of Formula (V), R 2 is —H, halogen, —S(═O) 2 R 5 , —NR 6 S(═O) 2 R 5 , —S(═O) 2 N(R 6 ) 2 , —C(O)R 5 , —C(O)OR 5 , —C(O)N(R 6 ) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, 6- to 10-membered aryl, or —O-phenyl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 7 , or R 1 and R 2 are taken together with the atoms to which they are attached to form an optionally substituted C 3-8 heterocycloalkyl. In some embodiments, for a compound of Formula (V), R 2 is —C(O)N(R 6 ) 2 or 6-membered aryl optionally substituted with one or more R 7 . In some embodiments, for a compound of Formula (V), R 2 is 4-fluorophenyl. In some embodiments, for a compound of Formula (V), R 2 is 4-chlorophenyl. In some embodiments, for a compound of Formula (V), R 2 is 2-methylpyridinyl. In some embodiments, for a compound of Formula (V), R 2 is —C(O)NH-(2-methyl-6-chlorophenyl). In some embodiments, for a compound of Formula (V), R 1 and R 2 are taken together with the atoms to which they are attached to form an optionally substituted C 3-8 heterocycloalkyl. In some embodiments, for a compound of Formula (V), R 1 and R 2 are taken together with the atoms to which they are attached to form a C 5 heterocycloalkyl.

›METHODS · 28 of 46

In some embodiments, for a compound of Formula (V), R 3 is —H, halogen, —NO 2 , —CN, —OH, —OR 5 , —SR 5 , —N(R 6 ) 2 , —S(O)R 5 , —S(═O) 2 R 5 , —NR 6 S(═O) 2 R 5 , —S(═O) 2 N(R 6 ) 2 , —C(O)R 5 , —C(O)OR 5 , —OC(O)R 5 , —C(O)N(R 6 ) 2 , —OC(O)N(R 6 ) 2 , —NR 6 C(O)N(R 6 ) 2 , —NR 6 C(O)R 5 , —NR 6 C(O)OR 5 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, —O—C 1-6 alkyl, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, 6- to 10-membered aryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 7 . In some embodiments, for a compound of Formula (V), R 3 is —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, 6- to 10-membered aryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 7 . In some embodiments, for a compound of Formula (V), R 3 is —H or C 2-9 heteroaryl optionally substituted with one or more R 7 . In some embodiments, for a compound of Formula (V), R 3 is H. In some embodiments, for a compound of Formula (V), R 3 is C 2-9 heteroaryl optionally substituted with one or more R 7 . In some embodiments, for a compound of Formula (V), R 3 is optionally substituted pyridinyl. In some embodiments, for a compound of Formula (V), R 3 is optionally substituted quinolinyl. In some embodiments, for a compound of Formula (V), R 3 is optionally substituted [1,2,4]triazolopyridinyl.

In some embodiments, for a compound of Formula (V), R 4 is —H, halogen, —NO 2 , —CN, —OH, —OR 5 , —SR 5 , —N(R 6 ) 2 , —S(O)R 5 , —S(═O) 2 R 5 , —NR 6 S(═O) 2 R 5 , —S(═O) 2 N(R 6 ) 2 , —C(O)R 5 , —C(O)OR 5 , —OC(O)R 5 , —C(O)N(R 6 ) 2 , —OC(O)N(R 6 ) 2 , —NR 6 C(O)N(R 6 ) 2 , —NR 6 C(O)R 5 , —NR 6 C(O)OR 5 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, —O—C 1-6 alkyl, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, 6- to 10-membered aryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 7 . In some embodiments, for a compound of Formula (V), R 4 is —H, —N(R 6 ) 2 , —C(O)R 5 , —C(O)OR 5 , —OC(O)R 5 , —C(O)N(R 6 ) 2 , —OC(O)N(R 6 ) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, 6- to 10-membered aryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 7 . In some embodiments, for a compound of Formula (V), R 4 is —N(R 6 ) 2 , C 1-6 alkyl, C 2-9 heteroaryl, or 6- to 10-membered aryl, wherein each aryl and heteroaryl is optionally substituted with one or more R 7 . In some embodiments, for a compound of Formula (V), R 4 is optionally substituted phenyl. In some embodiments, for a compound of Formula (V), R 4 is optionally substituted pyridyl. In some embodiments, for a compound of Formula (V), R 4 is —NHpyrimidine. In some embodiments, for a compound of Formula (V), R 4 is —CH 2 phenyl. In some embodiments, for a compound of Formula (V), R 4 is CH 2 NHphenyl.

In some embodiments a compound of Formula (V) or a pharmaceutically acceptable salt or isotopic variant thereof has the structure of:

Disclosed herein, are antagonists or partial antagonists of RIPK2 having a structure of Formula (VI) or a pharmaceutically acceptable salt or isotopic variant thereof:

wherein

X 1 and X 2 are independently N or C; X 3 is N or CR 4 ; Y is a bond, —O—, —S—, —C(R 5 ) 2 , —NR 6 —, —NR 6 C(O)—, —C(O)NR 6 —, or —NR 6 C(O)NR 6 —; R is —H, halogen, —NO 2 , —CN, —OH, —OR 5 , —SR 5 , —N(R 6 ) 2 , —S(O)R 5 , —S(═O) 2 R 5 , —NR 6 S(═O) 2 R 5 , —S(═O) 2 N(R 6 ) 2 , —C(O)R 5 , —C(O)OR 5 , —OC(O)R 5 , —C(O)N(R 6 ) 2 , —OC(O)N(R 6 ) 2 , —NR 6 C(O)N(R 6 ) 2 , —NR 6 C(O)R 5 , —NR 6 C(O)OR 5 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, —O—C 1-6 alkyl, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, 6- to 10-membered aryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 7 ; R 4 is —H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, or —C 1-6 alkyl-C 2-9 heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, phenyl, heteroaryl, and heterocycloalkyl are optionally substituted; R 5 is —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, or —C 1-6 alkyl-C 2-9 heteroaryl; each R 6 is independently —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, or C 2-9 heteroaryl; or

two R 6 are taken together with the nitrogen atom to which they are attached to form a 5- or 6-membered heterocycle; and

In some embodiments, for a compound of Formula (VII), X 1 and X 2 are independently N or C. In some embodiments, for a compound of Formula (VII), X 1 is N. In some embodiments, for a compound of Formula (VII), X 1 is C. In some embodiments, for a compound of Formula (VII), X 2 is N. In some embodiments, for a compound of Formula (VII), X 2 is C. In some embodiments, for a compound of Formula (VII), X 1 is N and X 2 is C. In some embodiments, for a compound of Formula (VII), X 1 is C and X 2 is N.

›METHODS · 29 of 46

In some embodiments, for a compound of Formula (VII), X 3 is N or CR 4 . In some embodiments, for a compound of Formula (VII), X 3 is N or CH. In some embodiments, for a compound of Formula (VII), X 3 is N. In some embodiments, for a compound of Formula (VII), X 3 is CH.

In some embodiments, for a compound of Formula (VI), Y is a bond, —O—, —S—, —C(R 5 ) 2 , —NR 6 —, —NR 6 C(O)—, —C(O)NR 6 —, or —NR 6 C(O)NR 6 —. In some embodiments, for a compound of Formula (VI), Y is —O— or —NR 6 —. In some embodiments, for a compound of Formula (VI), Y is —O— or —NH—. In some embodiments, for a compound of Formula (VI), Y is —O—. In some embodiments, for a compound of Formula (VI), Y is —NH—.

In some embodiments, for a compound of Formula (VI), R is —H, halogen, —NO 2 , —CN, —OH, —OR 5 , —SR 5 , —N(R 6 ) 2 , —S(O)R 5 , —S(═O) 2 R 5 , —NR 6 S(═O) 2 R 5 , —S(═O) 2 N(R 6 ) 2 , —C(O)R 5 , —C(O)OR 5 , —OC(O)R 5 , —C(O)N(R 6 ) 2 , —OC(O)N(R 6 ) 2 , —NR 6 C(O)N(R 6 ) 2 , —NR 6 C(O)R 5 , —NR 6 C(O)OR 5 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, —O—C 1-6 alkyl, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, 6- to 10-membered aryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 7 . In some embodiments, for a compound of Formula (VI), R is —H, halogen, —S(═O) 2 R 5 , —NR 6 S(═O) 2 R 5 , —S(═O) 2 N(R 6 ) 2 , —C(O)R 5 , —C(O)OR 5 , —OC(O)R 5 , —C(O)N(R 6 ) 2 , —OC(O)N(R 6 ) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, 6- to 10-membered aryl, or —O-phenyl, wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 7 . In some embodiments, for a compound of Formula (VI), R is —H or halogen. In some embodiments, for a compound of Formula (VI), R is —H. In some embodiments, for a compound of Formula (VI), R is —Cl.

In some embodiments a compound of Formula (VI) or a pharmaceutically acceptable salt or isotopic variant thereof has the structure of:

Disclosed herein, are antagonists or partial antagonists of RIPK2 having a structure of Formula (VII) or a pharmaceutically acceptable salt or isotopic variant thereof:

wherein

X 1 and X 2 are independently N or C; X 3 is N or CR 4 ; Y is a bond, —O—, —S—, —C(R 5 ) 2 , —NR 6 —, —NR 6 C(O)—, —C(O)NR 6 —, or —NR 6 C(O)NR 6 —; R 1 and R 2 are independently —H, halogen, —OH, —CN, —N(R 6 ) 2 , —NR 6 C(O)R 5 , —C(O)OR 5 , —C(O)N(R 6 ) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 5 , —C 1-6 alkyl-N(R 6 ) 2 , —O—C 1-6 alkyl, —O—C 1-6 alkyl-OH, —O—C 1-6 alkyl-OR 5 , —O—C 1-6 alkyl-N(R 6 ) 2 , or —S(═O) 2 R 5 ; R 3 is —H, halogen, —NO 2 , —CN, —OH, —OR 5 , —SR 5 , —N(R 6 ) 2 , —S(O)R 5 , —S(═O) 2 R 5 , —NR 6 S(═O) 2 R 5 , —S(═O) 2 N(R 6 ) 2 , —C(O)R 5 , —C(O)OR 5 , —OC(O)R 5 , —C(O)N(R 6 ) 2 , —OC(O)N(R 6 ) 2 , —NR 6 C(O)N(R 6 ) 2 , —NR 6 C(O)R 5 , —NR 6 C(O)OR 5 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, —O—C 1-6 alkyl, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, 6- to 10-membered aryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 7 ; R 4 is —H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, or —C 1-6 alkyl-C 2-9 heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, phenyl, heteroaryl, and heterocycloalkyl are optionally substituted; R 5 is —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, or —C 1-6 alkyl-C 2-9 heteroaryl; each R 6 is independently —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, or C 2-9 heteroaryl; or

two R 6 substituents are taken together with the nitrogen atom to which they are attached to form a 5- or 6-membered heterocycle;

In some embodiments, for a compound of Formula (VII), Y is a bond, —O—, —S—, —C(R 5 ) 2 , —NR 6 —, —NR 6 C(O)—, —C(O)NR 6 —, or —NR 6 C(O)NR 6 —. In some embodiments, for a compound of Formula (VII), Y is a bond, —NR 6 C(O)—, or —C(O)NR 6 —. In some embodiments, for a compound of Formula (VII), Y is a bond, —NHC(O)—, or —C(O)NH—. In some embodiments, for a compound of Formula (VII), Y is a bond. In some embodiments, for a compound of Formula (VII), Y is —NHC(O)—. In some embodiments, for a compound of Formula (VII), Y is —C(O)NH—.

›METHODS · 30 of 46

In some embodiments, for a compound of Formula (VII), R 1 is —H, halogen, —OH, —CN, —N(R 6 ) 2 , —NR 6 C(O)R 5 , —C(O)OR 5 , —C(O)N(R 6 ) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 5 , —C 1-6 alkyl-N(R 6 ) 2 , —O—C 1-6 alkyl, —O—C 1-6 alkyl-OH, —O—C 1-6 alkyl-OR 5 , —O—C 1-6 alkyl-N(R 6 ) 2 , or —S(═O) 2 R 5 . In some embodiments, for a compound of Formula (VII), R 1 is —H, halogen, —N(R 6 ) 2 , —NR 6 C(O)R 5 , C 1-6 alkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 5 , —C 1-6 alkyl-N(R 6 ) 2 , —O—C 1-6 alkyl-N(R 6 ) 2 , or —S(═O) 2 R 5 . In some embodiments, for a compound of Formula (VII), R 1 is —H or —S(═O) 2 R 5 . In some embodiments, for a compound of Formula (VII), R 1 is —H. In some embodiments, for a compound of Formula (VII), R 1 is —S(═O) 2 iso-propyl. In some embodiments, for a compound of Formula (VII), R 1 is —S(═O) 2 tert-butyl.

In some embodiments, for a compound of Formula (VII), R 2 is —H, halogen, —OH, —CN, —N(R 6 ) 2 , —NR 6 C(O)R 5 , —C(O)OR 5 , —C(O)N(R 6 ) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 5 , —C 1-6 alkyl-N(R 6 ) 2 , —O—C 1-6 alkyl, —O—C 1-6 alkyl-OH, —O—C 1-6 alkyl-OR 5 , —O—C 1-6 alkyl-N(R 6 ) 2 , or —S(═O) 2 R 5 . In some embodiments, for a compound of Formula (VII), R 2 is —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, —O—C 1-6 alkyl, —O—C 1-6 alkyl-OH, or —O—C 1-6 alkyl-OR 5 . In some embodiments, for a compound of Formula (VII), R 2 is —H or —O—C 1-6 alkyl. In some embodiments, for a compound of Formula (VII), R 2 is —H. In some embodiments, for a compound of Formula (VII), R 2 is —OCH 3 . In some embodiments, for a compound of Formula (VII), R 2 is —OCH 2 CH 3 .

In some embodiments, for a compound of Formula (VII), R 3 is —H, halogen, —NO 2 , —CN, —OH, —OR 5 , —SR 5 , —N(R 6 ) 2 , —S(O)R 5 , —S(═O) 2 R 5 , —NR 6 S(═O) 2 R 5 , —S(═O) 2 N(R 6 ) 2 , —C(O)R 5 , —C(O)OR 5 , —OC(O)R 5 , —C(O)N(R 6 ) 2 , —OC(O)N(R 6 ) 2 , —NR 6 C(O)N(R 6 ) 2 , —NR 6 C(O)R 5 , —NR 6 C(O)OR 5 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, —O—C 1-6 alkyl, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, 6- to 10-membered aryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 7 . In some embodiments, for a compound of Formula (VII), R 3 is —H, halogen, —N(R 6 ) 2 , —S(═O) 2 R 5 , —NR 6 S(═O) 2 R 5 , —S(═O) 2 N(R 6 ) 2 , —NR 6 C(O)N(R 6 ) 2 , —NR 6 C(O)R 5 , —NR 6 C(O)OR 5 , C 1-6 alkyl, C 1-6 heteroalkyl, —O—C 1-6 alkyl, C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, or 6- to 10-membered aryl, wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 7 . In some embodiments, for a compound of Formula (VII), R 3 is —H, halogen, —N(R 6 ) 2 , or C 1-6 alkyl. In some embodiments, for a compound of Formula (VII), R 3 is —H. In some embodiments, for a compound of Formula (VII), R 3 is —Cl. In some embodiments, for a compound of Formula (VII), R 3 is —F. In some embodiments, for a compound of Formula (VII), R 3 is —CH 3 .

In some embodiments a compound of Formula (VII) or a pharmaceutically acceptable salt or isotopic variant thereof has the structure of:

Disclosed herein, are antagonists or partial antagonists of RIPK2 having a structure of Formula (VIII) or a pharmaceutically acceptable salt or isotopic variant thereof:

wherein:

HET is

X is N and Y is CH; or

X is CH and Y is N;

R 1 is —H, or —F;

R 2 is C 1-3 alkyl, —Cl, or —F;

R 3 and R 4 are each independently —H; —OR 5 ; —O—C 1-6 alkyl-O—C 1-3 alkyl; —O—C 3-6 cycloalkyl; —C(O)R 5 , C 1-6 alkyl optionally substituted with one to three —OH, —F, C 3-8 heterocycloalkyl optionally substituted with oxo, C 3-6 cycloalkyl, —C(O)OR 5 , —O—C 1-6 alkyl, aryl, —N(R 5 )(R 6 ), —CN, or —C(O)N(R 5 )(R 6 ); C 3-6 cycloalkyl optionally substituted with one to three —OH, one to three —F, C 1-6 alkyl, —O—C 1-6 alkyl, C 1-6 alkyl-OC 1-6 alkyl, C 1-6 alkyl-OH, —CF 3 , —CN, —OC 3-6 cycloalkyl, —C(O)OH, —C(O)OR 5 , C 3-6 cycloalkyl, 5-6 membered heteroaryl, C 3-6 heterocycloalkyl, N(R 5 )(R 6 ), or —C(O)N(R 5 )(R 6 ); —C(O)OR 5 ; —C(O)N(R 5 )(R 6 ); —S(═O) 2 N(R 5 )(R 6 ); —S(O) n —R 5 ; a 4-10 membered monocyclic, bicyclic, or spirocyclic heterocyclyl group containing nitrogen, sulfur, or oxygen and optionally substituted with one to three —N(R 5 )(R 6 ), halogen, —C 1-6 alkyl, —O—C 1-6 alkyl, or —C 1-6 haloalkyl; aryl; —N(R 5 )(R 6 ); or halogen;

R 5 and R 6 are each independently —H; —C 1-6 alkyl-C 3-8 heterocycloalkyl; a 4-6 membered heterocycloalkyl wherein the heterocycloalkyl ring is optionally substituted with one to three C 1-6 alkyl, —C 1-6 haloalkyl, C 1-6 cycloalkyl, halogen, acyl, heterocycloalkyl, heterocycloalkyl-C 1-6 alkyl, heterocycloalkyl-O—C 1-6 alkyl, heterocycloalkyl-OH, heterocycloalkyl-C(O)CH 3 , heterocycloalkyl-C(O)OC 1-3 alkyl, —C 1-6 alkyl-heterocycloalkyl, —C 1-6 alkyl-heterocycloalkyl-C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-O—C 1-6 alkyl, C 3-6 cycloalkyl, —C 1-6 alkyl-cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 3-6 cycloalkyl-O—C 1-6 alkyl, or C 3-6 cycloalkyl-O—C 1-6 alkyl-OH; acyl; C 3-6 cycloalkyl-C(O)—C 1-3 alkyl; —C(O)—C 1-3 alkyl-O—CH 3 ; —C(O)—C 1-3 alkyl; —C(O)—C 3-6 cycloalkyl; —C(O)—NH—C 1-3 alkyl; —C(O)—NH—C 1-3 alkyl; —C(O)—NH—C 3-6 cycloalkyl optionally monosubstituted or disubstituted with —C 1-3 alkyl-OH, —C(O)—NH—C 3-6 heterocyclyl, —C(O)-aryl, —C(O)-heteroaryl, or —S(O) n —C 1-3 alkyl; and C 1-6 alkyl optionally substituted with —OH, O—C 1-3 alkyl, C 3-6 cycloalkyl, heterocyclyl, aryl, —NH—C 1-3 alkyl, or —N—(C 1-3 alkyl) 2 ; or

R 5 and R 6 together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring optionally substituted with methyl; and

n is 0, 1, or 2.

In some embodiments, for a compound of Formula (VIII), HET is

X is N, Y is CH, and n is 1 or 2. In some embodiments, for a compound of Formula (VIII), HET is

›METHODS · 31 of 46

X is N, Y is CH, R 2 is —CH 3 or —Cl, R 4 is H, and n is 2. In some embodiments, for a compound of Formula (VIII), HET is

X is N, Y is CH, R 2 is —CH 3 or —Cl, and n is 2. In some embodiments, for a compound of Formula (VIII), HET is

In some embodiments, for a compound of Formula (VIII), HET is

X is CH, Y is N, R 2 is —CH 3 or —Cl, and n is 2. In some embodiments, for a compound of Formula (VIII), HET is

X is CH, Y is N, R 2 is —CH 3 or —Cl, R 4 is —H, and n is 2. In some embodiments, for a compound of Formula (VIII), HET is

X is CH, Y is N, R 2 is —CH 3 or —Cl, R 4 is —H, and n is 2.

