The present invention relates to a human antibody specific for FcRn that is a receptor with a high affinity for IgG, a production method thereof, a composition for treating autoimmune disease, which comprises the antibody, and a method of treating and diagnosing autoimmune disease using the same. The FcRn-specific antibody according to the present invention can bind to FcRn non-competitively with IgG or the like to reduce serum auto-antibody levels, and thus can be used for the treatment of autoimmune diseases.

Description

41 parts

›TECHNICAL FIELD

The present invention relates to a human antibody specific for FcRn (stands for neonatal Fc receptor, also called FcRP, FcRB or Brambell receptor) that is a receptor with a high affinity for IgG, a production method thereof, a composition for treating autoimmune disease, which comprises the antibody, and a method of treating and diagnosing autoimmune disease using the same. The FcRn-specific antibody according to the present invention can bind to FcRn non-competitively with IgG or the like to reduce serum pathogenic auto-antibody levels, and thus can be used for the treatment of autoimmune diseases.

›BACKGROUND ART · 1 of 2

Antibodies are immunological proteins that bind to a specific antigen. In most animals, including humans and mice, antibodies are constructed from paired heavy and light polypeptide chains. Each chain is made up of two distinct regions, referred to as the variable and constant regions. The light and heavy chain variable regions show significant sequence diversity between antibodies, and are responsible for binding the target antigen. The constant regions show less sequence diversity, and are responsible for binding a number of natural proteins to elicit important biochemical events. In humans there are five different classes of antibodies including IgA (which includes subclasses IgA1 and IgA2), IgD, IgE, IgG (which includes subclasses IgG1, IgG2, IgG3, and IgG4), and IgM. The distinguishing feature between these antibody classes is their constant regions.

IgG antibodies are most abundantly present in serum, protect the body from the invasion of pathogens, hasten the recruitment of immune system components, and mediate inflammatory responses in tissues. IgG antibodies are tetrameric proteins composed of two heavy chains and two light chains. The IgG heavy chain is composed of four immunoglobulin domains linked from N- to C-terminus in the order VH-CH1-CH2-CH3, referring to the heavy chain variable domain (VH), heavy chain constant domain 1 (CH1), heavy chain constant domain 2 (CH2), and heavy chain constant domain 3 (CH3), respectively.

The IgG light chain is composed of two immunoglobulin domains linked from N- to C-terminus in the order of VL-CL, referring to the light chain variable domain (VL) and the light chain constant domain (CL), respectively.

Under normal conditions, the half-life of most IgG excluding IgG3 isotype in serum is about 22-23 days in humans, which is a prolonged period relative to the serum half-life of other plasma proteins. With respect to this prolonged serum half-life of IgG, IgG that entered cells by endocytosis can strongly bind to neonatal Fc receptor (FcRn, a kind of Fc gamma receptor) in endosomes at a pH of 6.0 to avoid the degradative lysosomal pathway. When the IgG-FcRn complex cycles to the plasma membrane, IgG dissociates rapidly from FcRn in the bloodstream at slightly basic pH (˜7.4). By this receptor-mediated recycling mechanism, FcRn effectively rescues the IgG from degradation in lysosomes, thereby prolonging the half-life of IgG (Roopenian et al. J. Immunol. 170:3528, 2003).

FcRn was identified in the neonatal rat gut, where it functions to mediate the absorption of IgG antibody from the mother's milk and facilitates its transport to the circulatory system. FcRn has also been isolated from human placenta, where it mediates absorption and transport of maternal IgG to the fetal circulation. In adults, FcRn is expressed in a number of tissues, including epithelial tissues of the lung, intestine, kidney, as well as nasal, vaginal, and biliary tree surfaces.

FcRn is a non-covalent heterodimer that typically resides in the endosomes of endothelial and epithelial cells. FcRn is a membrane bound receptor having three heavy chain alpha domains (α1, α2 and α3) and a single soluble light chain β2-microglobulin (β2m) domain. Structurally, it belongs to a family of major histocompatibility complex class 1 molecules that have β2m as a common light chain. The FcRn chain has a molecular weight of about 46 kD and is composed of an ectodomain containing the α1, α2, and α3 heavy chain domains and a β2m light chain domain and having a single sugar chain, a single-pass transmembrane, and a relatively short cytoplasmic tail (Burmeister et al. Nature 372:366, 1994.).

In order to study the contributions of FcRn to IgG homeostasis, mice have been engineered so that at least part of the genes encoding β2m and FcRn heavy chains have been “knocked out” so that these proteins are not expressed. In these mice, the serum half-life and concentrations of IgG were dramatically reduced (Junghans et al, Proc. Natl. Acad. Sci. 93:5512, 1996), suggesting a FcRn-dependent mechanism for IgG homeostasis. It has also been suggested that anti-human FcRn antibodies may be generated in these FcRn knockout mice and that these antibodies may prevent the binding of IgG to FcRn. However, such antibodies have not been generated or tested (WO 02/43658 A).

The inhibition of IgG binding to FcRn negatively alters IgG serum half-life by preventing IgG recycling, so that autoimmune diseases caused by auto-antibodies can be treated. This possibility was shown in a mouse model of autoimmune cutaneous bullous diseases (Li et al. J. Clin. Invest. 115:3440, 2005). Accordingly, agents that block or antagonize the binding of IgG to FcRn may be used in a method for treating or preventing autoimmune and inflammatory diseases, which are mediated by IgG.

Autoimmune diseases and alloimmune diseases are mediated by pathogenic antibodies, and typical examples thereof include immune neutropenia, Guillain-Barré syndrome, epilepsy, autoimmune encephalitis, Isaac's syndrome, nevus syndrome, pemphigus vulgaris, Pemphigus foliaceus, Bullous pemphigoid, epidermolysis bullosa acquisita, pemphigoid gestationis, mucous membrane pemphigoid, antiphospholipid syndrome, autoimmune anemia, autoimmune Grave's disease, Goodpasture's syndrome, myasthenia gravis, multiple sclerosis, rheumatoid arthritis, lupus, and idiopathic thrombocytopenic purpura (hereinafter referred to as ITP). ITP is a disease caused by the destruction of peripheral platelets due to the generation of auto-antibodies that bind to a specific platelet membrane glycoprotein. Anti-platelet antibodies opsonize platelets and result in rapid platelet destruction by reticular cells (e.g., macrophages).

In general, attempts to treat ITP include suppressing the immune system, and consequently causing an increase in platelet levels. ITP affects women more frequently than men, and more common in children than adults. The incidence is 1 out of 10,000 people. Chronic ITP is one of the major blood disorders in both adults and children. It is a source of significant hospitalization and treatment cost at specialized hematological departments in the US and around the world. Each year there are approximately 20,000 new cases in the US, and the cost for ITP care and special therapy is extremely high. Most children with ITP have a very low platelet count that causes sudden bleeding, with typical symptoms including bruises, small red dots on the skin, nosebleeds and bleeding gums. Although children can sometimes recover with no treatment, many doctors recommend careful observation and mitigation of bleeding and treatment with intravenous infusions of gamma globulin.

›BACKGROUND ART · 2 of 2

Methods of treating autoimmune diseases by intravenous administration of IgG (IVIG) in large amounts have been widely used (Arnson autoimmunity 42:553 (2009)). IVIG effects are explained by various mechanisms, but are also explained by a mechanism that increases the clearance of pathogenic antibodies by competition with endogenous IgG for FcRn. Intravenous administration of human immunoglobulin (IVIG) in large amounts has been shown to increase platelet counts in children afflicted with immune ITP, and IVIG has shown to be beneficial as a treatment for several other autoimmune conditions. Many studies have investigated the mechanisms by which IVIG achieves effects in the treatment of autoimmune diseases. With regard to ITP, early investigations led to the conclusion that IVIG effects are mainly due to blockade of the Fc receptors responsible for phagocytosis of antibody-opsonized platelets. Subsequent studies showed that Fc-depleted IVIG preparations provided increases in platelet counts in some patients with ITP, and recently it was reported that IVIG effects are due to stimulation of FcγRIIb expression on macrophage cells, leading to inhibition of platelet phagocytosis.