In some embodiments, for a compound of Formula (VIII), HET is

X is N, Y is CH, R 1 is —F, and R 2 is —CH 3 . In some embodiments, for a compound of Formula (VIII), HET is

X is N, Y is CH, R 1 is —F, and R 2 is —CH 3 .

In some embodiments, for a compound of Formula (VIII), HET is

X is N, Y is CH, R 2 is —CH 3 or —Cl, R 4 is H, and n is 2. In some embodiments, for a compound of Formula (VIII), HET is

X is N, and Y is CH. In some embodiments, for a compound of Formula (VIII), HET is

X is CH, and Y is N. In some embodiments, for a compound of Formula (VIII), HET is

X is CH, and Y is N.

In some embodiments, for a compound of Formula (VIII), HET is

X is N, Y is CH, R 2 is —CH 3 or —Cl, R 4 is H, and n is 2.

In some embodiments, a compound of Formula (VIII), or a pharmaceutically acceptable salt or isotopic variant thereof, has the structure of:

Disclosed herein, are antagonists or partial antagonists of RIPK2 having a structure of Formula (IX), or a pharmaceutically acceptable salt or isotopic variant thereof:

wherein

R is —H; or R is

at one available ring position;

A and D are independently N or CH;

E is N, CH, or CR;

B and C are independently N, CH, or C—Cl;

R 1 is H; or

R 1 is C—Cl, C—F, C—OCH 3 , C—C(CH 3 ) 3 , or C—OH at one available ring position; and

X—Y are C═C or

wherein R 2 is —H, C 1-6 alkyl, C 1-6 alkyl-OH, C 1-6 alkyl-OC 1-6 alkyl, or C 1-6 alkyl-aryl.

In some embodiments, for a compound of Formula (IX), R 2 is methyl, ethyl, isobutyl, 2-hydroxyethyl, 2-methoxyethyl, benzyl, or phenethyl. In some embodiments, for a compound of Formula (IX), R 2 is methyl. In some embodiments, for a compound of Formula (IX), R 2 is ethyl. In some embodiments, for a compound of Formula (IX), R 2 is isobutyl. In some embodiments, for a compound of Formula (IX), R 2 is 2-hydroxyethyl. In some embodiments, for a compound of Formula (IX), R 2 is 2-methoxyethyl. In some embodiments, for a compound of Formula (IX), R 2 is benzyl. In some embodiments, for a compound of Formula (IX), R 2 is phenethyl.

In some embodiments, a compound of Formula (IX), or a pharmaceutically acceptable salt and isotopic variant thereof, has the structure of:

Disclosed herein, are antagonists or partial antagonists of RIPK2 having a structure of Formula (IXa) or a pharmaceutically acceptable salt and isotopic variant thereof:

wherein

R is —H,

R 1 is C 1-6 alkyl or 6- to 10-membered aryl;

A and D are independently N or CH;

E is N, CH, or CR;

B and C are independently N, CH, or C—Cl;

R 3 is H; or

R 3 is C—Cl, C—F, C—OCH 3 , C—C(CH 3 ) 3 , or C—OH at one available ring position; and

X—Y are C═C or

wherein R 2 is —H, C 1-6 alkyl, C 1-6 alkyl-OH, C 1-6 alkyl-OC 1-6 alkyl, or C 1-6 alkyl-aryl.

In some embodiments, for a compound of Formula (IXa), R 1 is methyl, ethyl, or propyl. In some embodiments, for a compound of Formula (IXa), R 1 is methyl. In some embodiments, for a compound of Formula (IXa), R 1 is ethyl. In some embodiments, for a compound of Formula (IXa), R 1 is propyl.

In some embodiments, for a compound of Formula (IXa), R 2 is methyl, ethyl, isobutyl, 2-hydroxyethyl, 2-methoxyethyl, benzyl, or phenethyl. In some embodiments, for a compound of Formula (IXa), R 2 is methyl. In some embodiments, for a compound of Formula (IXa), R 2 is ethyl. In some embodiments, for a compound of Formula (IXa), R 2 is isobutyl. In some embodiments, for a compound of Formula (IXa), R 2 is 2-hydroxyethyl. In some embodiments, for a compound of Formula (IXa), R 2 is 2-methoxyethyl. In some embodiments, for a compound of Formula (IXa), R 2 is benzyl. In some embodiments, for a compound of Formula (IXa), R 2 is phenethyl.

Disclosed herein, are antagonists or partial antagonists of RIPK2 having a structure of Formula (X), or a pharmaceutically acceptable salt or isotopic variant thereof:

wherein

Cy is C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, 6- to 10-membered aryl, or C 2-9 heteroaryl; Y is absent, —CR b R b —, —O—, —NR b —, or —S(O) n —; R 1 is C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, 6- to 10-membered aryl, or C 2-9 heteroaryl, each of which is optionally substituted with one to three R a ; R 3 is —H, C 2-9 heterocycloalkyl, or C 2-9 heteroaryl, wherein the heterocycloalkyl and heteroaryl are optionally substituted with one to three —F, —Cl, —Br, I, —CN, —NO 2 , —OR b , C 1-4 alkyl, —C 1-3 alkyl-OR b ,—C 1-3 alkyl-NR b R b , C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-8 cycloalkyl, —NR b R b , —C(O)NR b R b , —NR b C(O)NR b R b , —S(O) n NR b R b , C(O)OR b , —OC(O)OR b , —S(O) n R b , —NR b S(O) n R b , —C(S)OR b , —OC(S)R b , —NR b C(O)R b , —C(S)NR b R b , —NR b C(S)R b , —NR b C(O)OR b , —OC(O)NR b R b , —NR b C(S)OR b , —OC(S)NR b R b , —NRC(S)NR b R b , —C(S)R b , or —C(O)R b ; each R 4 is independently halogen, —CN, —NR b R b , —OR b , C 1-4 alkyl, —C 1-3 alkyl-OR b , —C 1-3 alkyl-NR b R b , C 1-4 haloalkyl, or C 1-4 haloalkoxy;

each R a is independently —F, —Cl, —Br, I, —CN, OR b , C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, —C 1-3 alkyl-OR b , or —C 1-3 alkyl-NR b R b ; each R b is independently —H or C 1-4 alkyl;

x is 0, 1, 2, 3, or 4; each m is independently 0, 1, 2, or 3; and each n is independently 0, 1, or 2.

Disclosed herein, are antagonists or partial antagonists of RIPK2 having a structure of Formula (Xa) or a pharmaceutically acceptable salt or isotopic variant thereof:

›METHODS · 32 of 46

Disclosed herein, are antagonists or partial antagonists of RIPK2 having a structure of Formula (Xb) or a pharmaceutically acceptable salt or isotopic variant thereof:

In some embodiments, for a compound of Formula (X), R 1 is optionally substituted phenyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted thienyl, optionally substituted pyridinyl, optionally substituted thiazolyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted furanyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted pyrazolyl, optionally substituted isothiazolyl, optionally substituted pyrmidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, optionally substituted oxadiazolyl, optionally substituted tetrahydropyranyl, optionally substituted triazolyl, or optionally substituted thiadiazolyl. In some embodiments, for a compound of Formula (X), R 1 is optionally substituted phenyl, optionally substituted cyclopentyl, optionally substituted thienyl, or optionally substituted tetrahydropyranyl. In some embodiments, for a compound of Formula (X), R 1 is optionally substituted phenyl. In some embodiments, for a compound of Formula (X), R 1 is optionally substituted cyclopentyl. In some embodiments, for a compound of Formula (X), R 1 is optionally substituted thienyl. In some embodiments, for a compound of Formula (X), R 1 is optionally substituted tetrahydropyranyl.

In some embodiments, for a compound of Formula (X), R 3 is optionally substituted monocyclic heterocycloalkyl or optionally substituted monocyclic heteroaryl. In some embodiments, for a compound of Formula (X), R 3 is optionally substituted monocyclic heterocycloalkyl. In some embodiments, for a compound of Formula (X), R 3 is optionally substituted monocyclic heterocycloaryl.

In some embodiments, for a compound of Formula (X), m is 0 to 3. In some embodiments, for a compound of Formula (X), m is 0. In some embodiments, for a compound of Formula (X), m is 1. In some embodiments, for a compound of Formula (X), m is 2. In some embodiments, for a compound of Formula (X), m is 3.

In some embodiments, for a compound of Formula (X), R 3 is optionally substituted azetidinyl, optionally substituted morpholinyl, optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted tetrahydropyranyl, optionally substituted pyrrolidinyl, optionally substituted thiomorpholinyl, optionally substituted tetrahydrofuryanyl, optionally substituted homomorpholinyl, optionally substituted homopiperazinyl, optionally substituted thiomorpholine dioxide, or optionally substituted thienomorpholine oxide. In some embodiments, for a compound of Formula (X), R 3 is optionally substituted morpholinyl, optionally substituted piperazinyl, optionally substituted piperidinyl, or optionally substituted thiomorpholinyl. In some embodiments, for a compound of Formula (X), R 3 is optionally substituted morpholinyl. In some embodiments, for a compound of Formula (X), R 3 is optionally substituted piperazinyl. In some embodiments, for a compound of Formula (X), R 3 is optionally substituted piperidinyl. In some embodiments, for a compound of Formula (X), R 3 is optionally substituted thiomorpholinyl.

Disclosed herein, are antagonists or partial antagonists of RIPK2 having a structure of Formula (Xc) or a pharmaceutically acceptable salt or isotopic variant thereof:

wherein

R 5 is C 1-4 alkyl or —C 1-3 alkyl-OR b .

Disclosed herein, are antagonists or partial antagonists of RIPK2 having a structure of Formula (Xd) or a pharmaceutically acceptable salt or isotopic variant thereof:

wherein:

Y is absent or —CH 2 —; and

Y is attached to the meta or para position of the phenyl ring.

Disclosed herein, are antagonists or partial antagonists of RIPK2 having a structure of Formula (Xe) or a pharmaceutically acceptable salt or isotopic variant thereof:

wherein

R 5 is —H, C 1-4 alkyl, or —C 1-3 alkyl-OR b ;

Y is absent or —CH 2 —; and

Y is attached to the meta or para position of the phenyl ring.

In some embodiments, for a compound of Formula (X), R 1 is

wherein each R a is independently —F, —Cl, or —CH 3 .

Disclosed herein are additional therapeutic agents comprising a modulator of CD30 ligand (CD30L) (Entrez Gene ID: 943). In some embodiments, the modulator of CD30L is an agonist or an antagonist of CD30L. In some instances, the antagonist of CD30L is an inhibitor of CD30L. In some embodiments, an inhibitor of CD30L specifically binds directly or indirectly to CD30L, CD30, or a molecule that interferes directly or indirectly with binding between CD30L and CD30. In some embodiments, as used herein, an inhibitor of CD30L comprises an agent that modulates at least one functional activity of CD30L, such as binding to CD30. Non-limiting examples of inhibitors of CD30L include agents that specifically bind to CD30L, including a polypeptide such as an anti-CD30L antibody or antigen binding fragment thereof, and a nucleic acid, e.g., an antisense construct, siRNA, and ribozyme. An antisense construct includes an expression plasmid that when transcribed in the cell produces RNA complementary to a portion of mRNA encoding CD30L, and an oligonucleotide that inhibits protein expression by hybridizing with the CD30L mRNA. In some embodiments the inhibitor of CD30L comprises a non-polypeptide or non-nucleic acid portion as an active agent that binds to and inhibits CD30L activity.

In some embodiments, an inhibitor of CD30L is a polypeptide that binds to CD30L and/or CD30. In some cases, the polypeptide is a CD30 polypeptide or a portion thereof, wherein the portion retains the ability to bind to CD30L. A portion of a CD30 polypeptide includes at least about 10, 15, 20, 25, 30, 35, 40, 45, or 50 amino acids that have at least about 85%, 90%, or 95% identity to human CD30 having SEQ ID NO: 53, or SEQ ID NO: 54, or a sequence of any CD30 protein-coding isoform (for e.g., P28908). For example, an inhibitor of CD30L comprises a CD30 polypeptide that comprises all or part of the extracellular region of human CD30. In some embodiments, the CD30 polypeptide comprises amino acids 19-390 of SEQ ID NO: 2018 or a binding fragment thereof, having at least about 85%, 90%, or 95% sequence identity to CD30. In some embodiments, the CD30 polypeptide is a homologue of mammalian CD30, e.g., the CD30 polypeptide inhibitor of CD30L is a viral CD30 polypeptide or fragment thereof. As a non-limiting example, the viral CD30 polypeptide comprises viral CD30 from a poxvirus, such as ectromelia virus or cowpox virus.

›METHODS · 33 of 46

In a non-limiting example, the inhibitor is an anti-CD30L antibody or an anti-CD30 antibody. As used herein, an antibody includes an antigen-binding fragment of a full length antibody, e.g., a Fab or scFv. In some embodiments, the antibody binds to the extracellular domain of CD30L. In some embodiments, an anti-CD30L antibody comprises a heavy chain comprising three complementarity-determining regions: HCDR1, HCDR2, and HCDR3; and a light chain comprising three complementarity-determining regions: LCDR1, LCDR2, and LCDR3. In some embodiments, the anti-CD30L antibody comprises a HCDR1 comprising SEQ ID NO: 20100, a HCDR2 comprising SEQ ID NO: 20101, a HCDR3 comprising SEQ ID NO: 20102, a LCDR1 comprising SEQ ID NO: 20103, a LCDR2 comprising SEQ ID NO: 20104, and a LCDR3 comprising SEQ ID NO: 20105.

In some embodiments, the anti-CD30L antibody comprises a HCDR1 comprising SEQ ID NO: 20106, a HCDR2 comprising SEQ ID NO: 20107, a HCDR3 comprising SEQ ID NO: 20108, a LCDR1 comprising SEQ ID NO: 20109, a LCDR2 comprising SEQ ID NO: 20110, and a LCDR3 comprising SEQ ID NO: 20111.

In some embodiments, the anti-CD30L antibody comprises a HCDR1 comprising SEQ ID NO: 20112, a HCDR2 comprising SEQ ID NO: 20113, a HCDR3 comprising SEQ ID NO: 20114, a LCDR1 comprising SEQ ID NO: 20115, a LCDR2 comprising SEQ ID NO: 20116, and a LCDR3 comprising SEQ ID NO: 20117.

In some embodiments, the anti-CD30L antibody comprises a HCDR1 comprising SEQ ID NO: 20118, a HCDR2 comprising SEQ ID NO: 20119, a HCDR3 comprising SEQ ID NO: 20120, a LCDR1 comprising SEQ ID NO: 20121, a LCDR2 comprising SEQ ID NO: 20122, and a LCDR3 comprising SEQ ID NO: 20123.

In some embodiments, the anti-CD30L antibody comprises a HCDR1 comprising SEQ ID NO: 20124, a HCDR2 comprising SEQ ID NO: 20125, a HCDR3 comprising SEQ ID NO: 20126, a LCDR1 comprising SEQ ID NO: 20127, a LCDR2 comprising SEQ ID NO: 20128, and a LCDR3 comprising SEQ ID NO: 20129.

In some embodiments, the anti-CD30L antibody comprises a HCDR1 comprising SEQ ID NO: 20130, a HCDR2 comprising SEQ ID NO: 20131, a HCDR3 comprising SEQ ID NO: 20132, a LCDR1 comprising SEQ ID NO: 20133, a LCDR2 comprising SEQ ID NO: 20134, and a LCDR3 comprising SEQ ID NO: 20135.

In some cases, the anti-CD30L antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 20136 and a light chain (LC) variable domain comprising SEQ ID NO: 20137. In some cases, the anti-CD30L antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 20138 and a light chain (LC) variable domain comprising SEQ ID NO: 20139. In some cases, the anti-CD30L antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 20140 and a light chain (LC) variable domain comprising SEQ ID NO: 20141. In some cases, the anti-CD30L antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 20142 and a light chain (LC) variable domain comprising SEQ ID NO: 20143. In some cases, the anti-CD30L antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 20144 and a light chain (LC) variable domain comprising SEQ ID NO: 20145. In some cases, the anti-CD30L antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 20146 and a light chain (LC) variable domain comprising SEQ ID NO: 20154. In some cases, the anti-CD30L antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 20147 and a light chain (LC) variable domain comprising SEQ ID NO: 20154. In some cases, the anti-CD30L antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 20148 and a light chain (LC) variable domain comprising SEQ ID NO: 20154. In some cases, the anti-CD30L antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 20149 and a light chain (LC) variable domain comprising SEQ ID NO: 20154. In some cases, the anti-CD30L antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 20150 and a light chain (LC) variable domain comprising SEQ ID NO: 20154. In some cases, the anti-CD30L antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 20151 and a light chain (LC) variable domain comprising SEQ ID NO: 20154. In some cases, the anti-CD30L antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 20152 and a light chain (LC) variable domain comprising SEQ ID NO: 20154. In some cases, the anti-CD30L antibody comprises a heavy chain (HC) variable domain comprising SEQ ID NO: 20153 and a light chain (LC) variable domain comprising SEQ ID NO: 20154.

In some embodiments, the anti-CD30 antibody comprises a heavy chain variable region comprising SEQ ID NO: 55 and a light chain variable region comprising SEQ ID NO: 56. Non-limiting examples of anti-CD30 antibodies include MDX-60, Ber-H2, SGN-30 (cAC10), Ki-4.dgA, HRS-3/A9, AFM13, and H22xKi-4.

In some embodiments, the anti-CD30 antibody comprises an antibody drug conjugate. As a non-limiting example, the antibody drug conjugate is brentuximab, an anti-CD30 antibody conjugated to monomethyl auristatin E.

Disclosed herein are additional therapeutic agents that are effective to modify expression and/or activity of G-protein coupled receptor 35 (GPR35) (Entrez Gene ID: 2859) (e.g., modulator of GPR35). Alternatively or additionally, compositions, kits and methods disclosed herein may comprise and/or utilize a therapeutic agent or use thereof, wherein the therapeutic agent modifies expression and/or activity of a protein that functions upstream or downstream of a pathway that involves GPR35. In some embodiments, the modulator of GPR35 is effective to increase or activate the activity or expression of GPR35 in the subject (e.g., agonist or partial agonist). In some embodiments, the modulator of GPR35 is effective to decrease or reduce the activity or expression of GPR35 (e.g., antagonist or partial antagonist).

In some instances, the therapeutic agent is an antagonist of GPR35. In some instances, the antagonist acts as an inverse agonist. Non-limiting examples of inverse agonists are ML145 and ML144. In some instances, the therapeutic agent is an allosteric modulator of GPR35. Methods disclosed herein may comprise administering the modulator of GPR35 alone. In other instances, methods disclosed herein may comprise administering the modulator of GPR35along with another therapeutic agent disclosed herein (e.g., anti-TL1A antibody), a nutritional-based therapy, a nature-based therapy, a diet-based therapy, or a combination thereof.

›METHODS · 34 of 46

In some instances, the therapeutic agent is a small molecule drug. By way of non-limiting example, a small molecule drug may be a chemical compound. In some cases, a small molecule has a molecular weight less than about 1,000 Da, or less than about 900 Da, or less than about 800 Da. In some cases, a small molecule has a molecular weight from about 50 Da to about 1,000 Da. In some instances, the therapeutic agent is a large molecule drug. Large molecule drugs generally comprise a peptide or nucleic acid. By way of non-limiting example, the large molecule drug may comprise an antibody or antigen binding antibody fragment. In some instances, the therapeutic agent comprises a small molecule and a large molecule. By way of non-limiting example, the therapeutic agent may comprise an antibody-drug conjugate.

In some instances, the therapeutic agent is a small molecule that binds GPR35. In some instances, the small molecule that binds GPR35 is a GPR35 agonist. In some instances, the small molecule that binds GPR35 is a GPR35 partial agonist. In some instances, the small molecule that binds GPR35 is a GPR35 antagonist. In some instances, the small molecule that binds GPR35 is a GPR35 partial agonist.