However, such IVIG treatments have substantial side effects and are very costly to administer. Further, other therapies used for the treatment of autoimmune/alloimmune conditions other than IVIG include polyclonal anti-D immunoglobulin, corticosteroids, immuno-suppressants (including chemotherapeutics), cytokines, plasmapheresis, extracorporeal antibody adsorption (e.g., using Prosorba columns), surgical interventions such as splenectomy, and others. However, like IVIG, these therapies are also complicated by incomplete efficacy and high cost. Also, very high doses of IVIG are required to produce substantial increases in the clearance of pathogenic antibody due to the putative mechanism of IVIG inhibition of FcRn binding with pathogenic antibody (i.e., competitive inhibition) and due to the fact that IgG shows very low affinity for FcRn at physiologic pH (i.e., pH 7.2-7.4), and the typical clinical dose of IVIG is about 2 g/kg.

The use of an inhibitor that competitively inhibits the binding of IgG to FcRn to treat autoimmune diseases is a promising therapeutic method. However, owing to the high affinity of endogenous IgG for FcRn and to the high concentrations of endogenous IgG in blood, it is likely that competitive inhibition of FcRn would require very high doses, and thus have the same limitations similar to those of the current IVIG treatment.

Accordingly, there is an urgent need for the development of a human antibody that has a high affinity for FcRn, and thus can remove pathogenic antibody even at low doses and reduce immunogenicity.

›DISCLOSURE OF INVENTION · 1 of 18

Technical Problem

The present inventors have made extensive efforts to solve the above-described problems and to develop a human antibody that has a high affinity for FcRn, and thus can remove pathogenic antibody even at low doses and reduce immunogenicity. As a result, the present inventors have produced and selected a human antibody, which binds specifically to the FcRn chain in a pH-independent manner, from a human antibody cDNA library. In addition, the present inventors have found that the antibody can be used to prevent or treat autoimmune disease, thereby completing the present invention.

Therefore, it is an object of the present invention to provide a therapeutic agent capable of efficiently and radically treating autoimmune diseases, including ITP, an antibody having the ability to bind specifically to FcRn, and a method for producing the antibody.

The FcRn-specific antibody according to the present invention can bind specifically to FcRn in a pH-independent manner to non-competitively inhibit the binding of the antibody Fc to FcRn to thereby reduce in vivo auto-antibody that is the cause of autoimmune diseases, thereby treating autoimmune diseases.

Another object of the present invention is to provide a pharmaceutical composition for treating autoimmune diseases, including ITP, immune neutropenia, Guillain-Barré syndrome, epilepsy, autoimmune encephalitis, Isaac's syndrome, nevus syndrome, pemphigus vulgaris, Pemphigus foliaceus, Bullous pemphigoid, epidermolysis bullosa acquisita, pemphigoid gestationis, mucous membrane pemphigoid, antiphospholipid syndrome, autoimmune anemia, autoimmune Grave's disease, Goodpasture's syndrome, myasthenia gravis, multiple sclerosis, rheumatoid arthritis, and lupus, the composition containing the FcRn-specific antibody.

Still another object of the present invention is to provide methods for preventing or treating and diagnosing autoimmune diseases, including ITP, immune neutropenia, Guillain-Barré syndrome, epilepsy, autoimmune encephalitis, Isaac's syndrome, nevus syndrome, pemphigus vulgaris, Pemphigus foliaceus, Bullous pemphigoid, epidermolysis bullosa acquisita, pemphigoid gestationis, mucous membrane pemphigoid, antiphospholipid syndrome, autoimmune anemia, autoimmune Grave's disease, Goodpasture's syndrome, myasthenia gravis, multiple sclerosis, rheumatoid arthritis, and lupus, the method comprising using the FcRn-specific antibody.

Technical Solution

To achieve the above objects, the present inventors have developed a complete human antibody, which can bind specifically to FcRn with high affinity in a pH-independent manner and is composed of a human-derived sequence, and thus causes little or no immune response when being administered in vivo. The present inventors have also developed an antibody having a higher affinity by affinity maturation of this complete human antibody.

The antibody according to the present invention is a polyclonal or monoclonal antibody having binding specificity to FcRn. Preferably, it is in the form of monoclonal antibody, particularly human monoclonal antibody, for human FcRn, and acts as a non-competitive inhibitor of IgG in binding to FcRn. The binding of the antibody of the present invention to FcRn results in the inhibition of pathogenic antibody to FcRn, which promotes the clearance (i.e., removal) of pathogenic antibody from the body of the subject to reduce the half-life of the pathogenic antibody.

As used herein, the term “pathogenic antibody” means antibodies that cause pathological conditions or diseases. Examples of such antibodies include, but are not limited to, anti-platelet antibodies, anti-acetylcholine antibodies, anti-nucleic acid antibodies, anti-phospholipid antibodies, anti-collagen antibodies, anti-ganglioside antibodies, anti-desmoglein antibodies, etc.

The antibody according to the present invention has an advantage in that it makes it possible to non-competitively inhibit the binding of pathogenic antibody to FcRn at physiological pH (i.e., pH 7.0-7.4). US 2002/0138863A and the like describe that an antibody should bind to FcRn at the same site critical for the binding of IgG to Fc so that the binding of IgG to FcRn is inhibited. FcRn binds to its ligand (i.e., IgG) and does not substantially show affinity for IgG at physiological pH rather than acidic pH. Thus, the anti-FcRn antibody that binds specifically to FcRn at physiological pH acts as a non-competitive inhibitor of the binding of IgG to FcRn, and in this case, the binding of the anti-FcRn antibody to FcRn is not influenced by the presence of IgG. Thus, the inventive antibody that binds to FcRn non-competitively with IgG in a pH-independent manner has an advantage over conventional competitive inhibitors (i.e., antibodies that bind to FcRn competitively with IgG) in that it can treat diseases even at significantly low concentrations by the FcRn-mediated signaling of IgG. In addition, in the procedure of intracellular migration in a state bound to FcRn, the anti-FcRn antibody according to the present invention maintains its binding to FcRn with an affinity higher than IgG in blood, and thus can inhibit the binding of IgG to FcRn even in endosomes that are acidic pH environments in which IgG can bind to FcRn, thereby promoting the clearance of IgG.

In summary, unlike the antibodies disclosed in prior art documents, the antibody according to the present invention has an affinity for FcRn even in a physiological pH environment (i.e., pH 7.0-7.4) in which IgG does not bind to FcRn. At a pH of 6.0, the antibody of the present invention has a higher affinity for FcRn compared to serum IgG, suggesting that it acts as a non-competitive inhibitor.

In the present invention, a complete human antibody that binds to FcRn with high affinity and specificity was obtained from a single-chain Fv (scFv) phage library using phage display technology. Phage library preparation and phage display may be performed as described in U.S. Pat. Nos. 7,063,943B, 6,172,197B, and the like. From the library constructed by inducing random mutations in the selected variable region of the complete human antibody, a complete human antibody having increased specificity and affinity was obtained by performing affinity maturation for selecting a human antibody having higher affinity and specificity for FcRn using phage display technology. Affinity maturation may be performed according to the methods described in U.S. Pat. Nos. 5,977,322, 5,994,511, 6,218,149, and the like.

›DISCLOSURE OF INVENTION · 2 of 18

The inventive antibody that is obtained by the above-described method has any one of the heavy-chain variable regions of FcRn-specific antibody, which comprise CDR1, CDR2 and CDR3 contained in any one amino acid sequence selected from the group consisting of even numbers between SEQ ID NOS: 2 to 144 (e.g., 2, 4, 66, 128, etc.), or in an amino acid sequence set forth in SEQ ID NO: 289 or 291, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and/or any one of the light-chain variable regions of FcRn-specific antibody, which comprise CDR1, CDR2 and CDR3 contained in any one amino acid sequence selected from the group consisting of even numbers between SEQ ID NOS: 146 to 288 (e.g., 148, 196, 244, 266, etc.), or in an amino acid sequence set forth in SEQ ID NO: 290 or 292, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%.

Particularly, the antibody according to the present invention has a heavy-chain variable region and a light-chain variable region selected from among the following heavy-chain and light-chain variable regions (1) to (74):

(1) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 2, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 146, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(2) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 4, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 148, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(3) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 6, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 150, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(4) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 8, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 152, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(5) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 10, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 154, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(6) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 12, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 156, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(7) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 14, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 158, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(8) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 16, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 160, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(9) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 18, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 162, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(10) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 20, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 164, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(11) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 22, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 166, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

›DISCLOSURE OF INVENTION · 3 of 18

(12) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 24, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 168, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(13) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 26, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 170, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(14) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 28, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 172, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(15) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 30, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 174, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(16) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 32, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 176, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(17) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 34, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 178, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(18) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 36, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 180, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(19) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 38, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 182, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(20) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 40, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 184, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(21) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 42, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 186, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(22) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 44, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 188, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(23) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 46, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 190, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(24) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 48, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 192, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

›DISCLOSURE OF INVENTION · 4 of 18

(25) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 50, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 194, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(26) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 52, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 196, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(27) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 54, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 198, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(28) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 56, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 200, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(29) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 58, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 202, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(30) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 60, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 204, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(31) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 62, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 206, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(32) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 64, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 208, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(33) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 66, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 210, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(34) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 68, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 212, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(35) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 70, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 214, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(36) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 72, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 216, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(37) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 74, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 218, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

›DISCLOSURE OF INVENTION · 5 of 18

(38) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 76, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 220, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(39) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 78, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 222, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(40) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 80, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 224, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(41) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 82, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 226, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(42) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 84, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 228, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(43) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 86, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 230, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(44) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 88, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 232, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(45) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 90, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 234, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(46) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 92, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 236, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(47) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 94, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 238, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(48) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 96, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 240, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(49) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 98, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 242, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(50) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 100, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 244, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

›DISCLOSURE OF INVENTION · 6 of 18

(51) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 102, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 246, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(52) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 104, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 248, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(53) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 106, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 250, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(54) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 108, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 252, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(55) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 110, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 254, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(56) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 112, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 256, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(57) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 114, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 258, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(58) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 116, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 260, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(59) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 118 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 262 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(60) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 120 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 264 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(61) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 122 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 266 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(62) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 124 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 268 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(63) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 126 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 270 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

›DISCLOSURE OF INVENTION · 7 of 18

(64) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 128 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 272 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(65) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 130 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 274 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(66) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 132 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 276 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(67) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 134 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 278 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(68) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 136 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 280 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(69) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 138 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 282 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(70) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 140 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 284 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(71) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 142 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 286 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(72) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 144 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 288 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(73) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 289 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 290 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%; and

(74) a heavy-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 291 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region, which comprises CDR1, CDR2 and CDR3 contained in an amino acid sequence of SEQ ID NO: 292 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%.

More preferably, the antibody according to the present invention has a heavy-chain variable region and a light-chain variable region selected from among the following heavy-chain and light-chain variable regions (1) to (74):

(1) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 2, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 146, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(2) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 4, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 148, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

›DISCLOSURE OF INVENTION · 8 of 18

(3) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 6, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 150, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(4) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 8, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 152, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(5) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 10, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 154, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(6) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 12, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 156, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(7) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 14, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 158, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(8) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 16, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 160, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(9) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 18, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 162, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(10) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 20, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 164, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(11) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 22, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 166, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(12) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 24, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 168, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(13) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 26, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 170, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(14) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 28, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 172, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(15) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 30, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 174, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(16) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 32, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 176, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(17) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 34, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 178, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(18) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 36, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 180, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

›DISCLOSURE OF INVENTION · 9 of 18

(19) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 38, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 182, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(20) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 40, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 184, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(21) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 42, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 186, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(22) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 44, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 188, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(23) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 46, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 190, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(24) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 48, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 192, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(25) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 50, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 194, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(26) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 52, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 196, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(27) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 54, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 198, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(28) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 56, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 200, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(29) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 58, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 202, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(30) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 60, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 204, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(31) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 62, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 206, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(32) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 64, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 208, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(33) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 66, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 210, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(34) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 68, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 212, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

›DISCLOSURE OF INVENTION · 10 of 18

(35) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 70, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 214, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(36) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 72, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 216, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(37) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 74, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 218, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(38) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 76, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 220, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(39) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 78, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 222, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(40) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 80, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 224, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(41) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 82, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 226, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(42) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 84, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 228, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(43) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 86, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 230, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(44) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 88, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 232, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(45) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 90, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 234, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(46) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 92, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 236, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(47) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 94, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 238, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(48) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 96, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 240, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(49) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 98, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 242, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(50) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 100, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 244, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

›DISCLOSURE OF INVENTION · 11 of 18

(51) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 102, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 246, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(52) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 104, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 248, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(53) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 106, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 250, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(54) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 108, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 252, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(55) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 110, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 254, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(56) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 112, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 256, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(57) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 114, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 258, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(58) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 116, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 260, or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(59) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 118 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 262 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(60) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 120 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 264 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(61) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 122 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 266 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(62) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 124 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 268 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(63) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 126 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 270 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(64) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 128 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 272 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(65) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 130 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 274 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(66) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 132 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 276 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

›DISCLOSURE OF INVENTION · 12 of 18

(67) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 134 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 278 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(68) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 136 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 280 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(69) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 138 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 282 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(70) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 140 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 284 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(71) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 142 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 286 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(72) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 144 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 288 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%;

(73) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 289 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 290 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%; and

(74) a heavy-chain variable region having an amino acid sequence of SEQ ID NO: 291 or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%, and a light-chain variable region having an amino acid sequence of SEQ ID NO: 292 or a light-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%.

The antibodies according to the present invention also include fragments of the antibody. Fragments of the antibody according to the present invention include, but are not limited to, single-chain antibodies, diabodies, triabodies, tetrabodies, Fab fragments, F(ab′) 2 fragments, Fd, scFv, domain antibodies, dual-specific antibodies, minibodies, scap, IgD antibodies, IgE antibodies, IgM antibodies, IgG1 antibodies, IgG2 antibodies, IgG3 antibodies, IgG4 antibodies, derivatives in antibody constant regions, and synthetic antibodies based on protein scaffolds, which have the ability to bind to FcRn. It will be obvious to those skilled in the art that any fragment of the antibody according to the present invention will show the same properties as those of the antibody of the present invention, as long as its ability to bind to FcRn is maintained.