In some instances, the small molecule that binds GPR35 is a compound of Formula (I):

wherein:

X 1 and X 2 are independently selected from N and CR 14 ; R 1 is —CH 2 R 4 , —CN, —B(OH) 2 , —N(R 10 ) 2 , —NR 10 C(O)R 9 , —C(O)OH, —CH 2 C(O)OH, —C(O)N(R 10 ) 2 , —C(O)NHS(O) 2 N(R 10 ) 2 , —C 1-6 alkyl-OH, C 3-8 cycloalkyl,

or a 5- or 6-membered heteroaryl optionally substituted with one, two, or three R 8 groups;

R 2 is H, —OH, —N(R 10 ) 2 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)N(R 10 ) 2 , OC(O)N(R 10 ) 2 , —O—C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl; each R 3 is independently selected from halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl; R 4 is

each R 5 is independently selected from halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)NHS(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , —C 1-6 alkyl-C(O)OR 10 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkyl-OH, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, and C 1-9 heteroaryl; wherein phenyl, —C 1-6 alkyl-phenyl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and C 2-9 heterocycloalkyl; and wherein C 2-9 heterocycloalkyl is optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and oxo;

R 6 is —C(O)OR 7 , —C(O)NHS(O) 2 N(R 10 ) 2 ,

each R 7 is independently selected from H and C 1-6 alkyl;

each R 8 is independently selected from halogen, —OH, —OR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)NHS(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , —C 1-6 alkyl-C(O)OR 10 , C 1-6 haloalkyl, C 1-6 haloalkyl-OH, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, and C 1-9 heteroaryl; wherein phenyl, —C 1-6 alkyl-phenyl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and C 2-9 heterocycloalkyl; and wherein C 2-9 heterocycloalkyl is optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and oxo;

each R 9 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from C 1-6 alkyl, —OR 11 , —N(R 11 ) 2 , C 1-6 alkyl, C 3-8 cycloalkyl, —C(O)R 12 , and —C(O)OR 12 ;

each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, —N(R 11 ) 2 , and —C(O)OR 12 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 1-6 alkyl, oxo, and —C(O)OH;

each R 11 is independently selected from H and C 1-6 alkyl;

R 12 is independently selected from H and C 1-6 alkyl;

R 13 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl;

each R 14 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl;

›METHODS · 35 of 46

n is 0, 1, 2, or 3;

p is 0, 1, 2, 3, 4, or 5; and

q is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound of Formula (II):

wherein:

X 1 , X 2 , and Y 2 are independently selected from O, NR 13 , and C(R 14 ) 2 ; R 1 and R 2 are independently selected from —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , and —C 1-6 alkyl-N(R 10 ) 2 ; R 3 is selected from —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl; each R 4 and R 5 is independently selected from halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl; each R 9 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from C 1-6 alkyl, —OR 11 , —N(R 11 ) 2 , C 1-6 alkyl, C 3-8 cycloalkyl, —C(O)R 12 , and —C(O)OR 12 ; each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, and —N(R 11 ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 1-6 alkyl, oxo, and —C(O)OH; each R 11 is independently selected from H and C 1-6 alkyl; each R 12 is independently selected from H and C 1-6 alkyl; each R 13 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl; each R 14 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl; m is 1, 2, 3, 4, or 5; n is 1, 2, 3, 4, or 5; p is 0, 1, 2, or 3; and q is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound of Formula (III):

wherein:

X 1 and X 2 are independently selected from O, NR 13 , and C(R 14 ) 2 ; R 1 and R 2 are independently selected from —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , and —C 1-6 alkyl-N(R 10 ) 2 ; R 3 and R 4 are independently selected from H, halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl; each R 9 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from C 1-6 alkyl, —OR 11 , —N(R 11 ) 2 , C 1-6 alkyl, C 3-8 cycloalkyl, —C(O)R 12 , and —C(O)OR 12 ; each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, and —N(R 11 ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 1-6 alkyl, oxo, and —C(O)OH; each R 11 is independently selected from H and C 1-6 alkyl; each R 12 is independently selected from H and C 1-6 alkyl; each R 13 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl; and each R 14 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl;

›METHODS · 36 of 46

or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound of Formula (IV):

wherein:

or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound of Formula (V):

wherein:

R 1 and R 2 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl; each R 3 is independently selected from halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl; each R 9 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from C 1-6 alkyl, —OR 11 , —N(R 11 ) 2 , C 1-6 alkyl, C 3-8 cycloalkyl, —C(O)R 12 , and —C(O)OR 12 ; each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, and —N(R 11 ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 1-6 alkyl, oxo, and —C(O)OH; each R 11 is independently selected from H and C 1-6 alkyl; each R 12 is independently selected from H and C 1-6 alkyl; and p is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound of Formula (VI):

wherein:

X 1 and X 2 are independently selected from O, NR 13 , and C(R 14 ) 2 ; R 1 and R 2 are independently selected from —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , and —C 1-6 alkyl-N(R 10 ) 2 ; R 3 and R 4 are independently selected from H, halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 CC(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl; each R 9 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from C 1-6 alkyl, —OR 11 , —N(R 11 ) 2 , C 1-6 alkyl, C 3-8 cycloalkyl, —C(O)R 12 , and —C(O)OR 12 ; each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, and —N(R 11 ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 1-6 alkyl, oxo, and —C(O)OH; each R 11 is independently selected from H and C 1-6 alkyl; each R 12 is independently selected from H and C 1-6 alkyl; each R 13 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl; and each R 14 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl;

›METHODS · 37 of 46

or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound of Formula (V):

wherein:

or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound of Formula (VII):

R 1 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl;

R 2 is selected from H, halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl;

each R 3 and each R 4 is independently selected from halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl;

each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, and —N(R 11 ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 1-6 alkyl, oxo, and —C(O)OH;

each R 11 is independently selected from H and C 1-6 alkyl;

each R 12 is independently selected from H and C 1-6 alkyl;

p is 0, 1, 2, 3, or 4; and

q is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound of Formula (VIII):

wherein:

X is selected from —O—, —S—, and —SO 2 —; R 1 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl; each R 2 and each R 3 is independently selected from halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl; R 4 is selected from —C(O)OH, —C(O)OR 10 ,

R 5 is selected from H, halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl;

›METHODS · 38 of 46

each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, and —N(R 11 ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 1-6 alkyl, oxo, and —C(O)OH;

each R 11 is independently selected from H and C 1-6 alkyl;

each R 12 is independently selected from H and C 1-6 alkyl;

p is 0, 1, 2, 3, or 4; and

q is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound of Formula (IX):

wherein:

X is selected from —O— and —S—; R 1 is selected from H, halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl;

R 2 is selected from —C(O)OH, —C(O)OR 10 ,

each R 3 is independently selected from halogen, —CN, —OH, NO 2 , —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl;

each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, and —N(R 11 ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 1-6 alkyl, oxo, and —C(O)OH;

each R 11 is independently selected from H and C 1-6 alkyl;

each R 12 is independently selected from H and C 1-6 alkyl; and

p is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound of Formula (X):

wherein:

R 1 is selected from —C(O)OH, —C(O)OR 10 ,

each R 2 is independently selected from halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl;

each R 3 is independently selected from H, halogen, —CN, —OH, NO 2 , —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl;

each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, and —N(R 11 ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 1-6 alkyl, oxo, and —C(O)OH;

each R 11 is independently selected from H and C 1-6 alkyl;

each R 12 is independently selected from H and C 1-6 alkyl; and

p is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound of Formula (XI):

wherein:

X is selected from —O—, —S—, and —SO 2 —; R 1 is selected from H, halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl; each R 2 and each R 3 is independently selected from halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl; each R 9 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from C 1-6 alkyl, —OR 11 , —N(R 11 ) 2 , C 1-6 alkyl, C 3-8 cycloalkyl, —C(O)R 12 , and —C(O)OR 12 ; each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, and —N(R 11 ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 1-6 alkyl, oxo, and —C(O)OH; each R 11 is independently selected from H and C 1-6 alkyl; each R 12 is independently selected from H and C 1-6 alkyl; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4;

›METHODS · 39 of 46

or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound of Formula (XII):

wherein:

X is selected from —O—, —S—, —NR 13 —, and —C(R 14 ) 2 —; each R 1 is independently selected from H, halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl; R 2 is selected from H and C 1-6 alkyl; each R 3 and each R 4 is independently selected from halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl; each R 9 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from C 1-6 alkyl, —OR 11 , —N(R 11 ) 2 , C 1-6 alkyl, C 3-8 cycloalkyl, —C(O)R 12 , and —C(O)OR 12 ; each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, and —N(R 11 ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 1-6 alkyl, oxo, and —C(O)OH; each R 11 is independently selected from H and C 1-6 alkyl; each R 12 is independently selected from H and C 1-6 alkyl; R 13 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl; R 14 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound of Formula (XIII):

wherein:

X 1 and X 2 are independently —O—, —S—, or —NR 13 —; R 1 is selected from —C(O)OH, —C(O)OR 10 ,

each R 3 is independently selected from halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl;

each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, and —N(R 11 ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 1-6 alkyl, oxo, and —C(O)OH;

each R 11 is independently selected from H and C 1-6 alkyl;

each R 12 is independently selected from H and C 1-6 alkyl;

R 13 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl; and

p is 0, 1 or 2;

or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound of Formula (XIV):

wherein:

R 1 and R 2 are independently selected from H, halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl; each R 3 is independently selected from halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 ,—NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl; each R 9 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from C 1-6 alkyl, —OR 11 , —N(R 11 ) 2 , C 1-6 alkyl, C 3-8 cycloalkyl, —C(O)R 12 , and —C(O)OR 12 ; each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, and —N(R 11 ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 1-6 alkyl, oxo, and —C(O)OH; each R 11 is independently selected from H and C 1-6 alkyl; each R 12 is independently selected from H and C 1-6 alkyl; and p is 0, 1, 2, 3, or 4;

›METHODS · 40 of 46

or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound of Formula (XV):

wherein:

X is selected from —O—, —S—, and —SO 2 —; Y is N or CR 2 ; R 1 is —C(O)OH, —C(O)OR 10 ,

each R 2 is independently selected from H, halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl;

each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, and —N(R 11 ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 1-6 alkyl, oxo, and —C(O)OH;

each R 11 is independently selected from H and C 1-6 alkyl;

each R 12 is independently selected from H and C 1-6 alkyl; and

p is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound of Formula (XVI):

wherein:

X is selected from —O—, —S—, and —NR 13 —; R 1 is selected from —C(O)OH, —C(O)OR 10 ,

each R 2 and each R 7 is independently selected from halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl;

R 3 and R 4 are independently selected from H and C 1-6 alkyl;

R 5 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl;

R 6 is independently H, halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl;

each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, and —N(R 11 ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 1-6 alkyl, oxo, and —C(O)OH;

each R 11 is independently selected from H and C 1-6 alkyl;

each R 12 is independently selected from H and C 1-6 alkyl;

R 13 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl;

p is 0, 1, 2, or 3; and

q is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound of Formula (XVII):

wherein:

X is selected from —O—, —S—, and —SO 2 —; R 1 is selected from —C(O)OH, —C(O)OR 10 ,

each R 2 and each R 3 is independently selected from halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl;

›METHODS · 41 of 46

each R 9 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from C 1-6 alkyl, —OR 11 , —N(R 11 ) 2 , C 1-6 alkyl, C 3-8 cycloalkyl, —C(O)R 12 , and —C(O)OR 12 ;

each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, and —N(R 11 ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 1-6 alkyl, oxo, and —C(O)OH;

each R 11 is independently selected from H and C 1-6 alkyl;

each R 12 is independently selected from H and C 1-6 alkyl;

p is 0, 1, 2, or 3; and

q is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound of Formula (XVIII):

wherein:

R 1 is selected from —C(O)OH, —C(O)OR 10 ,

R 2 is independently selected from H, halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl;

each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, and —N(R 11 ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 1-6 alkyl, oxo, and —C(O)OH;

each R 11 is independently selected from H and C 1-6 alkyl;

each R 12 is independently selected from H and C 1-6 alkyl; and

p is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound of Formula (XIX):

wherein:

X is selected from —O—, —S—, and —NR 13 —; R 1 is selected from H and C 1-6 alkyl; R 2 is independently selected from H, halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl; R 3 is selected from H, halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl; each R 4 is independently selected from halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl; each R 9 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from C 1-6 alkyl, —OR 11 , —N(R 11 ) 2 , C 1-6 alkyl, C 3-8 cycloalkyl, —C(O)R 12 , and —C(O)OR 12 ; each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, and —N(R 11 ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 1-6 alkyl, oxo, and —C(O)OH; each R 11 is independently selected from H and C 1-6 alkyl; each R 12 is independently selected from H and C 1-6 alkyl; R 13 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl; and p is 0, 1, 2, 3, or 4;

›METHODS · 42 of 46

or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound of Formula (XX):

wherein:

X is selected from —O— and —C(R 14 ) 2 —; R 1 is selected from H, halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl; R 2 is selected from H, halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl; each R 3 and each R 4 is selected from H, halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl; each R 9 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from C 1-6 alkyl, —OR 11 , —N(R 11 ) 2 , C 1-6 alkyl, C 3-8 cycloalkyl, —C(O)R 12 , and —C(O)OR 12 ; each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, and —N(R 11 ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 1-6 alkyl, oxo, and —C(O)OH; each R 11 is independently selected from H and C 1-6 alkyl; each R 12 is independently selected from H and C 1-6 alkyl; each R 14 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl; and

or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound of Formula (XXI):

wherein:

X 1 and X 2 are independently selected from —O— and —S—; each R 1 and each R 2 are independently selected from halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl; each R 9 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from C 1-6 alkyl, —OR 11 , —N(R 11 ) 2 , C 1-6 alkyl, C 3-8 cycloalkyl, —C(O)R 12 , and —C(O)OR 12 ; each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, and —N(R 11 ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 1-6 alkyl, oxo, and —C(O)OH; each R 11 is independently selected from H and C 1-6 alkyl; each R 12 is independently selected from H and C 1-6 alkyl; R 13 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl; p is 0, 1, 2, or 3; q is 0, 1, 2, or 3; and

or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound of Formula (XXII):

wherein:

X is selected from —O— and —S—; R 1 , R 2 , and R 3 are independently selected from H, halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl; each R 4 is selected from halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl; each R 9 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from C 1-6 alkyl, —OR 11 , —N(R 11 ) 2 , C 1-6 alkyl, C 3-8 cycloalkyl, —C(O)R 12 , and —C(O)OR 12 ; each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, and —N(R 11 ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 1-6 alkyl, oxo, and —C(O)OH; each R 11 is independently selected from H and C 1-6 alkyl; each R 12 is independently selected from H and C 1-6 alkyl; and p is 0, 1, 2, 3, or 4;

›METHODS · 43 of 46

or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound of Formula (XXIII):

wherein:

each X is independently selected from —O— and —S—; R 1 is selected from —C(O)OH, —C(O)OR 10 ,

each R 2 is selected from halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl;

R 3 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl;

each R 4 and each R 5 are independently selected from H, halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl;

R 6 is selected from C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and phenyl, wherein C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and phenyl are optionally substituted with one or two groups independently selected from C 1-6 alkyl, —OR 11 , —N(R 11 ) 2 , C 1-6 alkyl, C 3-8 cycloalkyl, —C(O)R 12 , and —C(O)OR 12 ;

each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, and —N(R 11 ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 1-6 alkyl, oxo, and —C(O)OH;

each R 11 is independently selected from H and C 1-6 alkyl;

each R 12 is independently selected from H and C 1-6 alkyl; and

p is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound of Formula (XXIV):

wherein:

X is selected from —O— and —S—; R 1 is selected from —C(O)OH, —C(O)OR 10 ,

each R 2 is selected from H, halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl;

each R 3 is selected from halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl;

R 4 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-8 cycloalkyl;

R 5 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl;

R 6 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl;

each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, and —N(R 11 ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 1-6 alkyl, oxo, and —C(O)OH;

each R 11 is independently selected from H and C 1-6 alkyl;

each R 12 is independently selected from H and C 1-6 alkyl; and

p is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound of Formula (XXV):

wherein:

X is selected from CR 2 or N; R 1 is selected from C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and phenyl, wherein C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and phenyl are optionally substituted with one or two groups independently selected from C 1-6 alkyl, —OR 11 , —N(R 11 ) 2 , C 1-6 alkyl, C 3-8 cycloalkyl, —C(O)R 12 , and —C(O)OR 12 ; each R 2 and each R 6 is selected from halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl; R 3 and R 4 are independently selected from H, halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl; each R 5 are independently selected from H, halogen, —CN, —OH, —OR 9 , —SR 9 , —N(R 10 ) 2 , —S(O)R 9 , —S(O) 2 R 9 , —NHS(O) 2 R 9 , —S(O) 2 N(R 10 ) 2 , —C(O)R 9 , —C(O)OR 10 , —OC(O)R 9 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , —NR 10 C(O)N(R 10 ) 2 , —NR 10 C(O)R 9 , —NR 10 C(O)OR 9 , C 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-OR 9 , —C 1-6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and —C 1-6 alkyl-C 3-8 cycloalkyl; each R 9 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and —C 1-6 alkyl-C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from C 1-6 alkyl, —OR 11 , —N(R 11 ) 2 , C 1-6 alkyl, C 3-8 cycloalkyl, —C(O)R 12 , and —C(O)OR 12 ; each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, and —N(R 11 ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 1-6 alkyl, oxo, and —C(O)OH; each R 11 is independently selected from H and C 1-6 alkyl; each R 12 is independently selected from H and C 1-6 alkyl; p is 0, 1, 2, 3, 4, 5, or 6; and q is 0, 1, 2, 3, or 4;

›METHODS · 44 of 46

or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound of Formula (XXVI):

wherein:

R 1 is selected from —C(O)OH, —C(O)OR 10 ,

each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl-C 3-8 cycloalkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl, wherein C 1-6 alkyl, phenyl, —C 1-6 alkyl-phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, and —N(R 11 ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 1-6 alkyl, oxo, and —C(O)OH;

each R 11 is independently selected from H and C 1-6 alkyl;

each R 12 is independently selected from H and C 1-6 alkyl;

p is 0, 1, 2, 3, or 4; and

or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is selected from zaprinast, lodoxamide, bufrolin, TC-G 1001, nedocromil, PSB-13253, 6-bromo-7-hydroxy-8-nitro-3-(1H-tetrazol-5-yl)-2H-chromen-2-one, 6-bromo-7-hydroxy-8-nitro-2-oxo-2H-chromene-3-carboxylic acid, 7-deshydroxypyrogallin-4-carboxylic acid (DCA), morin, cromolyn, T3, reverse T3, YE-210, cromoglicic acid, nedocromil, pamoic acid, and tyrphostin-51.

In some instances, the small molecule that binds GPR35 is selected from pamoic acid, amlexanox, furosemide, doxantrazole, kynurenic acid, DHICA, cyclic guanosine monophosphate (cGMP), 2,3,5-THB, ellagic acid, LPA species, and YE120.

In some instances, the small molecule that binds GPR35 is selected from ML-145, ML-194, and ML-144.

In some instances, the small molecule that binds GPR35 is selected from:

Pharmaceutical Composition

A pharmaceutical composition, as used herein, refers to a mixture of a therapeutic agent, with other chemical components (i.e. pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, or one or more combination thereof. Optionally, the compositions include two or more therapeutic agent (e.g., one or more therapeutic agents and one or more additional agents) as discussed herein. In practicing the methods of treatment or use provided herein, therapeutically effective amounts of therapeutic agents described herein are administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated, e.g., an inflammatory disease, fibrostenotic disease, and/or fibrotic disease. In some embodiments, the mammal is a human. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the therapeutic agent used and other factors. The therapeutic agents can be used singly or in combination with one or more therapeutic agents as components of mixtures.

The pharmaceutical formulations described herein are administered to a subject by appropriate administration routes, including but not limited to, intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, inhalation, or intraperitoneal administration routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

Pharmaceutical compositions including a therapeutic agent are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

The pharmaceutical compositions may include at least a therapeutic agent as an active ingredient in free-acid or free-base form, or in a pharmaceutically acceptable salt form. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides (if appropriate), crystalline forms, amorphous phases, as well as active metabolites of these compounds having the same type of activity. In some embodiments, therapeutic agents exist in unsolvated form or in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the therapeutic agents are also considered to be disclosed herein.