In addition, antibodies having a mutation in the variable region are included in the scope of the present invention, as long as they retain the properties of the antibody of the present invention. Examples of such antibodies include antibodies having a conservative substitution of an amino acid residue in the variable region. As used herein, the term “conservative substitution” refers to substitution with another amino acid residue having properties similar to those of the original amino acid residue. For example, lysine, arginine and histidine have similar properties in that they have a basic side-chain, and aspartic acid and glutamic acid have similar properties in that they have an acidic side chain. In addition, glycine, aspargin, glutamine, serine, threonine, tyrosine, cysteine and tryptophan have similar properties in that they have an uncharged polar side-chain, and alanine, valine, leucine, threonine, isoleucine, proline, phenylalanine and methionine have similar properties in that they have a non-polar side-chain. Also, tyrosine, phenylalanine, tryptophan and histidine have similar properties in that they have an aromatic side-chain. Thus, it will be obvious to those skilled in the art that, even when substitution of amino acid residues in groups showing similar properties as described above occurs; it will show no particular change in the properties. Accordingly, antibodies having a mutation caused by conservative substitution in the variable region are included in the scope of the present invention, as long as they retain the properties of the antibody of the present invention.

In addition, the antibody according to the present invention or its fragment may be used as a conjugate with another substance. Substances that may be used as conjugates with the antibody according to the present invention or its fragment include therapeutic agents that is generally used for the treatment of autoimmune diseases, substances capable of inhibiting the activity of FcRn, and a moiety that is physically associated with the antibody to improve its stabilization and/or retention in circulation, for example, in blood, serum, lymph, or other tissues. For example, the FcRn-binding antibody can be associated with a polymer, e.g., a non-antigenic polymer such as polyalkylene oxide or polyethylene oxide. Suitable polymers will vary substantially by weight. Polymers having molecular number average weights ranging from about 200 to about 35,000 (or about 1,000 to about 15,000, and 2,000 to about 12,500) can be used. For example, the FcRn-binding antibody can be conjugated to water soluble polymers, e.g., hydrophilic polyvinyl polymers, e.g. polyvinylalcohol and polyvinylpyrrolidone. A non-limiting list of such polymers includes, but is not limited to, polyalkylene oxide homopolymers such as polyethylene glycol (PEG) or polypropylene glycols, polyoxyethylenated polyols, copolymers thereof and block copolymers thereof, provided that the water solubility of the block copolymers is maintained.

›DISCLOSURE OF INVENTION · 13 of 18

The present invention also provides a pharmaceutical composition comprising the antibody of the present invention or a fragment thereof. The pharmaceutical composition may comprise a pharmaceutically acceptable carrier, excipient, and the like, which are well known in the art. The pharmaceutically acceptable carrier that may be used in the present invention should be compatible with the active ingredient such as the antibody according to the present invention and may be physiological saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, or a mixture of two or more thereof. In addition, the pharmaceutical composition of the present invention may, if necessary, comprise other conventional additives, including antioxidants, buffers, and bacteriostatic agents. Further, the pharmaceutical composition of the present invention may be formulated as injectable forms such as aqueous solutions, suspensions or emulsions with the aid of diluents, dispersants, surfactants, binders and lubricants. In addition, the pharmaceutical composition of the present invention may be provided by formulating into a various form such as powder, tablet, capsule, liquid, inject, ointment, syrup etc, and single-dosage or multi-dosage container such as sealed ample or vial.

The pharmaceutical composition of the present invention may be applied to all autoimmune diseases that are mediated by IgG and FcRn, and typical examples of such autoimmune diseases include, but are not limited to, immune neutropenia, Guillain-Barré syndrome, epilepsy, autoimmune encephalitis, Isaac's syndrome, nevus syndrome, pemphigus vulgaris, Pemphigus foliaceus, Bullous pemphigoid, epidermolysis bullosa acquisita, pemphigoid gestationis, mucous membrane pemphigoid, antiphospholipid syndrome, autoimmune anemia, autoimmune Grave's disease, Goodpasture's syndrome, myasthenia gravis, multiple sclerosis, rheumatoid arthritis, lupus, and idiopathic thrombocytopenic purpura (ITP).

The present invention also provides a method for ameliorating an autoimmune or alloimmune condition, the method comprising administering the antibody of the present invention or a fragment of the antibody to a subject in need of treatment. The present invention also provides a specific anti-FcRn therapy.

The inventive method for ameliorating an autoimmune or alloimmune condition or the inventive anti-FcRn therapy can be achieved by administering the pharmaceutical composition of the present invention to a subject. The pharmaceutical composition of the present invention can be administered orally or parenterally. The pharmaceutical composition according to the present invention can be administered by various routes, including, but not limited to, oral, intravenous, intramuscular, intra-arterial, intramedullary, intradural, intracardial, transdermal, subcutaneous, intraperitoneal, gastrointestinal, sublingual, and local routes. The dose of the composition of the present invention may vary depending on various factors, such as a patient's body weight, age, sex, health condition and diet, the time and method of administration, excretion rate, and severity of a disease, and may be easily determined by a person of ordinary skill in the art. Generally, 1-200 mg/kg, and preferably, 1-40 mg/kg of the composition may be administered to patients afflicted with autoimmune or alloimmune conditions, and these regimens are preferably designed to reduce the serum endogenous IgG concentration to less than 75% of pretreatment values. Intermittent and/or chronic (continuous) dosing strategies may be applied in view of the conditions of patients.

The present invention also provides a diagnostic composition comprising the antibody of the present invention or a fragment thereof, and a diagnostic method that uses the diagnostic composition. In other words, the antibody of the present invention or a fragment thereof, which binds to FcRn, have in vitro and in vivo diagnostic utilities.

In one aspect, the present invention provides a method for detecting the presence of FcRn in vitro and in vivo.

The in vitro detection method may, for example, comprise the steps of: (1) bringing a sample into contact with the FcRn-binding antibody; (2) detecting the formation of a complex between the FcRn-binding antibody and the sample; and/or (3) bringing a reference sample (e.g., a control sample) into contact with the antibody; and (4) determining the degree of formation of the complex between the antibody and the sample by comparison with that in the reference sample. A change (e.g., a statistically significant change) in the formation of the complex in the sample or the subject as compared to that in the control sample or subject may mean the presence of FcRn in the sample.

The in vivo detection method may comprise the steps of: (1) administering the FcRn-binding antibody to a subject; and (2) detecting the formation of a complex between the FcRn-binding antibody and the subject. The detecting may include determining location or time of formation of the complex. The FcRn-binding antibody can be directly or indirectly labeled with a detectable substance to facilitate detection of the bound or unbound antibody. Suitable detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, and radioactive materials. The formation of a complex between the FcRn-binding antibody and FcRn can be detected by measuring or visualizing the antibody bound or not bound to FcRn. A conventional detection assay, for example, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA) or tissue immunohistochemistry may be used. In addition to labeling of the FcRn-binding antibody, the presence of FcRn can be assayed in a sample by competition immunoassay using a standard labeled with a detectable substance and an unlabeled FcRn-binding antibody. In one example of this assay, the biological sample, the labeled standard and the FcRn-binding antibody are combined and the amount of labeled standard unbound to FcRn is determined. The amount of FcRn in the biological sample is inversely proportional to the amount of labeled standard unbound to FcRn.

›DISCLOSURE OF INVENTION · 14 of 18

For use for therapeutic purposes, the antibody of the present invention or a fragment thereof can be labeled with a fluorophore and a chromophore. Because antibodies and other proteins absorb light having wavelengths up to about 310 nm, the fluorescent moieties should be selected to have substantial absorption at wavelengths above 310 nm and preferably above 400 nm. The antibody of the present invention or a fragment thereof can be labeled with a variety of suitable fluorescers and chromophores. One group of fluorescers is xanthene dyes, which include fluoresceins and rhodamines. Another group of fluorescent compounds are naphthylamines. Once labeled with a fluorophore or chromophore, the antibody can be used to detect the presence or localization of the FcRn in a sample, e.g., using fluorescent microscopy (such as confocal or deconvolution microscopy).

Detection of the presence or localization of FcRn using the antibody of the present invention or a fragment thereof can be performed by various methods as described below.