›METHODS · 45 of 46

In some embodiments, a therapeutic agent exists as a tautomer. All tautomers are included within the scope of the agents presented herein. As such, it is to be understood that a therapeutic agent or a salt thereof may exhibit the phenomenon of tautomerism whereby two chemical compounds that are capable of facile interconversion by exchanging a hydrogen atom between two atoms, to either of which it forms a covalent bond. Since the tautomeric compounds exist in mobile equilibrium with each other they may be regarded as different isomeric forms of the same compound.

In some embodiments, a therapeutic agent exists as an enantiomer, diastereomer, or other stereoisomeric form. The agents disclosed herein include all enantiomeric, diastereomeric, and epimeric forms as well as mixtures thereof.

In some embodiments, therapeutic agents described herein may be prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug would be a therapeutic agent described herein, which is administered as an ester (the “prodrug”) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the therapeutic agent. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the therapeutic agent.

Prodrug forms of the therapeutic agents, wherein the prodrug is metabolized in vivo to produce an agent as set forth herein are included within the scope of the claims. Prodrug forms of the herein described therapeutic agents, wherein the prodrug is metabolized in vivo to produce an agent as set forth herein are included within the scope of the claims. In some cases, some of the therapeutic agents described herein may be a prodrug for another derivative or active compound. In some embodiments described herein, hydrazones are metabolized in vivo to produce a therapeutic agent.

In certain embodiments, compositions provided herein include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

In some embodiments, formulations described herein benefit from antioxidants, metal chelating agents, thiol containing compounds and other general stabilizing agents. Examples of such stabilizing agents, include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

The pharmaceutical compositions described herein are formulated into any suitable dosage form, including but not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, solid oral dosage forms, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations. In one aspect, a therapeutic agent as discussed herein, e.g., therapeutic agent is formulated into a pharmaceutical composition suitable for intramuscular, subcutaneous, or intravenous injection. In one aspect, formulations suitable for intramuscular, subcutaneous, or intravenous injection include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propyleneglycol, polyethylene-glycol, glycerol, cremophor and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. In some embodiments, formulations suitable for subcutaneous injection also contain additives such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the growth of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. In some cases it is desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin.

›METHODS · 46 of 46

For intravenous injections or drips or infusions, a therapeutic agent described herein is formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. For other parenteral injections, appropriate formulations include aqueous or nonaqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are known.

Parenteral injections may involve bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi dose containers, with an added preservative. The pharmaceutical composition described herein may be in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. In one aspect, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

For administration by inhalation, a therapeutic agent is formulated for use as an aerosol, a mist or a powder. Pharmaceutical compositions described herein are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the therapeutic agent described herein and a suitable powder base such as lactose or starch.

Representative intranasal formulations are described in, for example, U.S. Pat. Nos. 4,476,116, 5,116,817 and 6,391,452. Formulations that include a therapeutic agent are prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, for example, Ansel, H. C. et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Ed. (1995). Preferably these compositions and formulations are prepared with suitable nontoxic pharmaceutically acceptable ingredients. These ingredients are known to those skilled in the preparation of nasal dosage forms and some of these can be found in REMINGTON: THE

›Tables in the description — 8

TABLE 1 — Exemplary Polymorphisms SEQ

			Minor	Major	ID
rsID	Chip_id	Gene	Allele	Allele	NO
rs11897732	1 kg_2_43394890	THADA	G	A	1
rs6740739	1 kg_2_43709147	THADA,	A	G	2
		PLEKHH2
rs17796285	1 kg_8_11161865	XKR6, MTMR9	G	C	3
rs7935393	imm_11_127948309	ETS1	C	A	4
rs12934476	imm_16_11239010	CLEC16A,	G	A	5
		SOCS1
rs12457255	imm_18_12749976	LOC100996324,	A	C	6
		PTPN2
rs2070557	imm_21_44479552	ICOSLG	A	T	7
rs4246905	imm_9_116593070	TNFSF15	A	G	8
rs10974900	imm_9_4977958	JAK2	A	G	9
rs12434976	rs12434976	LINC01550,	C	A	10
		C14orf177
rs16901748	rs16901748	CTNND2	A	C	11
rs2815844	rs2815844	RGS7	A	G	12
rs889702	rs889702	RBFOX1	G	A	13
rs2409750	1 kg_8_11125104	XKR6, MTMR9	C	A	14
rs1541020	imm_10_6205036	RBM17,	A	G	15
		PFKFB3
rs4942248	imm_13_43304805	ENOX1,	T	A	16
		CCDC122
rs12934476	imm_16_11239010	CLEC16A,	G	A	17
		SOCS1
rs12457255	imm_18_12749976	LOC100996324,	A	C	18
		PTPN2
rs2297437	imm_20_61775718	RTEL1-	A	G	19
		TNFRSF6B
rs41309367	imm_20_61779998	RTEL1-	G	A	20
		TNFRSF6B
rs10733509	imm_9_4298050	GLIS3, SLC1A1	A	G	21
rs10750376	rs10750376	LOC101929497,	G	A	22
		ETS1
rs10932456	rs10932456	MIR4776-2,	G	A	23
		IKZF2
rs1326860	rs1326860	LINC01031,	A	G	24
		NONE
rs1528663	rs1528663	FAR1, SPON1	G	A	25
rs1892231	rs1892231	LINC01550,	C	A	26
		C14orf177
rs951279	rs951279	PLXNA2,	G	A	27
		MIR205HG
rs9806914	rs9806914	RBFOX1	A	G	28
rs7935393	imm_11_127948309	ETS1	C	A	29
rs1690492	imm_16_11226317	CLEC16A,	G	C	30
		SOCS1
rs420726	imm_21_44483873	ICOSLG	G	A	31
rs7759385	imm_6_106695463	PRDM1, ATG5	T	A	32
rs10974900	imm_9_4977958	JAK2	A	G	33
rs1326860	rs1326860	LINC01031,	A	G	34
		NONE
rs2548147	rs2548147	LINC00603,	C	G	35
		PTGER4
rs2815844	rs2815844	RGS7	A	G	36
rs889702	rs889702	RBFOX1	G	A	37
rs9806914	rs9806914	RBFOX1	A	G	38
rs6478109	imm_9_116608587	TNFSF15	A	G	39
rs7278257	imm_21_44478192	ICOSLG	C	G	40
rs11221332	imm_11_127886184	ETS1	A	G	41
rs56124762	imm_21_44482902	ICOSLG	A	G	57
rs2070558	imm_21_44480086	ICOSLG	G	A	58
rs2070561	rs2070561	ICOSLG	T	C	59

TABLE 2A — Non-Limiting Examples of anti-TL1A and anti-DR3 Antibodies and Portions Thereof Antibody