Histological Analysis:

The antibody of the present invention or a fragment thereof can be synthesized with a label (such as a purification or epitope tag), or can be detectably labeled, e.g., by conjugating a label or label-binding group. The antibody is then contacted to a histological preparation, e.g., a fixed section of tissue that is on a microscope slide. After incubation for binding, the preparation is washed to remove unbound antibody. The preparation is then analyzed, e.g., using microscopy, to identify if the antibody bound to the preparation. Of course, the antibody can be unlabeled at the time of binding. After binding and washing, the antibody is labeled in order to render it detectable.

Protein Arrays:

The antibody of the present invention or a fragment thereof can be immobilized on a protein array. The protein array can be used as a diagnostic tool, e.g., to screen medical samples (such as isolated cells, blood, sera, biopsies, and the like). Of course, the protein array can also include other ligands, e.g., that bind to FcRn or to other target molecules. Polypeptides for the array can be spotted at high speed using commercially available robotic apparati, e.g., from Genetic MicroSystems or BioRobotics. The array substrate can be, for example, nitrocellulose, plastic, glass, e.g., surface-modified glass. The array can also include a porous matrix, e.g., acrylamide, agarose, or another polymer.

FACS (Fluorescence Activated Cell Sorting):

The antibody of the present invention or a fragment thereof can be used to label cells, e.g., cells in a sample (e.g., a patient sample). The antibody is also attached to a fluorescent compound. The cells can then be sorted using fluorescence activated cell sorter (e.g., using a sorter available from Becton Dickinson). As cells pass through the sorter, a laser beam excites the fluorescent compound while a detector counts cells that pass through and determines whether a fluorescent compound is attached to the cell by detecting fluorescence. The amount of label bound to each cell can be quantified and analyzed to characterize the sample.

In the present invention, the presence of FcRn or FcRn-expressing tissue in vivo can be performed by an in vivo Imaging method. The method includes (i) administering to a subject (e.g., a patient having an autoimmune disorder) an anti-FcRn antibody, conjugated to a detectable marker; and (ii) exposing the subject to a means for detecting said detectable marker to the FcRn-expressing tissues or cells. For example, the subject is imaged, e.g., by NMR or other tomographic means. Examples of labels useful for diagnostic imaging include radiolabels, fluorescent labels, positron emitting isotopes, chemiluminescers, and enzymatic markers. A radiolabeled antibody can also be used for in vitro diagnostic tests. The specific activity of a isotopically-labeled antibody depends upon the half life, the isotopic purity of the radioactive label, and how the label is incorporated into the antibody.

The present invention also provides a kit comprising an antibody that binds to FcRn and instructions for diagnostic use, e.g., the use of the FcRn-binding antibody or antigen-binding fragment thereof, to detect FcRn, in vitro, e.g., in a sample, e.g., a biopsy or cells from a patient having an autoimmune disorder, or in vivo, e.g., by imaging a subject. The kit can further contain at least one additional reagent, such as a label or additional diagnostic agent. For in vivo use, the antibody can be formulated as a pharmaceutical composition.

The present invention also provides polynucleotide sequences that encode the variable regions of the antibody of the present invention or a fragment thereof.

Specifically, a polynucleotide sequence that encodes the heavy-chain variable region of the antibody of the present invention or a fragment thereof is a sequence that encodes either any one of the heavy-chain variable regions of FcRn-specific antibody, which comprise CDR1, CDR2 and CDR3 contained in any one amino acid sequence selected from the group consisting of even numbers between SEQ ID NOS: 2 to 144 (e.g., 2, 4, 66, 128, etc.) or in an amino acid sequence set forth in SEQ ID NO: 289 or 291, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%.

A polynucleotide sequence that encodes the light-chain variable region of the antibody of the present invention or a fragment thereof is a sequence that encodes either any one of the light-chain variable regions of FcRn-specific antibody, which comprise CDR1, CDR2 and CDR3 contained in any one amino acid sequence selected from the group consisting of even numbers between SEQ ID NOS: 146 to 288 (e.g., 148, 196, 244, 266, etc.) or in an amino acid sequence set forth in SEQ ID NO: 290 or 292, or a heavy-chain variable region having a sequence homology thereto of at least 90%, preferably at least 95%.

Preferably, the polynucleotide sequence that encodes the heavy-chain variable region of the antibody of the present invention or a fragment thereof has either any one sequence selected from the group consisting of uneven numbers between SEQ ID NOS: 1 to 143 (e.g., 1, 3, 87, 121, etc.), or a sequence homology thereto of at least 90%, preferably at least 95%, and the polynucleotide sequence that encodes the light-chain variable region has either any one sequence selected from the group consisting of uneven numbers between SEQ ID NOS: 145 to 287 (e.g., 147, 193, 267, 283, etc.), or a sequence homology thereto of at least 90%, preferably at least 95%.

›DISCLOSURE OF INVENTION · 15 of 18

More preferably, the polynucleotide sequences that encode the heavy-chain or light-chain variable regions of the antibody of the present invention or a fragment thereof may be selected from the following sequences:

(1) a sequence of SEQ ID NO: 1 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 145 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(2) a sequence of SEQ ID NO: 3 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 147 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(3) a sequence of SEQ ID NO: 5 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 149 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(4) a sequence of SEQ ID NO: 7 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 151 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(5) a sequence of SEQ ID NO: 9 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 153 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(6) a sequence of SEQ ID NO: 11 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 155 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(7) a sequence of SEQ ID NO: 13 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 157 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(8) a sequence of SEQ ID NO: 15 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 159 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(9) a sequence of SEQ ID NO: 17 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 161 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(10) a sequence of SEQ ID NO: 19 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 163 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(11) a sequence of SEQ ID NO: 21 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 165 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(12) a sequence of SEQ ID NO: 23 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 167 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(13) a sequence of SEQ ID NO: 25 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 169 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(14) a sequence of SEQ ID NO: 27 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 171 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(15) a sequence of SEQ ID NO: 29 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 173 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(16) a sequence of SEQ ID NO: 31 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 175 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(17) a sequence of SEQ ID NO: 33 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 177 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(18) a sequence of SEQ ID NO: 35 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 179 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(19) a sequence of SEQ ID NO: 37 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 181 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(20) a sequence of SEQ ID NO: 39 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 183 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(21) a sequence of SEQ ID NO: 41 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 185 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(22) a sequence of SEQ ID NO: 43 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 187 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(23) a sequence of SEQ ID NO: 45 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 189 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(24) a sequence of SEQ ID NO: 47 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 191 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(25) a sequence of SEQ ID NO: 49 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 193 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(26) a sequence of SEQ ID NO: 51 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 195 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

›DISCLOSURE OF INVENTION · 16 of 18

(27) a sequence of SEQ ID NO: 53 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 197 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(28) a sequence of SEQ ID NO: 55 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 199 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(29) a sequence of SEQ ID NO: 57 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 201 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(30) a sequence of SEQ ID NO: 59 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 203 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(31) a sequence of SEQ ID NO: 61 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 205 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(32) a sequence of SEQ ID NO: 63 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 207 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(33) a sequence of SEQ ID NO: 65 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 209 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(34) a sequence of SEQ ID NO: 67 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 211 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(35) a sequence of SEQ ID NO: 69 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 213 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(36) a sequence of SEQ ID NO: 71 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 215 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(37) a sequence of SEQ ID NO: 73 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 217 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(38) a sequence of SEQ ID NO: 75 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 219 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(39) a sequence of SEQ ID NO: 77 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 221 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(40) a sequence of SEQ ID NO: 79 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 223 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(41) a sequence of SEQ ID NO: 81 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 225 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(42) a sequence of SEQ ID NO: 83 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 227 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(43) a sequence of SEQ ID NO: 85 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 229 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(44) a sequence of SEQ ID NO: 87 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 231 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(45) a sequence of SEQ ID NO: 89 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 233 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(46) a sequence of SEQ ID NO: 91 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 235 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(47) a sequence of SEQ ID NO: 93 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 237 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(48) a sequence of SEQ ID NO: 95 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 239 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(49) a sequence of SEQ ID NO: 97 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 241 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(50) a sequence of SEQ ID NO: 99 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 243 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(51) a sequence of SEQ ID NO: 101 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 245 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(52) a sequence of SEQ ID NO: 103 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 247 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(53) a sequence of SEQ ID NO: 105 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 249 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

›DISCLOSURE OF INVENTION · 17 of 18

(54) a sequence of SEQ ID NO: 107 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 251 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(55) a sequence of SEQ ID NO: 109 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 253 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(56) a sequence of SEQ ID NO: 111 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 255 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(57) a sequence of SEQ ID NO: 113 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 257 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(58) a sequence of SEQ ID NO: 115 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 259 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(59) a sequence of SEQ ID NO: 117 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 261 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(60) a sequence of SEQ ID NO: 119 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 263 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(61) a sequence of SEQ ID NO: 121 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 265 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(62) a sequence of SEQ ID NO: 123 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 267 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(63) a sequence of SEQ ID NO: 125 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 269 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(64) a sequence of SEQ ID NO: 127 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 271 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(65) a sequence of SEQ ID NO: 129 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 273 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(66) a sequence of SEQ ID NO: 131 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 275 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(67) a sequence of SEQ ID NO: 133 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 277 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(68) a sequence of SEQ ID NO: 135 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 279 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(69) a sequence of SEQ ID NO: 137 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 281 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(70) a sequence of SEQ ID NO: 139 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 283 or a sequence having a sequence homology thereto of at least 90%, preferably 95%;

(71) a sequence of SEQ ID NO: 141 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 285 or a sequence having a sequence homology thereto of at least 90%, preferably 95%; and

(72) a sequence of SEQ ID NO: 143 or a sequence having a sequence homology thereto of at least 90%, preferably 95%, and a sequence of SEQ ID NO: 287 or a sequence having a sequence homology thereto of at least 90%, preferably 95%.

The present invention also provides a recombinant vector comprising the above-described nucleotide sequence, a host cell comprising the recombinant vector, and a method of producing the inventive antibody, which binds specifically to FcRn, using the above recombinant vector or host cell. Particularly, the antibody of the present invention is preferably produced by expression and purification using a gene recombination method. Specifically, the variable regions that encode the inventive antibody that binds specifically to FcRn are preferably produced by being expressed in separate host cells or simultaneously in a single host cell.

As used herein, the term “recombinant vector” refers to an expression vector capable of expressing the protein of interest in a suitable host cell and means a DNA construct including essential regulatory elements operably linked to express a nucleic acid insert. As used herein, the term “operably linked” means that a nucleic acid expression control sequence is functionally linked to a nucleic acid sequence encoding the protein of interest so as to execute general functions. Operable linkage with the recombinant vector can be performed using a gene recombination technique well known in the art, and site-specific DNA cleavage and ligation can be easily performed using enzymes generally known in the art.

A suitable expression vector that may be used in the present invention may comprise expression regulatory elements such as a promoter, an operator, an initiation codon, a stop codon, a polyadenylation signal, and an enhancer, as well as a signal sequence for membrane targeting or secretion. The initiation and stop codons are generally considered as part of a nucleotide sequence encoding the immunogenic target protein, and are necessary to be functional in an individual to whom a genetic construct has been administered, and must be in frame with the coding sequence. Promoters may generally be constitutive or inducible. Prokaryotic promoters include, but are not limited to, lac, tac, T3 and T7 promoters. Eukaryotic promoters include, but are not limited to, simian virus 40 (SV40) promoter, mouse mammary tumor virus (MMTV) promoter, human immunodeficiency virus (HIV) promoter such as the HIV Long Terminal Repeat (LTR) promoter, moloney virus promoter, cytomegalovirus (CMV) promoter, epstein barr virus (EBV) promoter, rous sarcoma virus (RSV) promoter, as well as promoters from human genes such as human β-actin, human hemoglobin, human muscle creatine and human metallothionein. The expression vector may include a selectable marker that allows selection of host cells containing the vector. Genes coding for products that confer selectable phenotypes, such as resistance to drugs, nutrient requirement, resistance to cytotoxic agents or expression of surface proteins, are used as general selectable markers. Since only cells expressing a selectable marker survive in the environment treated with a selective agent, transformed cells can be selected. Also, a replicable expression vector may include a replication origin, a specific nucleic acid sequence that initiates replication. Recombinant expression vectors that may be used in the present invention include various vectors such as plasmids, viruses and cosmids. The kind of recombinant vector is not specifically limited, as long as it functions to express a desired gene and produce a desired protein in various host cells such as prokaryotic and eukaryotic cells. However, it is preferred to use a vector that can produce a large amount of a foreign protein similar to a natural protein while having strong expression ability with a promoter showing strong activity.

›DISCLOSURE OF INVENTION · 18 of 18

In the present invention, a variety of expression host/vector combinations may be used to express the antibody or an antibody fragment of the present invention. For example, expression vectors suitable for the eukaryotic host include, but are not limited to, SV40, bovine papillomavirus, adenovirus, adeno-associated virus, cytomegalovirus, and retrovirus. Expression vectors that may be used for bacterial hosts include bacterial plasmids such as pET, pRSET, pBluescript, pGEX2T, pUC, col E1, pCR1, pBR322, pMB9 and derivatives thereof, a plasmid such as RP4 having a wider host range, phage DNA represented as various phage lambda derivatives such as gt10, gt11 and NM989, and other DNA phages such as M13 and filamentous single-stranded DNA phage. Expression vectors useful in yeast cells include 2 μm plasmid and derivatives thereof. A vector useful in insect cells is pVL941.

The recombinant vector is introduced into a host cell to form a transformant. Host cells suitable for use in the present invention include prokaryotic cells such as E. coli, Bacillus subtilis, Streptomyces sp., Pseudomonas sp., Proteus mirabilis and Staphylococcus sp., fungi such as Aspergillus sp., yeasts such as Pichia pastoris, Saccharomyces cerevisiae, Schizosaccharomyces sp., and Neurospora crassa , and eukaryotic cells such as lower eukaryotic cells, and higher other eukaryotic cells such as insect cells.

Host cells that may be used in the present invention are preferably derived from plants and mammals, and examples thereof include, but are not limited to, monkey kidney cells (COST), NSO cells, SP2/0, Chinese hamster ovary (CHO) cells, W138, baby hamster kidney (BHK) cells, MDCK, myeloma cells, HuT 78 cells and HEK293 cells. Preferably, CHO cells are used.

In the present invention, transfection or transformation into a host cell includes any method by which nucleic acids can be introduced into organisms, cells, tissues or organs, and, as known in the art, may be performed using a suitable standard technique selected according to the kind of host cell. These methods include, but are not limited to, electroporation, protoplast fusion, calcium phosphate (CaPO 4 ) precipitation, calcium chloride (CaCl 2 ) precipitation, agitation with silicon carbide fiber, and agrobacterium -, PEG-, dextran sulfate-, lipofectamine- and desiccation/inhibition-mediated transformation.