SEQ ID	Region	Sequence
109	HCDR1	GFTFSTYG
110	HCDR2	ISGTGRTT
111	HCDR3	TKERGDYYYG VFDY
112	LCDR1	QTISSW
113	LCDR2	AAS
114	LCDR3	QQYHRSWT
115	HC Variable	EVQLLESGGG LVQPGKSLRL SCAVSGFTFS TYGMNWVRQA
		PGKGLEWVSS
		ISGTGRTTYH ADSVQGRFTV SRDNSKNILY LQMNSLRADD
		TAVYFCTKER
		GDYYYGVFDY WGQGTLVTVS S
116	LC Variable	DIQMTQSPST LSASVGDRVT ITCRASQTIS SWLAWYQQTP
		EKAPKLLIYA
		ASNLQSGVPS RFSGSGSGTE FTLTISSLQP DDFATYYCQQ
		YHRSWTFGQG
		TKVEIT
117	HCDR1	GFTFSSYW
118	HCDR2	IKEDGSEK
119	HCDR3	AREDYDSYYK YGMDV
120	LCDR1	QSILYSSNNK NY
121	LCDR2	WAS
122	LCDR3	QQYYSTPFT
123	HC Variable	EVQLVESGGG LVQPGGSLRL SCAVSGFTFS SYWMSWVRQA
		PGKGLEWVAN
		IKEDGSEKNY VDSVKGRFTL SSDNAKNSLY LQMNSLRAED
		TAVYYCARED
		YDSYYKYGMD VWGQGTAVIV SS
124	LC Variable	DIVMTQSPDS LAVSLGERAT INCKSSQSIL YSSNNKNYLA
		WYQQKPGQPP
		KLLIYWASTR ESGVPDRFSG SGSGTDFTLT ISSLQAEDVS
		VYYCQQYYST
		PFTFGPGTKV DIK
125	HCDR1	GGSFTGFY
126	HCDR2	INHRGNT
127	HCDR3	ASPFYDFWSG SDY
128	LCDR1	QSLVHSDGNT Y
129	LCDR2	MS
130	LCDR3	MQATQFPLT
131	HC Variable	QVQLQQWGAG LLKPSETLSL TCAVYGGSFT GFYWSWIRQP
		PGKGLEWIGE
		INHRGNTNYN PSLKSRVTMS VDTSKNQFSL NMISVTAADT
		AMYFCASPFY
		DFWSGSDYWG QGTLVTVSS
132	LC Variable	DIMLTQTPLT SPVTLGQPAS ISCKSSQSLV HSDGNTYLSW
		LQQRPGQPPR
		LLFYKISNRF SGVPDRFSGS GAGTDFTLKI SRVEAEDVGV
		YYCMQATQFP
		LTFGGGTKVE IK
133	HCDR1	GY(X1)F(X2)(X3)YGIS; X1 = P, S, D, Q, N; X2 = T, R;
		X3 = N, T, Y, H
134	HCDR2	WIS(X1)YNG(X2)(X3)(X4)YA(X5)(X6)(X7)QG; X1 = T, P, S, A;
		X2 = N, G, V, K, A; X3 = T, K; X4 = H, N; X5 = Q, R;
		X6 = K, M; X7 = L, H
135	HCDR3	ENYYGSG(X1)(X2)R GGMD(X3); X1 = S, A; X2 = Y, P; X3 = V,
		A, G
136	HCDR1	GYDFTYYGIS
137	HCDR2	WISTYNGNTH YARMLQG
138	HCDR3	ENYYGSGAYR GGMDV
139	LCDR1	RASQSVSSYL A
140	LCDR2	DASNRAT
141	LCDR3	QQRSNWPWT
142	HC Variable	QVQLVQSGAE VKKPGASVKV SCKASGYDFT YYGISWVRQA
		PGQGLEWMGW
		ISTYNGNTHY ARMLQGRVTM TTDTSTRTAY MELRSLRSDD
		TAVYYCAREN
		YYGSGAYRGG MDVWGQGTTV TVSS
143	LC Variable	EIVLTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQQKP
		GQAPRLLIYD
		ASNRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ
		RSNWPWTFGQ
		GTKVEIK
144	HC	QVQLVQSGAE VKKPGASVKV SCKASGYDFT YYGISWVRQA
		PGQGLEWMGW
		ISTYNGNTHY ARMLQGRVTM TTDTSTRTAY MELRSLRSDD
		TAVYYCAREN
		YYGSGAYRGG MDVWGQGTTV TVSSASTKGP SVFPLAPSSK
		STSGGTAALG
		CLVKDYFPEP VTVSWNSGAL TSGVHTFPAV LQSSGLYSLS
		SVVTVPSSSL
		GTQTYICNVN HKPSNTKVDK KVEPKSCDKT HTCPPCPAPE
		AAGAPSVFLF
		PPKPKDTLMI SRTPEVTCVV VDVSHEDPEV KFNWYVDGVE
		VHNAKTKPRE
		EQYNSTYRVV SVLTVLHQDW LNGKEYKCKV SNKALPAPIE
		KTISKAKGQP
		REPQVYTLPP SREEMTKNQV SLTCLVKGFY PSDIAVEWES
		NGQPENNYKT
		TPPVLDSDGS FFLYSKLTVD KSRWQQGNVF SCSVMHEALH
		NHYTQKSLSL
		SPG
145	LC	EIVLTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQQKP
		GQAPRLLIYD
		ASNRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ
		RSNWPWTFGQ
		GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY
		PREAKVQWKV
		DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK
		VYACEVTHQG
		LSSPVTKSFN RGEC
146	HCDR1	SRSYYWG
147	HCDR2	SIYYNGRTYY NPSLKS
148	HCDR3	EDYGDYGAFD I
149	LCDR1	RASQGISSAL A
150	LCDR2	DASSLES
151	LCDR3	QQFNSYPLT
152	HC Variable	QLQLQESGPG LVKPSETLSL TCTVSGGSIS SRSYYWGWIR
		QPPGKGLEWI
		GSIYYNGRTY YNPSLKSRVT ISVDTSKNQF SLKLSSVTAA
		DTAVYYCARE
		DYGDYGAFDI WGQGTMVTVS S
153	LC Variable	AIQLTQSPSS LSASVGDRVT ITCRASQGIS SALAWYQQKP
		GKAPKLLIYD
		ASSLESGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ
		FNSYPLTFGG
		GTKVEIK
154	HCDR1	TSNMGVV
155	HCDR2	HILWDDREYSNPALKS
156	HCDR3	MSRNYYGSSYVMDY
157	LCDR1	SASSSVNYMH
158	LCDR2	STSNLAS
159	LCDR3	HQWNNYGT
160	HC Variable	QVTLKESGPALVKPTQTLTLTCTFSGFSLSTSNMGVVWIRQPPGK
		ALEWLAHILWDD
		REYSNPALKSRLTISKDTSKNQVVLTMTNMDPVDTATYYCARM
		SRNYYGSSYVMD YWGQGTLVTVSS
161	LC Variable	DIQLTQSPSFLSASVGDRVTITCSASSSVNYMHWYQQKPGKAPK
		LLIYSTSNLASGVP
		SRFSGSGSGTEFTLTISSLQPEDFATYYCHQWNNYGTFGQGTKV
		EIKR
162	HCDR1	LYGMN
163	HCDR1	NYGMN
164	HCDR2	WINTYTGEPTYADDFKG
165	HCDR3	DTAMDYAMAY
166	HCDR3	DYGKYGDYYAMDY
167	LCDR1	KSSQNIVHSDGNTYLE
168	LCDR1	RSSQSIVHSNGNTYLD
169	LCDR2	KVSNRFS
170	LCDR3	FQGSHVPLT
171	HC Variable	QVQLVQSGSELKKPGASVKVSCKASGYTFTLYGMNWVRQAPG
		QGLEWMG
		WINTYTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAV
		YYCAR DTAMDYAMAYWGQGTLVTVSS
172	HC Variable	QVQLVQSGSELKKPGASVKVSCKASGYTFTLYGMNWVKQAPG
		KGLKWMG
		WINTYTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAV
		YFCAR DTAMDYAMAYWGQGTLVTVSS
173	HC Variable	QVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMNWVRQAPG
		QGLEWMG
		WINTYTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAV
		YYCAR DYGKYGDYYAMDYWGQGTLVTVSS
174	HC Variable	QVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMNWVRQAPG
		KGLKWMG
		WINTYTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAV
		YFCAR DYGKYGDYYAMDYWGQGTLVTVSS
175	LC Variable	DVVMTQSPLSLPVTLGQPASISCKSSQNIVHSDGNTYLEWFQQRP
		GQSP
		RRLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCF
		QGSH VPLTFGGGTKVEIKR
176	LC Variable	DVVMTQSPLSLPVTLGQPASISCKSSQNIVHSDGNTYLEWFQQRP
		GQSP
		RRLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCF
		QGSH VPLTFGQGTKVEIKR
177	LC Variable	DVVMTQTPLSLPVTPGEPASISCKSSQNIVHSDGNTYLEWYLQKP
		GQSP
		QLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCF
		QGSH VPLTFGGGTKVEIKR
178	LC Variable	DVVMTQTPLSLPVSLGDQASISCKSSQNIVHSDGNTYLEWYLQK
		PGQSP
		KVLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCF
		QGSH VPLTFGGGTKVEIKR
179	LC Variable	DVVMTQSPLSLPVTLGQPASISCRSSQSIVHSNGNTYLDWFQQRP
		GQSP
		RRLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCF
		QGSH VPLTFGGGTKVEIKR
180	LC Variable	DVVMTQSPLSLPVTLGQPASISCRSSQSIVHSNGNTYLDWFQQRP
		GQSP
		RRLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCF
		QGSH VPLTFGQGTKVEIKR
181	LC Variable	DVVMTQTPLSLPVTPGEPASISCRSSQSIVHSNGNTYLDWYLQKP
		GQSP
		QLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCF
		QGSH VPLTFGGGTKVEIKR
182	LC Variable	DVVMTQTPLSLPVSLGDQASISCRSSQSIVHSNGNTYLDWYLQK
		PGQSP
		KVLIYKVSNRFSGVPDRFSGSGSGTDFTLKINRVEAEDLGVYFCF
		QGSH VPLTFGGGTKLEIKR
183	HCDR1	GYTFTSSWMH
184	HCDR2	IHPNSGGT
185	HCDR3	ARGDYYGYVS WFAY
186	LCDR1	QNINVL
187	LCDR2	KAS
188	LCDR3	QQGQSYPYT
189	HC Variable	QVQLQQPGSV LVRPGASVKV SCKASGYTFT SSWMHWAKQR
		PGQGLEWIGE
		IHPNSGGTNY NEKFKGKATV DTSSSTAYVD LSSLTSEDSA
		VYYCARGDYY
		GYVSWFAYWG QGTLVTVSS
190	HC Variable	QVQLVQSGAE VKKPGASVKV SCKASGYTFT SSWMHWARQA
		PGQGLEWIGE
		IHPNSGGTNY AQKFQGRATL TVDTSSSTAY MELSRLRSDD
		TAVYYCARGD
		YYGYVSWFAY WGQGTLVTVS S
191	HC Variable	QVQLVQSGAE VKKPGASVKV SCKASGYTFT SSWMHWARQA
		PGQGLEWIGE
		IHPNSGGTNY AQKFQGRATM TVDTSISTAY MELSRLRSDD
		TAVYYCARGD
		YYGYVSWFAY WGQGTLVTVS S
192	HC Variable	QVQLVQSGAE VKKPGASVKV SCKASGYTFT SSWMHWARQA
		PGQGLEWIGE
		IHPNSGGTNY AQKFQGRVTM TVDTSISTAY MELSRLRSDD
		TAVYYCARGD
		YYGYVSWFAY WGQGTLVTVS S
193	HC Variable	QVQLVQSGAE VKKPGASVKV SCKASGYTFT SSWMHWARQA
		PGQGLEWMGE
		IHPNSGGTNY AQKFQGRVTM TVDTSISTAY MELSRLRSDD
		TAVYYCARGD
		YYGYVSWFAY WGQGTLVTVS S
194	LC Variable	DIQMNQSPSS LSASLGDTIT ITCHASQNIN VLLSWYQQKP
		GNIPKLLIYK
		ASNLHTGVPS RFSGSGSGTG FTFTISSLQP EDIATYYCQQ
		GQSYPYTFGG
		GTKLEIK
195	LC Variable	DIQMTQSPSS LSASVGDRVT ITCQASQDIS NYLNWYQQKP
		GKAPKLLIYD
		ASNLETGVPS RFSGSGSGTD FTFTISSLQP EDIATYYCQQ
		YDNLPYTFGQ
		GTKLEIK
196	LC Variable	DIQMTQSPSS LSASVGDRVT ITCQASQNIN VLLNWYQQKP
		GKAPKLLIYK
		ASNLHTGVPS RFSGSGSGTD FTFTISSLQP EDIATYYCQQ
		GQSYPYTFGQ
		GTKLEIK
197	LC Variable	DIQMNQSPSS LSASVGDRVT ITCQASQNIN VLLSWYQQKP
		GKAPKLLIYK
		ASNLHTGVPS RFSGSGSGTD FTFTISSLQP EDIATYYCQQ
		GQSYPYTFGQ
		GTKLEIK
198	HCDR1	GYTFTSYDIN
199	HCDR2	WLNPNSGXTG; X =N, Y
200	HCDR3	EVPETAAFEY
201	LCDR1	TSSSSDIGA(X1)(X2)GV(X3); X1 = G, A; X2 = L, S, Q;
		X3 = H, L
202	LCDR2	GYYNRPS
203	LCDR3	QSXDGTLSAL; X = Y, W, F
204	HC Variable	QVQLVQSGAE VKKPGASVKV SCKASGYTFT SYDINWVRQA
		PGQGLEWMGW
		LNPNSGNTGY AQKFQGRVTM TADRSTSTAY MELSSLRSED
		TAVYYCAREV
		PETAAFEYWG QGTLVTVSS
205	LC Variable	QSVLTQPPSV SGAPGQRVTI SCTSSSSDIG AXXGVXWYQQ
		LPGTAPKLLI
		EGYYNRPSGV PDRFSGSKSG TSASLTITGL LPEDEGDYYC
		QSXDGTLSAL
		FGGGTKLTVL G
206	HC Variable	QVQLVQSGAE VKKPGASVKV SCKASGYTFT SYDINWVRQA
		PGQGLEWMGW
		LNPNSGNTGY AQKFQGRVTM TADRSTSTAY MELSSLRSED
		TAVYYCAREV
		PETAAFEYWG QGTLVTVSS
207	LC Variable	QSVLTQPPSV SGAPGQRVTI SCTSSSSDIG AGLGVHWYQQ
		LPGTAPKLLI
		EGYYNRPSGV PDRFSGSKSG TSASLTITGL LPEDEGDYYC
		QSWDGTLSAL
		FGGGTKLTVL G
208	HC Variable	QVQLVQSGAE VKKPGASVKV SCKASGYTFT SYDINWVRQA
		PGQGLEWMGW
		LNPNSGYTGY AQKFQGRVTM TADRSTSTAY MELSSLRSED
		TAVYYCAREV
		PETAAFEYWG QGTLVTVSS
209	LC Variable	QSVLTQPPSV SGAPGQRVTI SCTSSSSDIG AGLGVHWYQQ
		LPGTAPKLLI
		EGYYNRPSGV PDRFSGSKSG TSASLTITGL LPEDEGDYYC
		QSYDGTLSAL
		FGGGTKLTVL G
210	HC Variable	QVQLVQSGAE VKKPGASVKV SCKASGYTFT SYDINWVRQA
		PGQGLEWMGW
		LNPNSGNTGY AQKFQGRVTM TADRSTSTAY MELSSLRSED
		TAVYYCAREV
		PETAAFEYWG QGTLVTVSS
211	LC Variable	QSVLTQPPSV SGAPGQRVTI SCTSSSSDIG AALGVHWYQQ
		LPGTAPKLLI
		EGYYNRPSGV PDRFSGSKSG TSASLTITGL LPEDEGDYYC
		QSWDGTLSAL
		FGGGTKLTVL G
212	HC Variable	QVQLVQSGAE VKKPGASVKV SCKASGYTFT SYDINWVRQA
		PGQGLEWMGW
		LNPNSGNTGY AQKFQGRVTM TADRSTSTAY MELSSLRSED
		TAVYYCAREV
		PETAAFEYWG QGTLVTVSS
213	LC Variable	QSVLTQPPSV SGAPGQRVTI SCTSSSSDIG AGSGVHWYQQ
		LPGTAPKLLI
		EGYYNRPSGV PDRFSGSKSG TSASLTITGL LPEDEGDYYC
		QSWDGTLSAL
		FGGGTKLTVL G
214	HC Variable	QVQLVQSGAE VKKPGASVKV SCKASGYTFT SYDINWVRQA
		PGQGLEWMGW
		LNPNSGNTGY AQKFQGRVTM TADRSTSTAY MELSSLRSED
		TAVYYCAREV
		PETAAFEYWG QGTLVTVSS
215	LC Variable	QSVLTQPPSV SGAPGQRVTI SCTSSSSDIG AGQGVHWYQQ
		LPGTAPKLLI
		EGYYNRPSGV PDRFSGSKSG TSASLTITGL LPEDEGDYYC
		QSWDGTLSAL
		FGGGTKLTVL G
216	HC Variable	QVQLVQSGAE VKKPGASVKV SCKASGYTFT SYDINWVRQA
		PGQGLEWMGW
		LNPNSGNTGY AQKFQGRVTM TADRSTSTAY MELSSLRSED
		TAVYYCAREV
		PETAAFEYWG QGTLVTVSS
217	LC Variable	QSVLTQPPSV SGAPGQRVTI SCTSSSSDIG AGLGVLWYQQ
		LPGTAPKLLI
		EGYYNRPSGV PDRFSGSKSG TSASLTITGL LPEDEGDYYC
		QSWDGTLSAL
		FGGGTKLTVL G
218	HC Variable	QVQLVQSGAE VKKPGASVKV SCKASGYTFT SYDINWVRQA
		PGQGLEWMGW
		LNPNSGYTGY AQKFQGRVTM TADRSTSTAY MELSSLRSED
		TAVYYCAREV
		PETAAFEYWG QGTLVTVSS
219	LC Variable	QSVLTQPPSV SGAPGQRVTI SCTSSSSDIG AGLGVHWYQQ
		LPGTAPKLLI
		EGYYNRPSGV PDRFSGSKSG TSASLTITGL LPEDEGDYYC
		QSWDGTLSAL
		FGGGTKLTVL G
220	HC Variable	QVQLVQSGAE VKKPGASVKV SCKASGYTFT SYDINWVRQA
		PGQGLEWMGW
		LNPNSGYTGY AQKFQGRVTM TADRSTSTAY MELSSLRSED
		TAVYYCAREV
		PETAAFEYWG QGTLVTVSS
221	LC Variable	QSVLTQPPSV SGAPGQRVTI SCTSSSSDIG AGSGVHWYQQ
		LPGTAPKLLI
		EGYYNRPSGV PDRFSGSKSG TSASLTITGL LPEDEGDYYC
		QSWDGTLSAL
		FGGGTKLTVL G
222	HC Variable	QVQLVQSGAE VKKPGASVKV SCKASGYTFT SYDINWVRQA
		PGQGLEWMGW
		LNPNSGYTGY AQKFQGRVTM TADRSTSTAY MELSSLRSED
		TAVYYCAREV
		PETAAFEYWG QGTLVTVSS
223	LC Variable	QSVLTQPPSV SGAPGQRVTI SCTSSSSDIG AGQGVHWYQQ
		LPGTAPKLLI
		EGYYNRPSGV PDRFSGSKSG TSASLTITGL LPEDEGDYYC
		QSWDGTLSAL
		FGGGTKLTVL G
224	HC Variable	QVQLVQSGAE VKKPGASVKV SCKASGYTFT SYDINWVRQA
		PGQGLEWMGW
		LNPNSGYTGY AQKFQGRVTM TADRSTSTAY MELSSLRSED
		TAVYYCAREV
		PETAAFEYWG QGTLVTVSS
225	LC Variable	QSVLTQPPSV SGAPGQRVTI SCTSSSSDIG AGLGVLWYQQ
		LPGTAPKLLI
		EGYYNRPSGV PDRFSGSKSG TSASLTITGL LPEDEGDYYC
		QSWDGTLSAL
		FGGGTKLTVL G
226	HC Variable	QVQLVQSGAE VKKPGASVKV SCKASGYTFT SYDINWVRQA
		PGQGLEWMGW
		LNPNSGYTGY AQKFQGRVTM TADRSTSTAY MELSSLRSED
		TAVYYCAREV
		PETAAFEYWG QGTLVTVSS
227	LC Variable	QSVLTQPPSV SGAPGQRVTI SCTSSSSDIG AGLGVHWYQQ
		LPGTAPKLLI
		EGYYNRPSGV PDRFSGSKSG TSASLTITGL LPEDEGDYYC
		QSFDGTLSAL
		FGGGTKLTVL G
228	HCDR1	SYFWS
229	HCDR2	YIYYSGNTKYNPSLKS
230	HCDR3	ETGSYYGFDY
231	LCDR1	RASQSINNYLN
232	LCDR2	AASSLQS
233	LCDR3	QQSYSTPRT
234	HC Variable	QVQLQESGPGLVKPSETLSLTCTVSGGSISSYFWSWIRQPPGKGL
		EWIGYIYYSGNTKYNPSLKSRVTISIDTSKNQFSLKLSSVTAADT
		AVYYCARETGSYYGFDYWGQGTLVTVSS
235	LC Variable	DIQMTQSPSSLSASVGDRVTITCRASQSINNYLNWYQQRPGKAP
		KLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPGDFATYYCQQ
		SYSTPRTFGQGTKLEIK
236	HCDR1	GYYWN
237	HCDR2	EINHAGNTNYNPSLKS
238	HCDR3	GYCRSTTCYFDY
239	LCDR1	RASQSVRSSYLA
240	LCDR2	GASSRAT
241	LCDR3	QQYGSSPT
242	HC Variable	QVQLQQWGAGLLKPSETLSLTCAVHGGSFSGYYWNWIRQPPGK
		GLEWIGEINHAGNTNYNPSLKSRVTISLDTSKNQFSLTLTSVTAA
		DTAVYYCARGYCRSTTCYFDYWGQGTLVTVSS
243	LC Variable	EIVLTQSPGTLSLSPGERATLSCRASQSVRSSYLAWYQQKPGQAP
		RLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQ
		YGSSPTFGQGTRLEIK
244	HC Variable	EVQLQQSGAELVKPGASVKLSCTASGFDIQDTYMHWVKQRPEQ
		GLEWIGRIDPASGHTKYDPKFQVKATITTDTSSNTAYLQLSSLTS
		EDTAVYYCSRSGGLPDVWGAGTTVTVSS
245	LC Variable	QIVLSQSPAILSASPGEKVTMTCRASSSVSYMYWYQQKPGSSPKP
		WIYATSNLASGVPDRFSGSGSGTSYSLTISRVEAEDAATYYCQQ
		WSGNPRTFGGGTKLEIK
246	HCDR1	GFDIQDTYMH
247	HCDR2	RIDPASGHTKYDPKFQV
248	HCDR3	SGGLPDV
249	LCDR1	RASSSVSYMY
250	LCDR2	ATSNLAS
251	LCDR3	QQWSGNPRT
252	HC Variable	QVQLVQSGAEVKKPGASVKLSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIDPASGHTKYDPKFQVRVTMTTDTSTSTVYMELSS
		LRSEDTAVYYCSRSGGLPDVWGQGTTVTVSS
253	LC Variable	EIVLTQSPGTLSLSPGERVTMSCRASSSVSYMYWYQQKPGQAPR
		PWIYATSNLASGVPDRFSGSGSGTDYTLTISRLEPEDFAVYYCQQ
		WSGNPRTFGGGTKLEIK
254	(CDR-grafted	QVQLVQSGAEVKKPGASVKLSCKASGFDIQDTYMHWVRQAPG
	LC) HC	QGLEWMGRIDPASGHTKYDPKFQVRVTMTRDTSTSTVYMELSS
	variable region	LRSEDTAVYYCSRSGGLPDVWGQGTTVTVSS
255	(CDR-grafted	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
	LC) HC	LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
	variable region	SGNPRTFGGGTKLEIK
256	(CDR-grafted	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
	HC) HC	QGLEWMGRIDPASGHTKYDPKFQVRVTMTRDTSTSTVYMELSS
	variable region	LRSEDTAVYYCARSGGLPDVWGQGTTVTVSS
257	(CDR-grafted	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
	HC) LC	LLIYATSNLASGVPDRFSGSGSGTDYTLTISRLEPEDFAVYYCQQ
	variable region	WSGNPRTFGGGTKLEIK
258	HC variable	EVMLVESGGGLVKPGGSLKLSCAASGFTFTNYAMSWVRQTPEK
		RLEWVATITSGGSYIYYLDSVKGRFTISRDNAKSTLYLQMSSLRS
		EDTAIYNCARRKDGNYYYAMDYWGQGTSVTVSS