The FcRn-specific antibody according to the present invention can be produced in large amounts by culturing the transformant comprising the recombinant vector in nutrient medium, and the medium and culture conditions that are used in the present invention can be suitable selected depending on the kind of host cell. During culture, conditions, including temperature, the pH of medium, and culture time, can be controlled so as to be suitable for the growth of cells and the mass production of protein. The antibody or antibody fragment produced by the recombination method as described can be collected from the medium or cell lysate and can be isolated and purified by conventional biochemical isolation techniques (Sambrook et al., Molecular Cloning: A laboratory Manual, 2nd Ed., Cold Spring Harbor Laboratory Press (1989); Deuscher, M., Guide to Protein Purification Methods Enzymology, Vol. 182. Academic Press. Inc., San Diego, Calif. (1990)). These techniques include, but are not limited to, electrophoresis, centrifugation, gel filtration, precipitation, dialysis, chromatography (ion exchange chromatography, affinity chromatography, immunosorbent chromatography, size exclusion chromatography, etc.), isoelectric point focusing, and various modifications and combinations thereof. Preferably, the antibody or the antibody fragment is isolated and purified using protein A.

Advantageous Effects

The inventive human antibody specific for FcRn that is a receptor having a high affinity for IgG has high affinity and specificity, causes little or no immunogenicity-related problems, and binds to FcRn non-competitively with IgG or the like to reduce serum auto-antibody levels. By virtue of such properties, the antibody is useful for the treatment and diagnosis of autoimmune diseases.

›BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the results of selecting antibody variable domains that bind only to the αFcRn of human FcRn protein without binding to β2m. The results in FIG. 1 were obtained by treating αFcRn (heavy chain)-, β2m- and α-Myc-coated 96-well plates with phages constructed from a human antibody cDNA library and panning phages, which bind to αFcRn (heavy chain) at a pH of 6.0 and a pH of 7.4 without binding to β2m, by ELISA.

FIG. 2 shows the ability of HIT antibodies to bind to human FcRn (hFcRn) on the cell surface. The results in FIG. 2 were obtained by treating human FcRn-overexpressing HEK293 cells with 8 different antibodies that bind to human FcRn on the cell surface and confirming antibodies that bind to the cell surface FcRn at a pH of 6.0 and a pH of 7.4. The binding of the antibody to FcRn was measured by treating cells with the antibody at each pH, and then analyzing the cells by fluorescent activated cell sorter (FACS) using Alexa488-labeled anti-human goat antibody, and measurement results for the ability of the HIT antibodies to bind to the cell surface were expressed as values relative to the MFI of human IgG1 (hIgG1).

FIG. 3 shows the results of observing whether HIT antibodies that bind to human FcRn on the cell surface can inhibit the binding of human IgG to human FcRn, at the cellular level. Human FcRn-overexpressing HEK293 cells were treated with 8 HIT antibodies confirmed to bind to the cells and 250 nM, 500 nM and 1000 nM of human IgG1, and the ability of the antibodies to inhibit the binding of human IgG to human FcRn was measured based on a decrease in the binding of Alexa488-labeled human IgG1 to the cell surface.

FIG. 4 shows the results of examining whether antibodies that bind to human FcRn also bind to FcRn of other species, by cross-reactivity with mice, rats and monkeys. The results in FIG. 4 were obtained by treating NIH3T3L1, Rat-2 and Cos 7 cells, which overexpress mouse FcRn, rat FcRn and monkey FcRn, with various IgG antibodies, treating the cells with FITC-labeled anti-mouse, anti-rat and anti-human goat antibodies that recognize the antibodies, and analyzing the fluorescence intensity of each antibody bound to the cell surface by FACS. The fluorescence intensities were expressed as the ratios of the MFI values of three HIT antibodies, anti-mouse and anti-rat FcRn antibodies and cynomolgus IgG antibody relative to the MFI of human IgG1.

FIG. 5 shows the results of examining the effects of the HIT antibodies HL161_1A and HL161_11H, selected from the human FcRn-expressing transgenic mice Tg276 (hFcRn+/+, hβ2m+/+, mFcRn−/−, mβ2m−/−) on the catabolism of hIgG1. The results in FIG. 5 were obtained by intraperitoneally injecting 5 mg/kg of biotinylated human IgG1 into Tg276 mice, and after 24, 48, 72 and 96 hours, intraperitoneally injecting 10 mg/kg of human IgG1, HL161_1A, HL161_11H or PBS into the mice. Sampling was performed at 6, 12, 24, 48, 72, 96, 120 and 168 hours after injection of biotin-IgG and analyzed by ELISA to determine the level of the remaining biotin-IgG. The results were expressed as the ratio of the level of biotin-IgG remaining at each time point relative to 100% for the level of biotin-IgG remaining at 6 hours.

FIG. 6 is a schematic view of a pComb3X vector cloned with a gene encoding a scFv-type fragment of HL161-1A or HL161-11H to achieve affinity maturation.

›EXAMPLES

Hereinafter, the present invention will be described in further detail with reference to examples. It will be obvious to a person having ordinary skill in the art that these examples are illustrative purposes only and are not to be construed to limit the scope of the present invention.

Part I: Development of FcRn-Specific Human Antibody

›Examples12

›Example 1: Construction of Soluble FcRn Expression Vector

FcRn is a non-covalently associated heterodimeric protein composed of a transmembrane anchored-α heavy chain (αFcRn) and a β, chain (β2m), in which are linked by non-covalent bond. Thus, to construct a soluble FcRn expression vector, the two genes were constructed in a single expression vector using the multisite gateway system. The αFcRn and β2m genes having the signal sequences of human growth hormone were amplified by PCR using the primers, shown in Table 1 below and comprised of the restriction enzyme sequences of αFcRn 5-end NheI/3-end XhoI and β2m 5-end NheI/3-end XbaI in addition to the genes, respectively. The amplification products were cloned into a pcDNA3.1(+) vector.

Specifically, a clone (αFcRn: hMU008093/β2m: hMU005156) was purchased from the Korea Research Institute of Bioscience and Biotechnology, and plasmid DNA was extracted from the clone. 2 μl of 200 ng template, 2 μl of 10 pmole N-primer, 2 μl of 10 pmole C-primer, 25 μl of 2× Solgent mixture and 19 μl of distilled water were mixed with each other to make 50 μl of a reaction solution.

The PCR reaction was performed under the following conditions: initial denaturation at 95° C. for 2 min, and then 25 cycles of denaturation at 95° C. at 20 sec, primer annealing at 60° C. for 40 sec and elongation at 72° C. for 1 min, followed by final enzymatic reaction at 72° C. for 5 min. The amplification of the hGH signaling sequence was performed using the same composition as above, and after completion of each PCR reaction, DNA was extracted from the PCR band on agarose gel and used as a template for the next PCR reaction. The hGH leader αFcRn gene amplification product was treated with NheI and XhoI enzymes at 37° C. for at least 4 hours, and the hGH leader β2m gene amplification product was treated with NheI and XbaI enzymes at 37° C. for at least 4 hours, and the pcDNA3.1(+) vector was treated with NheI/XhoI and NheI/XbaI enzymes at 37° C. for at least 4 hours, followed by electrophoresis.

Each of the DNA fragments was electrophoresed on agarose gel to confirm its size and recovered using an agarose gel extraction kit. The DNA fragment and the vector fragment were mixed with each other at a ratio of 1:5 to form a total of 10 μl of a mixture, and 10 μl of NEB ligase buffer and 1 j of ligase were added thereto, followed by incubation at room temperature for 2 hours. 5 μl of the ligation mixture was added to DH5α competent cells and transformed into the cells by heat shock at 42° C. for 1 minute, and the cells were stationary cultured in ampicillin-containing LB solid medium to obtain colonies. The colonies were cultured in ampicillin-containing LB liquid medium at 37° C. for 24 hours, and plasmid DNA was isolated therefrom and sequenced. The results of the sequencing indicated that each of natural leader αFcRn, hGH leader αFcRn, natural leader β2m and hGH leader β2m genes was cloned into pcDNA3.1(+).