259	HC variable	EVMLVESGGGLVKPGGSLKLSCAASGFTFTNYAMSWVRQTPEK
		RLEWVATITSGGSYIYYLDSVKGRFTISRDNAKSTLYLQMSSLRS
		EDTAIYYCARRKDGNYYYAMDYWGQGTSVTVSS
260	HC variable	EVQLVESGGGLVKPGGSLRLSCAASGFTFTNYAMSWVRQAPGQ
		RLEWVSTITSGGSYIYYLDSVKGRFTISRDNAKSTLYLQMNSLRA
		EDTAVYNCARRKDGNYYYAMDYWGQGTTVTVSS
261	HC variable	EVQLVESGGGLVKPGGSLRLSCAASGFTFTNYAMSWVRQAPGQ
		RLEWVSTITSGGSYIYYLDSVKGRFTISRDNAKSTLYLQMNSLRA
		EDTAVYYCARRKDGNYYYAMDYWGQGTTVTVSS
262	HC variable	EVQLLESGGGLVQPGRSLRLSCAASGFTFTNYAMSWVRQAPGQ
		RLEWLATITSGGSYIYYLDSVKGRFTISRDNSKSTLYLQMGSLRA
		EDMAVYNCARRKDGNYYYAMDYWGQGTTVTVSS
263	HC variable	EVQLLESGGGLVQPGRSLRLSCAASGFTFTNYAMSWVRQAPGQ
		RLEWLATITSGGSYIYYLDSVKGRFTISRDNSKSTLYLQMGSLRA
		EDMAVYYCARRKDGNYYYAMDYWGQGTTVTVSS
264	HC variable	QVQLVESGGGLIQPGGSLRLSCAASGFTFTNYAMSWVRQARGQ
		RLEWVSTITSGGSYIYYLDSVKGRFTISRDNSKSTLYMELSSLRSE
		DTAVYNCARRKDGNYYYAMDYWGQGTTVTVSS
265	HC variable	QVQLVESGGGLIQPGGSLRLSCAASGFTFTNYAMSWVRQARGQ
		RLEWVSTITSGGSYIYYLDSVKGRFTISRDNSKSTLYMELSSLRSE
		DTAVYYCARRKDGNYYYAMDYWGQGTTVTVSS
266	HC variable	QVQLVQSGSELKKPGASVKVSCKASGFTFTNYAMSWVRQAPGK
		RLEWVSTITSGGSYIYYLDSVKGRFTISRENAKSTLYLQMNSLRT
		EDTALYNCARRKDGNYYYAMDYVVGQGTTVTVSS
267	HC variable	QVQLVQSGSELKKPGASVKVSCKASGFTFTNYAMSWVRQAPGK
		RLEWVATITSGGSYIYYLDSVKGRFTISRENAKSTLYLQMNSLRT
		EDTALYYCARRKDGNYYYAMDYVVGQGTTVTVSS
268	HC variable	EVQLLQSGAEVKKPGASVKVSCKASGFTFTNYAMSWVRQAPG
		QRLEWVATITSGGSYIYYLDSVKGRFTISRDNAKSTLHLQMNSL
		RAEDTAVYNCARRKDGNYYYAMDYWGQGTTVTVSS
269	HC variable	EVQLLQSGAEVKKPGASVKVSCKASGFTFTNYAMSWVRQAPG
		QRLEWVATITSGGSYIYYLDSVKGRFTISRDNAKSTLHLQMNSL
		RAEDTAIYYCARRKDGNYYYAMDYWGQGTTVTVSS
270	HC variable	EVMLLQSGAEVKKPGASVKVSCKASGFTFTNYAMSWVRQAPG
		QRLEWVATITSGGSYIYYLDSVKGRFTISRDNAKSTLHLQMNSL
		RAEDTAVYYCARRKDGNYYYAMDYWGQGTTVTVSS
271	LC variable	DIVLTQSPASLAVSLGQRATISCRASESVDSYGNSFIHWYQQKAG
		QPPKLLIYRASNLESGIPARFSGSGSRTDFTLTINPVEADDVATYY
		CQQSYEDPWTFGGGTKLEIK
272	LC variable	DIVLTQSPATLSLSPGERATLSCRASESVDSYGNSFIHWYQQKPG
		QPPKLLIYRASNLESGIPARFSGSGSRTDFTLTISSLEPEDFAVYYC
		QQSYEDPWTFGGGTKXEIK
273	LC variable	DIVLTQSPSSLSASVGDRVTITCRASESVDSYGNSFIHWYQQKPG
		QPPKLLIYRASNLESGIPARFSGSGSRTDFTLTISSLQPEDFATYYC
		QQSYEDPWTFGGGTKXEIK
274	LC variable	DIVLTQSPDFQSVTPKEKVTITCRASESVDSYGNSFIHWYQQKPG
		QPPKLLIYRASNLESGIPARFSGSGSRTDFTLTISSLEAEDAATYY
		CQQSYEDPWTFGGGTKXEIK
275	LC variable	DIVLTQTPLSLSVTPGQPASISCRASESVDSYGNSFIHWYQQKPG
		QPPKLLIYRASNLESGIPARFSGSGSRTDFTLKISRVEAEDVGVYY
		CQQSYEDPWTFGGGTKXEIK
276	HCDR1	TYGMS
277	HCDR2	WMNTYSGVTTYADDFKG
278	HCDR3	EGYVFDDYYATDY
279	LCDR1	RSSQNIVHSDGNTYLE
280	LCDR2	KVSNRFS
281	LCDR3	FQGSHVPLT
282	HC Variable	QIQLVQSGPELKKPGETVKISCKASGYTFTTYGMSWVKQAPGKG
		LKWMGWMNTYSGVTTYADDFKGRFAFSLETSASTAYMQIDNL
		KNEDTATYFCAREGYVFDDYYATDYWGQGTSVTVSS
283	LC Variable	DVLMTQTPLSLPVSLGDQASISCRSSQNIVHSDGNTYLEWYLQK
		PGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGI
		YYCFQGSHVPLTFGAGTKLELK
284	HCDR1	KYDIN
285	HCDR2	WIFPGDGRTDYNEKFKG
286	HCDR3	YGPAMDY
287	LCDR1	RSSQTIVHSNGDTYLD
288	LCDR2	KVSNRFS
289	LCDR3	FQGSHVPYT
290	HC Variable	MGWSWVFLFLLSVTAGVHSQVHLQQSGPELVKPGASVKLSCKA
		SGYTFTKYDINWVRQRPEQGLEWIGWIFPGDGRTDYNEKFKGK
		ATLTTDKSSSTAYMEVSRLTSEDSAVYFCARYGPAMDYWGQGT
		SVTVAS
291	LC Variable	MKLPVRLLVLMFWIPASSSDVLMTQTPLSLPVSLGDQASISCRSS
		QTIVHSNGDTYLDWFLQKPGQSPKLLIYKVSNRFSGVPDRFSGS
		GSGTDFTLKISRVEAEDLGVYYCFQGSHVPYTFGGGTKLEIK
484	HCDR1	DTYMH
485	HCDR2	PASGH
486	HCDR3	SGGLPD
487	LCDR1	ASSSVSYMY
488	LCDR2	ATSNLAS
489	LCDR3	GNPRT
490	VL	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		SGNPRTFGGGTKLEIK
491	VH	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIDPASGHTKYDPKFQVRVTMTRDTSTSTVYMELSS
		LRSEDTAVYYCARSGGLPDVWGQGTTVTVSS
492	VL	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		EGNPRTFGGGTKLEIK
493	VH	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIEPASGHIKYDPKFQGRVTMTRDTSTSTVYMELSSL
		RSEDTAVYYCARSGGLPDWWGQGTTVTVSS
494	VL	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		EGNPRTFGGGTKLEIK
495	VH	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIEPASGHIKYSPKFQGRVTMTRDTSTSTVYMELSSL
		RSEDTAVYYCARSGGLPDWWGQGTTVTVSS
496	VL	EIVLTQSPGTLSLSPGERATLSCGASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		EGNPRTFGGGTKLEIK
497	VH	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIEPASGHIKYSPKFQGRVTMTRDTSTSTVYMELSSL
		RSEDTAVYYCARSGGLPDWWGQGTTVTVSS
498	VL	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		EGNPRTFGGGTKLEIK
499	VH	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIEPASGHVKYSPKFQVRVTMTRDTSTSTVYMELSS
		LRSEDTAVYYCARSGGLPDWWGQGTTVTVSS
500	VL	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		EGNPRTFGGGTKLEIK
501	VH	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIEPASGHVKYDPKFQTRVTMTRDTSTSTVYMELSS
		LRSEDTAVYYCARSGGLPDWWGQGTTVTVSS
502	VL	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		QGNPRTFGGGTKLEIK
503	VH	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIDPASGHiKYDPKFQkRVTMTRDTSTSTVYMELSSL
		RSEDTAVYYCARSGGLPDMWGQGTTVTVSS
504	VL	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		QGNPRTFGGGTKLEIK
505	VH	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIDPASGHvKiDPKFQVRVTMTRDTSTSTVYMELSSL
		RSEDTAVYYCARSGGLPDMWGQGTTVTVSS
506	VL	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		QGNPRTFGGGTKLEIK
507	VH	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIDPASGHLKYDPKFQVRVTMTRDTSTSTVYMELSS
		LRSEDTAVYYCARSGGLPDMWGQGTTVTVSS
508	VL	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		QGNPRTFGGGTKLEIK
509	VH	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIDPASGHLKYDPKFQRRVTMTRDTSTSTVYMELSS
		LRSEDTAVYYCARSGGLPDMWGQGTTVTVSS
510	VL	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		EGNPRTFGGGTKLEIK
511	VH	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIDPASGHLKYDPKFQNRVTMTRDTSTSTVYMELSS
		LRSEDTAVYYCARSGGLPDKWGQGTTVTVSS
512	VL	EIVLTQSPGTLSLSPGERATLSCGASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		EGNPRTFGGGTKLEIK
513	VH	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIDPASGHLKYDPKFQNRVTMTRDTSTSTVYMELSS
		LRSEDTAVYYCARSGGLPDKWGQGTTVTVSS
514	VL	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		EGNPRTFGGGTKLEIK
515	VH	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIEPASGHLKYDPKFQERVTMTRDTSTSTVYMELSS
		LRSEDTAVYYCARSGGLPDKWGQGTTVTVSS
516	VL	EIVLTQSPGTLSLSPGERATLSCGASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		EGNPRTFGGGTKLEIK
517	VH	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIEPASGHLKYDPKFQERVTMTRDTSTSTVYMELSS
		LRSEDTAVYYCARSGGLPDKWGQGTTVTVSS
518	VL	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		QGNPRTFGGGTKLEIK
519	VH	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIDPASGHLKYDPKFQGRVTITRDTSASTAYMELSSL
		RSEDTAVYYCARSGGLPDMWGQGTTVTVSS
520	VL	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		QGNPRTFGGGTKLEIK
521	VH	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIDPASGHLKYDPKFQGRVTITRDTSASTVYMELSSL
		RSEDTAVYYCARSGGLPDMWGQGTTVTVSS
522	VL	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		SGNPRTFGGGTKLEIK
523	VH	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIDPASGHTKYDPKFQGRATITTDTSASTAYLQLSSL
		RSEDTAVYYCARSGGLPDVWGQGTTVTVSS
524	VL	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		SGNPRTFGGGTKLEIK
525	VH	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIDPASGHTKYDPKFQVRATITTDTSASTAYLQLSSL
		RSEDTAVYYCARSGGLPDFWGQGTTVTVSS
526	VL	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		SGNPRTFGGGTKLEIK
527	VH	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIDPASGHTKYDPKFQGRATITTDTSASTAYLQLSSL
		RSEDTAVYYCARSGGLPDFWGQGTTVTVSS
528	VL	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		SGNPRTFGGGTKLEIK
529	VH	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIDPASGHTKYDPKFQGRATITTDTSASTAYLQLSSL
		RSEDTAVYYCARSGGLPDLWGQGTTVTVSS
530	VL	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCSQW
		SGNPRTFGGGTKLEIK
531	VH	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIDPASGHTKYDPKFQGRATITTDTSASTAYLQLSSL
		RSEDTAVYYCARSGGLPDFWGQGTTVTVSS
532	VL	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		SGNPRSFGGGTKLEIK
533	VH	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIDPASGHTKYDPKFQGRATITTDTSASTAYLQLSSL
		RSEDTAVYYCARSGGLPDFWGQGTTVTVSS
534	VL	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		SRNPRTFGGGTKLEIK
535	VH	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIDPASGHTKYDPKFQGRATITTDTSASTAYLQLSSL
		RSEDTAVYYCARSGGLPDFWGQGTTVTVSS
536	VL	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		KGNPRTFGGGTKLEIK
537	VH	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIDPASGHTKYDPKFQGRATITTDTSASTAYLQLSSL
		RSEDTAVYYCARSGGLPDFWGQGTTVTVSS
538	VL	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		SGNPRTFGGGTKLEIK
539	VH	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIDPASGHSKYDPKFQVRATITTDTSASTAYLQLSSL
		RSEDTAVYYCARSGGLPDFWGQGTTVTVSS
540	VL	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		SGNPRTFGGGTKLEIK
541	VH	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIDPASGHYKYDPKFQVRATITTDTSASTAYLQLSSL
		RSEDTAVYYCARSGGLPDFWGQGTTVTVSS
542	Modified	ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG
	IgG1-Constant	ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP
	region	SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTL
		MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE
		QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK
		AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
		SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS
		VMHEALHNHYTQKSLSLSPGK
543	IgG2 constant	ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGA
	region	LTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPS
		NTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRT
		PEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNST
		FRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQP
		REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP
		ENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE
		ALHNHYTQKSLSLSPGK
544	Kappa constant	RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVD
	region	NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE
		VTHQGLSSPVTKSFNRGEC
545	HFR1	QVQLVQSGAEVKKPGASVKVSCKAS
546	HFR2	WVRQAPGQGLEWMG
547	HFR3	RVTMTRDTSTSTVYMELSSLRSEDTAVYYC
548	HFR4	WGQGTTVTVSS
549	LFR1	EIVLTQSPGTLSLSPGERATLSC
550	LFR2	WYQQKPGQAPRLLIY
551	LFR3	GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC
552	LFR4	FGGGTKLEIK
553	HCDR1	GFDIQDTYMH
554	HCDR2	RIDPASGHTKYDPKFQV
555	HCDR2	RIEPASGHIKYDPKFQG
556	HCDR2	RIEPASGHIKYSPKFQG
557	HCDR2	RIEPASGHVKYSPKFQV
558	HCDR2	RIEPASGHVKYDPKFQT
559	HCDR2	RIDPASGHIKYDPKFQK
560	HCDR2	RIDPASGHVKIDPKFQV
561	HCDR2	RIDPASGHLKYDPKFQV
562	HCDR2	RIDPASGHLKYDPKFQR
563	HCDR2	RIDPASGHLKYDPKFQN
564	HCDR2	RIEPASGHLKYDPKFQE
565	HCDR3	ARSGGLPDV
566	HCDR3	ARSGGLPDW
567	HCDR3	ARSGGLPDM
568	HCDR3	ARSGGLPDK
569	LCDR1	RASSSVSYMY
570	LCDR1	GASSSVSYMY
571	LCDR3	QQWSGNPRT
572	LCDR3	QQWEGNPRT
573	LCDR3	QQWQGNPRT
574	HCDR2	RIDPASGHLKYDPKFQG
575	HCDR2	RIDPASGHTKYDPKFQG
576	HCDR2	RIDPASGHSKYDPKFQV
577	HCDR2	RIDPASGHYKYDPKFQV
578	HCDR3	ARSGGLPDV
579	HCDR3	ARSGGLPDM
580	HCDR3	ARSGGLPDF
581	HCDR3	ARSGGLPDL
582	LCDR3	SQWSGNPRT
583	LCDR3	QQWSGNPRS
584	LCDR3	QQWSRNPRT
585	LCDR3	QQWKGNPRT
586	HFR3	RATITTDTSASTAYLQLSSLRSEDTAVYYC
587	HFR3	RVTITRDTSASTVYMELSSLRSEDTAVYYC
588	HFR3	RVTITRDTSASTAYMELSSLRSEDTAVYYC
1001	HC Variable	GAAGTTCAGCTGCAACAGTCTGGCGCCGAGCTGGTTAAGCCT
		GGCGCTTCTGTGAAGCTGAGCTGTACCGCCTCTGGCTTCGACA
		TCCAAGACACCTACATGCACTGGGTCAAGCAGAGGCCTGAGC
		AGGGACTCGAGTGGATCGGCAGAATTGATCCTGCCAGCGGCC
		ACACCAAATACGACCCCAAGTTCCAAGTGAAGGCCACCATCA
		CCACCGACACCAGCAGCAATACCGCCTACCTGCAGCTGAGCA
		GCCTGACCTCTGAAGATACCGCCGTGTACTACTGCAGCAGAT
		CTGGCGGACTGCCCGATGTTTGGGGAGCCGGAACAACCGTGA
		CAGTGTCCAGC
1002	HC Variable	GAGGTTCAACTTCAACAATCGGGGGCCGAGCTGGTTAAGCCC
		GGCGCTTCTGTAAAATTGTCTTGCACTGCCTCTGGGTTTGACA
		TCCAAGATACATATATGCATTGGGTGAAACAGCGTCCCGAGC
		AGGGCTTGGAGTGGATTGGACGTATTGACCCCGCCTCTGGGC
		ACACGAAATATGATCCTAAGTTCCAGGTTAAAGCGACTATCA
		CAACGGACACCTCCAGCAATACGGCTTATTTACAGTTATCCTC
		GCTGACCTCTGAGGATACTGCAGTGTACTACTGCTCTCGCTCT
		GGTGGTCTGCCAGACGTGTGGGGTGCAGGAACTACAGTTACT
		GTGTCTTCA
1003	HC Variable	EVQLQQSGAELVKPGASVKLSCTASGFDIQDTYMHWVKQRPEQ
		GLEWIGRIDPASGHTKYDPKFQVKATITTDTSSNTAYLQLSSLTS
		EDTAVYYCSRSGGLPDVWGAGTTVTVSS
1004	LC Variable	CAAATTGTGCTGTCTCAGAGCCCCGCCATCCTGAGTGCTTCTC
		CAGGCGAGAAAGTGACCATGACCTGCAGAGCCAGCAGCAGC
		GTGTCCTACATGTACTGGTATCAGCAGAAGCCCGGCAGCAGC
		CCCAAGCCTTGGATCTACGCCACAAGCAATCTGGCCAGCGGC
		GTGCCCGATAGATTTTCTGGCTCTGGCAGCGGCACCAGCTAC
		AGCCTGACAATCTCTAGAGTGGAAGCCGAGGATGCCGCCACC
		TACTACTGTCAACAGTGGAGCGGCAACCCCAGAACCTTTGGC
		GGAGGCACCAAGCTGGAAATCAAG
1005	LC Variable	CAAATCGTCCTGTCACAGTCCCCGGCGATCCTTTCTGCTTCAC
		CAGGAGAGAAGGTAACCATGACATGTCGCGCCTCTTCCTCAG
		TTTCTTACATGTACTGGTACCAGCAGAAACCAGGATCATCTCC
		CAAACCCTGGATCTACGCTACATCAAACCTTGCATCTGGCGT
		GCCAGACCGTTTTTCAGGGTCGGGCTCGGGGACTTCCTATTCA
		TTAACCATTTCTCGCGTAGAAGCGGAAGACGCCGCCACGTAT
		TATTGTCAGCAGTGGTCAGGAAATCCGCGCACATTCGGAGGC
		GGAACGAAATTGGAGATCAAA
1006	LC Variable	QIVLSQSPAILSASPGEKVTMTCRASSSVSYMYWYQQKPGSSPKP
		WIYATSNLASGVPDRFSGSGSGTSYSLTISRVEAEDAATYYCQQ
		WSGNPRTFGGGTKLEIK
1007	HCDR1	GGCTTCGACATCCAAGACACCTACATGCAC
1008	HCDR1	GGGTTTGACATCCAAGATACATATATGCAT
1009	HCDR1	GFDIQDTYMH
10010	HCDR2	AGAATTGATCCTGCCAGCGGCCACACCAAATACGACCCCAAG
		TTCCAAGTG
10011	HCDR2	CGTATTGACCCCGCCTCTGGGCACACGAAATATGATCCTAAG
		TTCCAGGTT
10012	HCDR2	RIDPASGHTKYDPKFQV
10013	HCDR3	TCTGGCGGACTGCCCGATGTT
10014	HCDR3	TCTGGTGGTCTGCCAGACGTG
10015	HCDR3	SGGLPDV
10016	LCDR1	AGAGCCAGCAGCAGCGTGTCCTACATGTAC
10017	LCDR1	CGCGCCTCTTCCTCAGTTTCTTACATGTAC
10018	LCDR1	RASSSVSYMY
10019	LCDR2	GCCACAAGCAATCTGGCCAGC
10020	LCDR2	GCTACATCAAACCTTGCATCT
10021	LCDR2	ATSNLAS
10022	LCDR3	CAACAGTGGAGCGGCAACCCCAGAACC
10023	LCDR3	CAGCAGTGGTCAGGAAATCCGCGCACA
10024	LCDR3	QQWSGNPRT
10025	HC Variable	CAAGTACAATTAGTCCAGTCGGGTGCCGAGGTAAAAAAACCT
		GGAGCATCCGTAAAACTGTCTTGCAAAGCATCGGGGTTTGAC
		ATCCAGGACACCTACATGCACTGGGTGCGTCAAGCTCCAGGA
		CAGGGATTAGAGTGGATGGGTCGCATCGACCCCGCGAGCGGA
		CACACGAAATACGACCCTAAATTTCAAGTACGTGTCACGATG
		ACTACCGACACTAGTACGAGCACTGTTTATATGGAATTGTCCT
		CGTTACGCTCAGAGGATACGGCAGTCTATTATTGCAGCCGTTC
		CGGAGGCTTACCCGACGTCTGGGGACAGGGAACTACTGTAAC
		AGTCAGTAGT
10026	HC Variable	QVQLVQSGAEVKKPGASVKLSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIDPASGHTKYDPKFQVRVTMTTDTSTSTVYMELSS
		LRSEDTAVYYCSRSGGLPDVWGQGTTVTVSS
10027	LC Variable	GAGATTGTGTTAACGCAATCACCGGGGACTTTATCGCTGTCG
		CCGGGGGAGCGCGTTACAATGTCTTGTCGCGCTTCCTCTTCGG
		TTTCATACATGTATTGGTATCAACAAAAACCGGGACAGGCTC
		CACGCCCCTGGATTTACGCTACTAGCAATTTGGCCTCGGGCGT
		TCCCGACCGCTTCAGCGGGTCAGGGAGCGGCACCGATTACAC
		GTTGACCATCTCTCGTCTGGAACCTGAAGACTTCGCGGTCTAT
		TACTGTCAACAATGGTCGGGAAATCCCCGTACATTTGGCGGA
		GGGACGAAGTTGGAAATTAAA
10028	LC Variable	EIVLTQSPGTLSLSPGERVTMSCRASSSVSYMYWYQQKPGQAPR
		PWIYATSNLASGVPDRFSGSGSGTDYTLTISRLEPEDFAVYYCQQ
		WSGNPRTFGGGTKLEIK
10029	HCDR1	GGGTTTGACATCCAGGACACCTACATGCAC
10030	HCDR2	CGCATCGACCCCGCGAGCGGACACACGAAATACGACCCTAAA
		TTTCAAGTA
10031	HCDR3	TCCGGAGGCTTACCCGACGTC
10032	LCDR1	CGCGCTTCCTCTTCGGTTTCATACATGTATTGGTAT
10033	LCDR2	GCTACTAGCAATTTGGCCTCG
10034	LCDR3	CAACAATGGTCGGGAAATCCCCGTACA
10035	LC Variable	CAAGTACAATTAGTCCAGTCGGGTGCCGAGGTAAAAAAACCT
		GGAGCATCCGTAAAACTGTCTTGCAAAGCATCGGGGTTTGAC
		ATCCAGGACACCTACATGCACTGGGTGCGTCAAGCTCCAGGA
		CAGGGATTAGAGTGGATGGGTCGCATCGACCCCGCGAGCGGA
		CACACGAAATACGACCCTAAATTTCAAGTACGTGTCACGATG
		ACTCGTGACACTAGTACGAGCACTGTTTATATGGAATTGTCCT
		CGTTACGCTCAGAGGATACGGCAGTCTATTATTGCAGCCGTTC
		CGGAGGCTTACCCGACGTCTGGGGACAGGGAACTACTGTAAC
		AGTCAGTAGT
10036	LC Variable	QVQLVQSGAEVKKPGASVKLSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIDPASGHTKYDPKFQVRVTMTRDTSTSTVYMELSS
		LRSEDTAVYYCSRSGGLPDVWGQGTTVTVSS
10037	LC Variable	GAGATTGTGTTAACGCAATCACCGGGGACTTTATCGCTGTCG
		CCGGGGGAGCGCGCGACACTGTCTTGTCGCGCTTCCTCTTCGG
		TTTCATACATGTATTGGTATCAACAAAAACCGGGACAGGCTC
		CACGCCTGCTGATTTACGCTACTAGCAATTTGGCCTCGGGCAT
		CCCCGACCGCTTCAGCGGGTCAGGGAGCGGCACCGATTTTAC
		GTTGACCATCTCTCGTCTGGAACCTGAAGACTTCGCGGTCTAT
		TACTGTCAACAATGGTCGGGAAATCCCCGTACATTTGGCGGA
		GGGACGAAGTTGGAAATTAAA
10038	LC Variable	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		SGNPRTFGGGTKLEIK
10039	HC Variable	CAAGTACAATTAGTCCAGTCGGGTGCCGAGGTAAAAAAACCT
		GGAGCATCCGTAAAAGTCTCTTGCAAAGCATCGGGGTTTGAC
		ATCCAGGACACCTACATGCACTGGGTGCGTCAAGCTCCAGGA
		CAGGGATTAGAGTGGATGGGTCGCATCGACCCCGCGAGCGGA
		CACACGAAATACGACCCTAAATTTCAAGTACGTGTCACGATG
		ACTCGTGACACTAGTACGAGCACTGTTTATATGGAATTGTCCT
		CGTTACGCTCAGAGGATACGGCAGTCTATTATTGCGCACGTTC
		CGGAGGCTTACCCGACGTCTGGGGACAGGGAACTACTGTAAC
		AGTCAGTAGT
10040	HC Variable	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIDPASGHTKYDPKFQVRVTMTRDTSTSTVYMELSS
		LRSEDTAVYYCARSGGLPDVWGQGTTVTVSS
10041	HC Variable	GAGATTGTGTTAACGCAATCACCGGGGACTTTATCGCTGTCG
		CCGGGGGAGCGCGCGACACTGTCTTGTCGCGCTTCCTCTTCGG
		TTTCATACATGTATTGGTATCAACAAAAACCGGGACAGGCTC
		CACGCCTGCTGATTTACGCTACTAGCAATTTGGCCTCGGGCGT
		TCCCGACCGCTTCAGCGGGTCAGGGAGCGGCACCGATTACAC
		GTTGACCATCTCTCGTCTGGAACCTGAAGACTTCGCGGTCTAT
		TACTGTCAACAATGGTCGGGAAATCCCCGTACATTTGGCGGA
		GGGACGAAGTTGGAAATTAAA
10042	HC Variable	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGVPDRFSGSGSGTDYTLTISRLEPEDFAVYYCQQ
		WSGNPRTFGGGTKLEIK
10043	HC Variable	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIDPASGHTKYDPKFQVRVTMTRDTSTSTVYMELSS
		LRSEDTAVYYCARSGGLPDKWGQGTTVTVSS
10044	HC Variable	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIDPASGHTKYDPKFQVRVTMTRDTSTSTVYMELSS
		LRSEDTAVYYCARSGGLPDMWGQGTTVTVSS
10045	HC Variable	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIDPASGHTKYDPKFQVRVTMTRDTSTSTVYMELSS
		LRSEDTAVYYCARSGGLPDQWGQGTTVTVSS
10046	HC Variable	QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPG
		QGLEWMGRIDPASGHTKYDPKFQVRVTMTRDTSTSTVYMELSS
		LRSEDTAVYYCARSGGLPDWWGQGTTVTVSS
10047	LC Variable	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		DGNPRTFGGGTKLEIK
10048	LC Variable	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		EGNPRTFGGGTKLEIK
10049	LC Variable	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		HGNPRTFGGGTKLEIK
10050	LC Variable	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		NGNPRTFGGGTKLEIK
10051	LC Variable	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQW
		QGNPRTFGGGTKLEIK
10052	HC Variable	QVQLVQSGAEVKKPGASVKVSCKASGFX 1 X2X 3 DTX 4 X 5 HWVRQ
		APGQGLEWMGRIDPASGHTKYDPKFQVRVTMTRDTSTSTVYME
		LSSLRSEDTAVYYCARSGGX 6 PDX 7 WGQGTTVTVSS
		X 1 = D, OR E
		X 2 = I, P, OR V
		X 3 = G, Q, S, OR V
		X 4 = F, OR Y
		X 5 = I, OR M
		X 6 = L, OR M
		X 7 = E, I, K, L, M, Q, T, V, W, OR Y
10053	LC Variable	EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPR
		LLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCX 1 Q
		WX 2 X 3 X 4 PRTFGGGTKLEIK
		X 1 = Q, OR N
		X 2 = D, E, H, N, Q, OR S
		X 3 = A, OR G
		X 4 = D, F, K, N, R, S, OR T
10054	HC Variable	QVQLVQSGAEVKKPGASVKVSCKASGFX 1 X 2 X 3 DTX 4 X 5 HWVRQ
		APGQGLEWMGRIDPASGHTKYDPKFQVRVTMTRDTSTSTVYME
		LSSLRSEDTAVYYCSRSGGX 6 PDX 7 WGQGTTVTVSS
		X 1 = D, OR E
		X 2 = I, P, OR V
		X 3 = G, Q, S, OR V
		X 4 = F, OR Y
		X 5 = I, OR M
		X 6 = L, OR M
		X 7 = E, I, K, L, M, Q, T, V, W, OR Y
100100	HCFR1a	QVQLVQSGAEVKKPGASVKLSCKAS
100101	HCFR2a	WVRQAPGQGLEWMG
100102	HCFR3a	RVTMTRDTSTSTVYMELSSLRSEDTAVYYCSR
100103	HCFR4a	WGQGTTVTVSS
100104	LCFRla	EIVLTQSPGTLSLSPGERATLSC
100105	LCFR2a	WYQQKPGQAPRLLIY
100106	LCFR3a	GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC
100107	LCFR4a	FGGGTKLEIK
100108	HCFR1b	QVQLVQSGAEVKKPGASVKVSCKAS
100109	HCFR3b	RVTMTRDTSTSTVYMELSSLRSEDTAVYYCAR
100110	LCFR3b	GVPDRFSGSGSGTDYTLTISRLEPEDFAVYYC
100150	HCDR1 A	GFX 1 X2X 3 DTX 4 X 5 H
		X 1 = D, OR E
		X 2 = I, P, OR V
		X 3 = G, Q, S, OR V
		X 4 = F, OR Y
		X 5 = I, OR M
100152	HCDR3 A	SGGX 1 PDX 2
		X 1 = L, OR M
		X 2 = E, I, K, L, M, Q, T, V, W, OR Y
100155	LCDR3 A	X 1 QWX 2 X 3 X 4 PRT
		X 1 = Q, OR N
		X 2 = D, E, H, N, Q, OR S
		X 3 = A, OR G
		X 4 = D, F, K, N, R, S, OR T
100200	HCDR1 A1	GFDIGDTFIH
100201	HCDR1 B1	GFDIGDTFMH
100202	HCDR1 C1	GFDIGDTYIH
100203	HCDR1 D1	GFDIGDTYMH
100204	HCDR1 E1	GFDIQDTFIH
100205	HCDR1 F1	GFDIQDTFMH
100206	HCDR1 G1	GFDIQDTYIH
100207	HCDR1 H1	GFDIQDTYMH
100208	HCDR1 I1	GFDISDTFIH
100209	HCDR1 J1	GFDISDTFMH
100210	HCDR1 K1	GFDISDTYIH
100211	HCDR1 L1	GFDISDTYMH
100212	HCDR1 M1	GFDIVDTFIH
100213	HCDR1 N1	GFDIVDTFMH
100214	HCDR1 O1	GFDIVDTYIH
100215	HCDR1 P1	GFDIVDTYMH
100216	HCDR1 Q1	GFDPGDTFIH
100217	HCDR1 R1	GFDPGDTFMH
100218	HCDR1 S1	GFDPGDTYIH
100219	HCDR1 T1	GFDPGDTYMH
100220	HCDR1 U1	GFDPQDTFIH
100221	HCDR1 V1	GFDPQDTFMH
100222	HCDR1 W1	GFDPQDTYIH
100223	HCDR1 X1	GFDPQDTYMH
100224	HCDR1 Y1	GFDPSDTFIH
100225	HCDR1 Z1	GFDPSDTFMH
100226	HCDR1 A2	GFDPSDTYIH
100227	HCDR1 B2	GFDPSDTYMH
100228	HCDR1 C2	GFDPVDTFIH
100229	HCDR1 D2	GFDPVDTFMH
100230	HCDR1 E2	GFDPVDTYIH
100231	HCDR1 F2	GFDPVDTYMH
100232	HCDR1 G2	GFDVGDTFIH
100233	HCDR1 H2	GFDVGDTFMH
100234	HCDR1 I2	GFDVGDTYIH
100235	HCDR1 J2	GFDVGDTYMH
100236	HCDR1 K2	GFDVQDTFIH
100237	HCDR1 L2	GFDVQDTFMH
100238	HCDR1 M2	GFDVQDTYIH
100239	HCDR1 N2	GFDVQDTYMH
100240	HCDR1 O2	GFDVSDTFIH
100241	HCDR1 P2	GFDVSDTFMH
100242	HCDR1 Q2	GFDVSDTYIH
100243	HCDR1 R2	GFDVSDTYMH
100244	HCDR1 S2	GFDVVDTFIH
100245	HCDR1 T2	GFDVVDTFMH
100246	HCDR1 U2	GFDVVDTYIH
100247	HCDR1 V2	GFDVVDTYMH
100248	HCDR1 W2	GFEIGDTFIH
100249	HCDR1 X2	GFEIGDTFMH
100250	HCDR1 Y2	GFEIGDTYIH
100251	HCDR1 Z2	GFEIGDTYMH
100252	HCDR1 A3	GFEIQDTFIH
100253	HCDR1 B3	GFEIQDTFMH
100254	HCDR1 C3	GFEIQDTYIH
100255	HCDR1 D3	GFEIQDTYMH
100256	HCDR1 E3	GFEISDTFIH
100257	HCDR1 F3	GFEISDTFMH
100258	HCDR1 G3	GFEISDTYIH
100259	HCDR1 H3	GFEISDTYMH
100260	HCDR1 I3	GFEIVDTFIH
100261	HCDR1 J3	GFEIVDTFMH
100262	HCDR1 K3	GFEIVDTYIH
100263	HCDR1 L3	GFEIVDTYMH
100264	HCDR1 M3	GFEPGDTFIH
100265	HCDR1 N3	GFEPGDTFMH
100266	HCDR1 O3	GFEPGDTYIH
100267	HCDR1 P3	GFEPGDTYMH
100268	HCDR1 Q3	GFEPQDTFIH
100269	HCDR1 R3	GFEPQDTFMH
100270	HCDR1 S3	GFEPQDTYIH
100271	HCDR1 T3	GFEPQDTYMH
100272	HCDR1 U3	GFEPSDTFIH
100273	HCDR1 V3	GFEPSDTFMH
100274	HCDR1 W3	GFEPSDTYIH
100275	HCDR1 X3	GFEPSDTYMH
100276	HCDR1 Y3	GFEPVDTFIH
100277	HCDR1 Z3	GFEPVDTFMH
100278	HCDR1 A4	GFEPVDTYIH
100279	HCDR1 B4	GFEPVDTYMH
100280	HCDR1 C4	GFEVGDTFIH
100281	HCDR1 D4	GFEVGDTFMH
100282	HCDR1 E4	GFEVGDTYIH
100283	HCDR1 F4	GFEVGDTYMH
100284	HCDR1 G4	GFEVQDTFIH
100285	HCDR1 H4	GFEVQDTFMH
100286	HCDR1 I4	GFEVQDTYIH
100287	HCDR1 J4	GFEVQDTYMH
100288	HCDR1 K4	GFEVSDTFIH
100289	HCDR1 L4	GFEVSDTFMH
100290	HCDR1 M4	GFEVSDTYIH
100291	HCDR1 N4	GFEVSDTYMH
100292	HCDR1 O4	GFEVVDTFIH
100293	HCDR1 P4	GFEVVDTFMH
100294	HCDR1 Q4	GFEVVDTYIH
100295	HCDR1 R4	GFEVVDTYMH
100296	HCDR3 A1	SGGLPDE
100297	HCDR3 B1	SGGLPDI
100298	HCDR3 C1	SGGLPDK
100299	HCDR3 D1	SGGLPDL
100300	HCDR3 E1	SGGLPDM
100301	HCDR3 F1	SGGLPDQ
100302	HCDR3 G1	SGGLPDT
100303	HCDR3 H1	SGGLPDW
100304	HCDR3 I1	SGGLPDY
100305	HCDR3 J1	SGGMPDE
100306	HCDR3 K1	SGGMPDI
100307	HCDR3 L1	SGGMPDK
100308	HCDR3 M1	SGGMPDL
100309	HCDR3 N1	SGGMPDM
100310	HCDR3 O1	SGGMPDQ
100311	HCDR3 P1	SGGMPDT
100312	HCDR3 Q1	SGGMPDV
100313	HCDR3 R1	SGGMPDW
100314	HCDR3 S1	SGGMPDY
100315	LCDR3 A1	QQWDADPRT
100316	LCDR3 B1	QQWDAFPRT
100317	LCDR3 C1	QQWDAKPRT
100318	LCDR3 D1	QQWDANPRT
100319	LCDR3 E1	QQWDARPRT
100320	LCDR3 F1	QQWDASPRT
100321	LCDR3 G1	QQWDATPRT
100322	LCDR3 H1	QQWDGDPRT
100323	LCDR3 I1	QQWDGFPRT
100324	LCDR3 J1	QQWDGKPRT
100325	LCDR3 K1	QQWDGNPRT
100326	LCDR3 L1	QQWDGRPRT
100327	LCDR3 M1	QQWDGSPRT
100328	LCDR3 N1	QQWDGTPRT
100329	LCDR3 O1	QQWEADPRT
100330	LCDR3 P1	QQWEAFPRT
100331	LCDR3 Q1	QQWEAKPRT
100332	LCDR3 R1	QQWEANPRT
100333	LCDR3 S1	QQWEARPRT
100334	LCDR3 T1	QQWEASPRT
100335	LCDR3 U1	QQWEATPRT
100336	LCDR3 V1	QQWEGDPRT
100337	LCDR3 W1	QQWEGFPRT
100338	LCDR3 X1	QQWEGKPRT
100339	LCDR3 Y1	QQWEGNPRT
100340	LCDR3 Z1	QQWEGRPRT
100341	LCDR3 A2	QQWEGSPRT
100342	LCDR3 B2	QQWEGTPRT
100343	LCDR3 C2	QQWHADPRT
100344	LCDR3 D2	QQWHAFPRT
100345	LCDR3 E2	QQWHAKPRT
100346	LCDR3 F2	QQWHANPRT
100347	LCDR3 G2	QQWHARPRT
100348	LCDR3 H2	QQWHASPRT
100349	LCDR3 I2	QQWHATPRT
100350	LCDR3 J2	QQWHGDPRT
100351	LCDR3 K2	QQWHGFPRT
100352	LCDR3 L2	QQWHGKPRT
100353	LCDR3 M2	QQWHGNPRT
100354	LCDR3 N2	QQWHGRPRT
100355	LCDR3 O2	QQWHGSPRT
100356	LCDR3 P2	QQWHGTPRT
100357	LCDR3 Q2	QQWNADPRT
100358	LCDR3 R2	QQWNAFPRT
100359	LCDR3 S2	QQWNAKPRT
100360	LCDR3 T2	QQWNANPRT
100361	LCDR3 U2	QQWNARPRT
100362	LCDR3 V2	QQWNASPRT
100363	LCDR3 W2	QQWNATPRT
364100	LCDR3 X2	QQWNGDPRT
100365	LCDR3 Y2	QQWNGFPRT
100366	LCDR3 Z2	QQWNGKPRT
100367	LCDR3 A3	QQWNGNPRT
100368	LCDR3 B3	QQWNGRPRT
100369	LCDR3 C3	QQWNGSPRT
100370	LCDR3 D3	QQWNGTPRT
100371	LCDR3 E3	QQWQADPRT
100372	LCDR3 F3	QQWQAFPRT
100373	LCDR3 G3	QQWQAKPRT
100374	LCDR3 H3	QQWQANPRT
100375	LCDR3 I3	QQWQARPRT
100376	LCDR3 J3	QQWQASPRT
100377	LCDR3 K3	QQWQATPRT
100378	LCDR3 L3	QQWQGDPRT
100379	LCDR3 M3	QQWQGFPRT
100380	LCDR3 N3	QQWQGKPRT
100381	LCDR3 O3	QQWQGNPRT
100382	LCDR3 P3	QQWQGRPRT
100383	LCDR3 Q3	QQWQGSPRT
100384	LCDR3 R3	QQWQGTPRT
100385	LCDR3 S3	QQWSADPRT
100386	LCDR3 T3	QQWSAFPRT
100387	LCDR3 U3	QQWSAKPRT
100388	LCDR3 V3	QQWSANPRT
100389	LCDR3 W3	QQWSARPRT
100390	LCDR3 X3	QQWSASPRT
100391	LCDR3 Y3	QQWSATPRT
100392	LCDR3 Z3	QQWSGDPRT
100393	LCDR3 A4	QQWSGFPRT
100394	LCDR3 B4	QQWSGKPRT
100395	LCDR3 C4	QQWSGNPRT
100396	LCDR3 D4	QQWSGRPRT
100397	LCDR3 E4	QQWSGSPRT
100398	LCDR3 F4	QQWSGTPRT
100399	LCDR3 G4	QQWDADPRT
100400	LCDR3 H4	NQWDAFPRT
100401	LCDR3 I4	NQWDAKPRT
100402	LCDR3 J4	NQWDANPRT
100403	LCDR3 K4	NQWDARPRT
100404	LCDR3 L4	NQWDASPRT
100405	LCDR3 M4	NQWDATPRT
100406	LCDR3 N4	NQWDGDPRT
100407	LCDR3 O4	NQWDGFPRT
100408	LCDR3 P4	NQWDGKPRT
100409	LCDR3 Q4	NQWDGNPRT
100410	LCDR3 R4	NQWDGRPRT
100411	LCDR3 S4	NQWDGSPRT
100412	LCDR3 T4	NQWDGTPRT
100413	LCDR3 U4	NQWEADPRT
100414	LCDR3 V4	NQWEAFPRT
100415	LCDR3 W4	NQWEAKPRT
100416	LCDR3 X4	NQWEANPRT
100417	LCDR3 Y4	NQWEARPRT
100418	LCDR3 Z4	NQWEASPRT
100419	LCDR3 A5	NQWEATPRT
100420	LCDR3 B5	NQWEGDPRT
100421	LCDR3 C5	NQWEGFPRT
100422	LCDR3 D5	NQWEGKPRT
100423	LCDR3 E5	NQWEGNPRT
100424	LCDR3 F5	NQWEGRPRT
100425	LCDR3 G5	NQWEGSPRT
100426	LCDR3 H5	NQWEGTPRT
100427	LCDR3 I5	NQWHADPRT
100428	LCDR3 J5	NQWHAFPRT
100429	LCDR3 K5	NQWHAKPRT
100430	LCDR3 L5	NQWHANPRT
100431	LCDR3 M5	NQWHARPRT
100432	LCDR3 N5	NQWHASPRT
100433	LCDR3 O5	NQWHATPRT
100434	LCDR3 P5	NQWHGDPRT
100435	LCDR3 Q5	NQWHGFPRT
100436	LCDR3 R5	NQWHGKPRT
100437	LCDR3 S5	NQWHGNPRT
100438	LCDR3 T5	NQWHGRPRT
100439	LCDR3 U5	NQWHGSPRT
100440	LCDR3 V5	NQWHGTPRT
100441	LCDR3 W5	NQWNADPRT
100442	LCDR3 X5	NQWNAFPRT
100443	LCDR3 Y5	NQWNAKPRT
100444	LCDR3 Z5	NQWNANPRT
100445	LCDR3 A6	NQWNARPRT
100446	LCDR3 B6	NQWNASPRT
100447	LCDR3 C6	NQWNATPRT
100448	LCDR3 D6	NQWNGDPRT
100449	LCDR3 E6	NQWNGFPRT
100450	LCDR3 F6	NQWNGKPRT
100451	LCDR3 G6	NQWNGNPRT
100452	LCDR3 H6	NQWNGRPRT
100453	LCDR3 I6	NQWNGSPRT
100454	LCDR3 J6	NQWNGTPRT
100455	LCDR3 K6	NQWQADPRT
100456	LCDR3 L6	NQWQAFPRT
100457	LCDR3 M6	NQWQAKPRT
100458	LCDR3 N6	NQWQANPRT
100459	LCDR3 O6	NQWQARPRT
100460	LCDR3 P6	NQWQASPRT
100461	LCDR3 Q6	NQWQATPRT
100462	LCDR3 R6	NQWQGDPRT
100463	LCDR3 S6	NQWQGFPRT
100464	LCDR3 T6	NQWQGKPRT
100465	LCDR3 U6	NQWQGNPRT
100466	LCDR3 V6	NQWQGRPRT
100467	LCDR3 W6	NQWQGSPRT
100468	LCDR3 X6	NQWQGTPRT
100469	LCDR3 Y6	NQWSADPRT
100470	LCDR3 Z6	NQWSAFPRT
100471	LCDR3 A7	NQWSAKPRT
100472	LCDR3 B7	NQWSANPRT
100473	LCDR3 C7	NQWSARPRT
100474	LCDR3 D7	NQWSASPRT
100475	LCDR3 E7	NQWSATPRT
100476	LCDR3 F7	NQWSGDPRT
100477	LCDR3 G7	NQWSGFPRT
100478	LCDR3 H7	NQWSGKPRT
100479	LCDR3 I7	NQWSGNPRT
100480	LCDR3 J7	NQWSGRPRT
100481	LCDR3 K7	NQWSGSPRT
100482	LCDR3 L7	NQWSGTPRT

TABLE 3 — Exemplary CD30 Ligand Antibodies SEQ

Antibody	ID NO	Sequence
HCDR1 A1	20100	SYIWS
HCDR2 A1	20101	RIYASGNTNYNPSLKS
HCDR3 A1	20102	DYRVAGTYYYYYGLDV
LCDR1 A1	20103	TGTSSDVGVYDYVS
LCDR2 A1	20104	EVSNRPS
LCDR3 A1	20105	SSYTSRSTWV
HCDR1 A2	20106	SYYWT
HCDR2 A2	20107	RIYTSGITNYNPSLKS
HCDR3 A2	20108	ERVVGASRYYYYGVDV
LCDR1 A2	20109	TGTSSDVGLYNYVS
LCDR2 A2	20110	EVNNRPS
LCDR3 A2	20111	SSYTSSSTWV
HCDR1 A3	20112	SYYWT
HCDR2 A3	20113	RIYTSGITNYNPSLKS
HCDR3 A3	20114	ERVVGASRYYYYGVDV
LCDR1 A3	20115	TGTSSDIGLYDYVS
LCDR2 A3	20116	EVNNRPS
LCDR3 A3	20117	SSYTSSSTWV
HCDR1 A4	20118	SYSWS
HCDR2 A4	20119	RTSTSGRNNYNPSLKS
HCDR3 A4	20120	DFTIAARRYYYYGMDV
LCDR1 A4	20121	TGTSSDIGLYNYVS
LCDR2 A4	20122	EVINRPS
LCDR3 A4	20123	SSYTSSSTWV
HCDR1 A5	20124	NNYWS
HCDR2 A5	20125	RVYSSGLTNYKPSLKS
HCDR3 A5	20126	ERATVTTRYHYDGMDV
LCDR1 A5	20127	TGSSSDIGTYNYVS
LCDR2 A5	20128	EVNNRPS
LCDR3 A5	20129	SSYSSSSTWV
HCDR1 A6	20130	SYYWS
HCDR2 A6	20131	RIFASGSTNYNPSLRS
HCDR3 A6	20132	ERVGVQDYYHYSGMDV
LCDR1 A6	20133	TGTSSDVGLYNYVS
LCDR2 A6	20134	EVSKRPS
LCDR3 A6	20135	SSYTSSSTWV
HC Var 1	20136	QVQLQESGPGLVKPSETLSLTCTVSGGSI
		SSYYWTWIRQPAGKGLEWIGRIYTSGITN
		YNPSLKSRVTMSVDTSKNQFSLKLSSVTA
		ADTAVYYCARERVVGASRYYYYGVDVWGQ
		GTTVTVSS
LC Var 1	20137	QSALTQPASVSGSPGQSITISCTGTSSDV
		GLYNYVSWYQQHPDKAPKLMIFEVNNRPS
		GVSNRFSGSNSGNTASLTISGLQAEDEAD
		YYCSSYTSSSTWVFGGGTKLTVL
HC Var 2	20138	QVQLQESGPGLVKPSETLSLTCTVSGGSI
		SSYYWTWIRQPAGKGLEWIGRIYTSGITN
		YNPSLKSRVTMSVDTSKNQFSLKLSSVTA
		ADTAVYYCARERVVGASRYYYYGVDVWGQ
		GTTVTVSS
LC Var 2	20139	QSALTQPASVSGSPGQSITISCTGTSSDI
		GLYDYVSWYQQHPDRAPKLIIFEVNNRPS
		GVSYRFSGSNSGNTASLTISGLQAEDEAD
		YYCSSYTSSSTWVFGGGTKLTVL
HC Var 3	20140	QVQLQESGPGLVKPSETLSLTCTVSGGSI
		SSYSWSWIRQPAGKGLEWIGRTSTSGRNN
		YNPSLKSRVTMSVDTSKNQFSLKLNSVTA
		ADTAVYYCARDFTIAARRYYYYGMDVWGQ
		GTTVTVSS
LC Var 3	20141	QSALTQPASVSGSPGQSITISCTGTSSDI
		GLYNYVSWYQQHPGKAPKLIIYEVINRPS
		GVSNRFSGSESGNTASLTISGLQAEDEAN
		YYCSSYTSSSTWVFGGGTKLTVL
HC Var 4	20142	QVQLQESGPRLVKPSETLSLTCTVSGGSI
		TNNYWSWIRQPAGKGLEWIGRVYSSGLTN
		YKPSLKSRVTMSVDTSKNQFSLRLNSVTA
		ADTAVYYCARERATVTTRYHYDGMDVWGQ
		GTSVTVSS
LC Var 4	20143	QSALTQPASVSGSPGQSITISCTGSSSDI
		GTYNYVSWYQQYPGKAPELMIYEVNNRPS
		GVSDRFSGSTSGNTASLTISGLQANDEAD
		YYCSSYSSSSTWVFGGGTKLTVL
HC Var 5	20144	QVQLQESGPGLVKPSETLSLTCTVSGGSI
		SSYYWSWIRQPAGKGLEWIGRIFASGSTN
		YNPSLRSRVTMSRDTSKNQFSLKLSSVTA
		ADTAVYYCAKERVGVQDYYHYSGMDVWGQ
		GTTVTVSS
LC Var 5	20145	QSALTQPASVSGSPGQSITISCTGTSSDV
		GLYNYVSWYQQQPGKAPKLMIYEVSKRPS
		GVSNRFSGSTSGNTASLTISGLQADDEAD
		YSCSSYTSSSTWVFGGGTKLTVL
HC Var 6	20146	QVQLQESGPGLVKPSETLSLTCTVSGGSI
		SSYIWSWIRQPAGKGLEWIGRIYASGNTN
		YNPSLKSRVTISVDTSKNQFSLKLSSMTA
		ADTAVYYCARDYRVAGTYYYYYGLDVWGQ
		GTTVTVSS
HC Var 7	20147	QVQLQESGPGLVKPSETLSLTCTVSGGSI
		SSYIWSWIRQPAGKGLEWIGRIYASGNTN
		YNPSLKSRVTMSVDTSKNQFSLKLSSMTA
		ADTAVYYCARDYRVAGTYYYYYGLDVWGQ
		GTTVTVSS
HC Var 8	20148	QVQLQESGPGLVKPSETLSLTCTVSGGSI
		SSYIWSWIRQPAGKGLEWIGRIYASGNTN
		YNPSLKSRVTMSVDTSKNQFSLKLSSVTA
		ADTAVYYCARDYRVAGTYYYYYGLDVWGQ
		GTTVTVSS
HC Var 9	20149	QVQLQESGPGLVKPSETLSLTCTVSGGSI
		SSYIWSWIRQPAGKGLEWIGRIYASGQTN
		YNPSLKSRVTMSVDTSKNQFSLKLSSMTA
		ADTAVYYCARDYRVAGTYYYYYGLDVWGQ
		GTTVTVSS
HC Var 10	20150	QVQLQESGPGLVKPSETLSLTCTVSGGSI
		SSYIWSWIRQPAGKGLEWIGRIYASGQTN
		YNPSLKSRVTISVDTSKNQFSLKLSSVTA
		ADTAVYYCARDYRVAGTYYYYYGLDVWGQ
		GTTVTVSS
HC Var 11	20151	QVQLQESGPGLVKPSETLSLTCTVSGGSI
		SSYIWSWIRQPAGKGLEWIGRIYASGNTN
		YNPSLKSRVTISVDTSKNQFSLKLSSVTA
		ADTAVYYCARDYRVAGTYYYYYGLDVWGQ
		GTTVTVSS
HC Var 12	20152	QVQLQESGPGLVKPSETLSLTCTVSGGSI
		SSYIWSWIRQPAGKGLEWIGRIYASGQTN
		YNPSLKSRVTISVDTSKNQFSLKLSSMTA
		ADTAVYYCARDYRVAGTYYYYYGLDVWGQ
		GTTVTVSS
HC Var 13	20153	QVQLQESGPGLVKPSETLSLTCTVSGGSI
		SSYIWSWIRQPAGKGLEWIGRIYASGQTN
		YNPSLKSRVTMSVDTSKNQFSLKLSSVTA
		ADTAVYYCARDYRVAGTYYYYYGLDVWGQ
		GTTVTVSS
LC Var 6-13	20154	QSALTQPASVSGSPGQSITISCTGTSSDV
		GVYDYVSWYQQHPGKAPKLMIYEVSNRPS
		GVSNRFSGSKSGNTASLTISGLQTEDEAD
		YYCSSYTSRSTWVFGGGTKLTVL

TABLE 4 — TNFSF15 Polygenic Risk Score (PRS) Polymorphisms

			Minor				Seq
		Minor	Allele	Major			ID
rsID	Illumina_id	Allele	Frequency	Allele	Chromosome	Gene	No.
rs11221332	imm_11_127_886184	A	0.232475	G	chr11	ETS1	41
rs7134599	imm_12_667_86342	A	0.381954	G	chr12	IFNG	42
rs6062496	imm_20_617_99543	G	0.406514	A	chr20	TNFRSF6B	43
rs4246905	imm_9_1165_93070	A	0.270925	G	chr9	TNFSF15	8
rs7468800	imm_9_1166_31826	A	0.124622	C	chr9	TNFSF15; TNFSF8	44
rs1569328	rs1569328	A	0.14869	G	chr14	U2; FOS	45
rs2284553	rs2284553	A	0.386244	G	chr21	IFNGR2	46
rs6062504	rs6062504	A	0.27128	G	chr20	ZGPAT	47
rs7556897	rs7556897	G	0.334936	A	chr2	SLC19A3: CCL20	48

TABLE 5 — GRCh38.p13 Primary Assembly Positions of Polymorphisms SEQ ID

dbSNP	NO:	SNP_SEQ_GRCh38.p13 Primary Assembly
rs11897732	60	>NC_000002.12: 43313747-43314246
		Homo sapiens chromosome 2
		SEQ = [G/A]
		>NC_000002.12: 43314248-43314747
		Homo sapiens chromosome 2
rs6740739	61	>NC_000002.12: 43628004-43628503
		Homo sapiens chromosome 2
		SEQ = [G/A]
		>NC_000002.12: 43628505-43629004
		Homo sapiens chromosome 2
rs17796285	62	>NC_000008.11: 11266446-11266945
		Homo sapiens chromosome 8
		SEQ = [G/A/
		>NC_000008.11: 11266947-11267446
		Homo sapiens chromosome 8
rs7935393	63	>NC_000011.10: 128572704-128573203
		Homo sapiens chromosome 11
		SEQ = [A/C]
		>NC_000011.10: 128573205-128573704
		Homo sapiens chromosome 11
rs12934476	64	>NC_000016.10: 11237152-11237651
		Homo sapiens chromosome 16
		SEQ = [A/G]
		>NC_000016.10: 1123 7653-11238152
		Homo sapiens chromosome 16
rs12457255	65	>NC_000018.10: 12759477-12759976
		Homo sapiens chromosome 18
		SEQ = [C/A]
		>NC_000018.10: 12759978-12760477
		Homo sapiens chromosome 18
rs2070557	66	>NC_000021.9: 44234741-44235240
		Homo sapiens chromosome 21
		SEQ = [A/T]
		>NC_000021.9: 44235242-44235741
		Homo sapiens chromosome 21
rs4246905	67	>NC_000009.12: 114790469-114790968
		Homo sapiens chromosome 9
		SEQ = [T/A/
		>NC_000009.12: 114790970-114791469
		Homo sapiens chromosome 9
rs10974900	68	>NC_000009.12: 4987458-4987957
		Homo sapiens chromosome 9
		SEQ = [C/T]
		>NC_000009.12: 4987959-4988458
		Homo sapiens chromosome 9
rs12434976	69	>NC_000014.9: 98185370-98185869
		Homo sapiens chromosome 14
		SEQ = [A/C]
		>NC_000014.9: 98185871-98186370
		Homo sapiens chromosome 14
rs16901748	70	>NC_000005.10: 11561609-11562108
		Homo sapiens chromosome 5
		SEQ = [G/T]
		>NC_000005.10: 11562110-11562609
		Homo sapiens chromosome 5
rs2815844	71	>NC_000001.11: 241083704-241084203
		Homo sapiens chromosome 1
		SEQ = [C/T]
		>NC_000001.11: 241084205-241084704
		Homo sapiens chromosome 1
rs889702	72	>NC_000016.10: 6088639-6089138
		Homo sapiens chromosome 16
		SEQ = [G/A]
		>NC_000016.10: 6089140-6089639
		Homo sapiens chromosome 16
rs2409750	73	>NC_000008.11: 11229685-11230184
		Homo sapiens chromosome 8
		SEQ = [A/C]
		>NC_000008.11: 11230186-11230685
		Homo sapiens chromosome 8
rs1541020	74	>NC_000010.11: 6122567-6123066
		Homo sapiens chromosome 10
		SEQ = [C/T]
		>NC_000010.11: 6123068-6123567
		Homo sapiens chromosome 10
rs4942248	75	>NC_000013.11: 43832169-43832668
		Homo sapiens chromosome 13
		SEQ = [T/A]
		>NC_000013.11: 43832670-43833169
		Homo sapiens chromosome 13
rs12934476	76	>NC_000016.10: 11237152-11237651
		Homo sapiens chromosome 16
		SEQ = [A/G]
		>NC_000016.10: 1123 7653-11238152
		Homo sapiens chromosome 16
rs12457255	77	>NC_000018.10: 12759477-12759976
		Homo sapiens chromosome 18
		SEQ = [C/A]
		>NC_000018.10: 12759978-12760477
		Homo sapiens chromosome 18
rs2297437	78	>NC_000020.11: 63673421-63673920
		Homo sapiens chromosome 20
		SEQ = [G/A]
		>NC_000020.11: 63673922-63674421
		Homo sapiens chromosome 20
rs41309367	79	>NC_000020.11: 63677701-63678200
		Homo sapiens chromosome 20
		SEQ = [C/T]
		>NC_000020.11: 63678202-63678701
		Homo sapiens chromosome 20
rs10733509	80	>NC_000009.12: 4307550-4308049
		Homo sapiens chromosome 9
		SEQ = [A/G]
		>NC_000009.12: 4308051-4308550
		Homo sapiens chromosome 9
rs10750376	81	>NC_000011.10: 127867534-127868033
		Homo sapiens chromosome 11
		SEQ = [C/T]
		>NC_000011.10: 127868035-127868534
		Homo sapiens chromosome 11
rs10932456	82	>NC_000002.12: 212988031-212988530
		Homo sapiens chromosome 2
		SEQ = [A/G]
		>NC_000002.12: 212988532-212989031
		Homo sapiens chromosome 2
rs1326860	83	>NC_000001.11: 193834579-193835078
		Homo sapiens chromosome 1
		SEQ = [A/G]
		>NC_000001.11: 193835080-193835579
		Homo sapiens chromosome 1
rs1528663	84	>NC_000011.10: 13945175-13945674
		Homo sapiens chromosome 11
		SEQ = [G/A]
		>NC_000011.10: 13945676-13946175
		Homo sapiens chromosome 11
rs1892231	85	>NC_000014.9: 98267730-98268229
		Homo sapiens chromosome 14
		SEQ = [A/C]
		>NC_000014.9: 98268231-98268730
		Homo sapiens chromosome 14
rs951279	86	>NC_000001.11: 208593050-208593549
		Homo sapiens chromosome 1
		SEQ = [A/G]
		>NC_000001.11: 208593551-208594050
		Homo sapiens chromosome 1
rs9806914	87	>NC_000016.10: 6097144-6097643
		Homo sapiens chromosome 16
		SEQ = [A/C]
		>NC_000016.10: 6097645-6098144
		Homo sapiens chromosome 16
rs7935393	88	>NC_000011.10: 128572704-128573203
		Homo sapiens chromosome 11
		SEQ = [A/C]
		>NC_000011.10: 128573205-128573704
		Homo sapiens chromosome 11
rs1690492	89	>NC_000016.10: 11224459-11224958
		Homo sapiens chromosome 16
		SEQ = [G/C]
		>NC_000016.10: 11224960-11225459
		Homo sapiens chromosome 16
rs420726	90	>NC_000021.9: 44239062-44239561
		Homo sapiens chromosome 21
		SEQ = [T/C]
		>NC_000021.9: 44239563-44240062
		Homo sapiens chromosome 21
rs7759385	91	>NC_000006.12: 106140395-106140894
		Homo sapiens chromosome 6
		SEQ = [T/A]
		>NC_000006.12: 106140896-106141395
		Homo sapiens chromosome 6
rs10974900	92	>NC_000009.12: 4987458-4987957
		Homo sapiens chromosome 9
		SEQ = [C/T]
		>NC_000009.12: 4987959-4988458
		Homo sapiens chromosome 9
rs1326860	93	>NC_000001.11: 193834579-193835078
		Homo sapiens chromosome 1
		SEQ = [A/G]
		>NC_000001.11: 193835080-193835579
		Homo sapiens chromosome 1
rs2548147	94	>NC_000005.10: 40151459-40151958
		Homo sapiens chromosome 5
		SEQ = [G/C]
		>NC_000005.10: 40151960-40152459
		Homo sapiens chromosome 5
rs2815844	95	>NC_000001.11: 241083704-241084203
		Homo sapiens chromosome 1
		SEQ = [C/T]
		>NC_000001.11: 241084205-241084704
		Homo sapiens chromosome 1
rs889702	96	>NC_000016.10: 6088639-6089138
		Homo sapiens chromosome 16
		SEQ = [G/A]
		>NC_000016.10: 6089140-6089639
		Homo sapiens chromosome 16
rs9806914	97	>NC_000016.10: 6097144-6097643
		Homo sapiens chromosome 16
		SEQ = [A/C/
		>NC_000016.10: 6097645-6098144
		Homo sapiens chromosome 16
rs6478109	98	>NC_000009.12: 114805986-114806485
		Homo sapiens chromosome 9
		SEQ = [A/G
		>NC_000009.12: 114806487-114806986
		Homo sapiens chromosome 9
rs7278257	99	>NC_000021.9: 44233381-44233880
		Homo sapiens chromosome 21
		SEQ = [G/C]
		>NC_000021.9: 44233882-44234381
		Homo sapiens chromosome 21
rs11221332	100	>NC_000011.10: 128510579-128511078
		Homo sapiens chromosome 11
		SEQ = [C/A/
		>NC_000011.10: 128511080-128511579
		Homo sapiens chromosome 11
rs56124762	101	>NC_000021.9: 44238091-44238590
		Homo sapiens chromosome 21
		SEQ = [A/G]
		>NC_000021.9: 44238592-44239091
		Homo sapiens chromosome 21
rs2070558	102	>NC_000021.9: 44235275-44235774
		Homo sapiens chromosome 21
		SEQ = [G/A]
		>NC_000021.9: 44235776-44236275
		Homo sapiens chromosome 21
rs2070561	103	>NC_000021.9: 44237587-44238086
		Homo sapiens chromosome 21
		SEQ = [T/C]
		>NC_000021.9: 44238088-44238587
		Homo sapiens chromosome 21
rs7134599	104	>NC_000012.12: 68105795-68106294
		Homo sapiens chromosome 12
		SEQ = [G/A]
		>NC_000012.12: 68106296-68106795
		Homo sapiens chromosome 12
rs6062496	105	>NC_000020.11: 63697246-63697745
		Homo sapiens chromosome 20
		SEQ = [G/A]
		>NC_000020.11: 63697747-63698246
		Homo sapiens chromosome 20
rs7468800	106	>NC_000009.12: 114829225-114829724
		Homo sapiens chromosome 9
		SEQ = [C/A]
		>NC_000009.12: 114829726-114830225
		Homo sapiens chromosome 9
rs1569328	107	>NC_000014.9: 75274548-75275047
		Homo sapiens chromosome 14
		SEQ = [C/T]
		>NC_000014.9: 75275049-75275548
		Homo sapiens chromosome 14
rs2284553	108	>NC_000021.9: 33403889-33404388
		Homo sapiens chromosome 21
		SEQ = [A/G]
		>NC_000021.9: 33404390-33404889
		Homo sapiens chromosome 21
rs6062504	364141	>NC_000020.11: 63717055-63717554
		Homo sapiens chromosome 20
		SEQ = [A/G/
		>NC_000020.11: 63717556-63718055
		Homo sapiens chromosome 20
rs7556897	364142	>NC_000002.12: 227794896-227795395
		Homo sapiens chromosome 2
		SEQ = [C/G/
		>NC_000002.12: 227795397-227795896
		Homo sapiens chromosome 2

TABLE 8 — Exemplary 3-SNP Models A-C

	Training Cohort	Validation Cohort	Combined
Model	PPV	SPEC	PPV	SPEC	PPV	SPEC	CD FREQ
A	0.902	0.867	0.643	0.783	0.797	0.816	38.7
B	0.806	0.767	0.682	0.848	0.759	0.816	26.3
C	0.838	0.800	0.576	0.696	0.714	0.737	36.7

TABLE 9 — 3-SNP Models D-K

	Cohort 1		Cohort 2		Combined
Model	PPV	SPEC	PPV	SPEC	PPV	SPEC	CD FREQ
D	0.815	0.833	0.750	0.848	0.782	0.842	18.6
E	0.848	0.833	0.606	0.717	0.727	0.763	31.2
F	0.909	0.933	0.667	0.870	0.800	0.895	18.3
G	0.917	0.933	0.609	0.804	0.766	0.855	22.6
H	0.923	0.967	0.727	0.935	0.833	0.947	12.9
I	0.941	0.967	0.733	0.913	0.844	0.934	17.2
J	0.923	0.967	0.727	0.935	0.833	0.947	12.9
K	0.844	0.833	0.731	0.848	0.793	0.842	23.9

TABLE 10 — Proxy SNPs Utilized in Validation

RS Number	Coord	Alleles	MAF	Distance	Dprime	R2
rs7278257	chr21: 45653764	(G/C)	0.2833	0	1	1
rs56124762	chr21: 45658474	(A/G)	0.2763	4710	0.9849	0.9372
rs11558819	chr21: 45656774	(C/T)	0.2873	3010	0.9705	0.9236
rs2070557	chr21: 45655124	(A/T)	0.2972	1360	0.9651	0.8705
rs2070558	chr21: 45655658	(G/A)	0.2952	1894	0.9602	0.87
rs2329718	chr21: 45656199	(T/C)	0.2952	2435	0.9602	0.87
rs2070559	chr21: 45657700	(C/G)	0.2982	3936	0.96	0.8573
rs2070560	chr21: 45657848	(C/G)	0.2972	4084	0.9551	0.8526
rs2070561	chr21: 45657970	(T/C)	0.2972	4206	0.9551	0.8526

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Claims as granted

53 claims

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6 codes

IPC · International Patent Classification

Section A — Human necessities

A61K39/00
A61P1/00
A61P1/04

Section C — Chemistry; metallurgy

C12Q1/6883
C07K16/28
C07K16/24

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