PCR was performed using the two plasmid DNAs cloned into the pcDNA3.1(+) vector as a template together with PCR primers having an attB site inserted into the 5′ and 3′ ends, using a Jump-In™ fast gateway cloning kit according to the manufacturer's instructions, thereby constructing an expression vector comprising the hGH leader αFcRn/β2m cloned into the pJTI™ FastDEST vector. The genes in the constructed expression vector were sequenced.

›Example 2: Construction of Cell Line Expressing Soluble FcRn

Because plasmid DNA to be used for transfection should have high concentration and purity, QIAGEN plasmid purification was performed. The bacterial clone of the sequenced hGH leader FcRn pJTI™ FastDEST vector was inoculated into a 100-ml LB flask containing ampicillin. The bacterial cells were recovered by centrifugation at 3600 rpm for 15 minutes. After removal of the medium, the pellet was completely dissolved in 10 ml of P1 solution by vortexing, and then 10 ml of P2 solution was added thereto. The mixture was gently inverted five times and incubated at room temperature for 5 minutes. Then, 10 ml of P3 solution was added to the mixture, which was then inverted five times and incubated on ice for 30 minutes. After completion of incubation, the solution was centrifuged at 4° C. and 15,000 rpm for 30 minutes. The supernatant was transferred into a 50-ml fresh centrifuge tube and additionally centrifuged for minutes. The supernatant was loaded into a column equilibrated with 10 ml of QBT solution. When loading of the solution by gravity was completed, the column was washed twice with 30 ml of QC solution. A 50-ml centrifuge tube was placed below the column, and then elution with 15 ml of QF solution was performed. 10.5 ml of isopropanol was added to the eluate and centrifuged at 4° C. and 15,000 rpm for 30 minutes. After the DNA pellet was visually observed, the supernatant was carefully removed, and 5 ml of 70% ethanol was added to the pellet. Then, the solution was centrifuged for 15 minutes, and the supernatant was removed so that the pellet was not detached, after which the pellet was dissolved in 150 μl of LAR water. After the pellet was completely dissolved, the solution was filtered through a 0.22 μm filter. The DNA concentration was analyzed by a Nanodrop spectrophotometer, and the DNA measured to have a purity corresponding to an A260 value of 0.1-1.0 was used for transfection.

24 hours before transfection, 6-7×10 3 cells/ml were inoculated. After 24 hours, the cell viability and number were measured. To remove a cell clump, the cells were transferred into a 50 ml tube and vortexed at 20° C. for 30 seconds. Then, the cells were transferred to 28 ml of medium in a fresh flask at a concentration of 3×10 7 viable cells.

20 μg of each of an FcRn DEST vector having the hGH leader sequence and a phiC31 integrase vector was diluted in ml of OptiMEM® medium. Then, 80 μg of 293 fectin was diluted in 1 ml of OptiMEM® medium and allowed to stand at room temperature for 5 minutes. When fectin is allowed to stand for 5 minutes or longer, the activity of fectin will decrease, and for this reason, fectin was not allowed to stand for a long period of time. Next, 1 ml of the diluted vector was mixed with 1 ml of the diluted fectin, and the mixture was allowed to stand at room temperature for 30 minutes so that a complex of DNA and fectin could be formed. Next, the mixture was added to the flask containing 3×10 7 viable cells. The flask was mounted in an orbital shaker in an 8% CO 2 incubator at 37° C., and then shaken at 125 rpm. After 24 hours of transfection, the medium was replaced with fresh 293 medium, and the cells were cultured.

The expression level of FcRn could be increased by selectively killing non-integrated cells using a process for selecting cells comprising the FcRn expression vector permanently integrated into the chromosome. After 48 hours of transfection, hygromycin B was added to the cells, and selection of cells was started. Medium replacement and antibiotic treatment were performed once at 3-day intervals during culture, and the cell viability and number were measured as a function of time, thereby constructing an expression cell line.

The expression of FcRn in the constructed stable cell line was analyzed by Western blotting using primary antibodies against αFcRn and β2m. Quantitative analysis was performed using commercially available human β2-microglobulin as a standard, and the results were analyzed by imaging.

During culture of the FcRn stable cell line, the medium was sampled and centrifuged at 15,000 rpm for 10 minutes. 20 μl of the supernatant was collected, and 4 μl of 5× reducing sample loading dye was added thereto and allowed to stand at 95° C. for 5 minutes. 12 μl of the resulting sample was loaded onto 12% NuPAGE Bis-Tris gel. The human β2-microglobulin standard was loaded in amounts of 5 ng and 10 ng. The PAGE gel was run at 250 volt for 35 minutes and transferred to a PVDF membrane at 30 volt for 90 minutes. Blocking was performed with 10% skim milk for 1 hour. Primary antibody against each of αFcRn and β2m was diluted at 1:1,000 in TBST solution and incubated at room temperature for 1 hour, and secondary antibody was diluted at 1:5,000 in TBST solution and incubated at room temperature for 30 minutes. Next, the membrane was washed with TBST solution for 30 minutes more. ECL solutions A and B were mixed with each other at a ratio of 1:1, applied to the membrane, and then allowed to react for 1 minute. Color was developed with manual increment at 10-sec intervals, and the results were imaged.

›Example 3: Expression and Purification of Soluble FcRn

FcRn expressed in the constructed stable cell line is secreted from the medium. An experiment was performed to determine the time when soluble FcRn is collected from the culture of the stable cell line. 30-ml flasks containing 30×10 4 cells/ml and 60×10 4 cells/ml were prepared, and samples were collected for 7 days from the day of inoculation of cells. The samples were analyzed by WB (Western blotting), and the day at which the expression of soluble FcRn reached the highest after inoculation was determined as the time for collecting the sample medium. After inoculation and culture of the cells, the medium was centrifuged at 4° C. and 3,600 rpm for 10 minutes. Only the supernatant medium was collected in such a manner that the cell pellet was not detached, and then the supernatant was filtered through a 0.22 μm filter. To purify 800-1,000 ml of the collected sample, a buffer change and concentration process by UF (ultra filtration) was performed. In order to remove NaOH from the filter, about 2 L of distilled water was allowed to flow through the filter, and the filter was sufficiently washed with distilled water, and then 200 ml or more of a buffer comprising 20 mM Bis-Tris and 150 mM NaCl (pH 6.0) was allowed to flow through the filter. The degree of removal of NaOH from the filter could be determined by measuring and comparing the pH of the buffer added to the feed reservoir and the pH of the permeate. When the pH of the permeate reached pH 6.0, the sample was injected into the feed reservoir and concentrated to 200 ml. To change the buffer of the medium sample into a buffer comprising 20 mM Bis-Tris and 150 mM NaCl (pH 6.0), about 2 L (corresponding to about 10 times or more) was filtered. The pressure sensor used was connected to the feed/inlet P1 and operated in a manual mode. The trans-membrane pressure (TMP) was between 0.15 and 0.20 and did not exceed 0.5. After completion of buffer change, 200 ml of the sample medium was concentrated to 50 ml. The concentrated sample was centrifuged at 4° C., 3,600 rpm for 15 minutes, and the supernatant was collected.

About 50 ml of the sample prepared by UF was purified by affinity chromatography using IgG Sepharose 6 Fast Flow. IgG Sepharose 6 Fast Flow was packed into an XK16 column and used in a column volume of 8 ml, and affinity chromatography was performed at a linear velocity of 150 cm/hr (5 ml/min). After 50 ml of the concentrated sample was injected at a flow rate of 2 ml/min, the column was washed with about 5 CV or more of washing buffer (20 mM Bis-Tris, 150 mM NaCl pH 5.8) until the baseline was restored. Next, elusion buffer (50 mM Tris-Cl, pH8.0) was allowed to flow through the column at a flow rate of 4 ml/min, and the eluate was collected as 2-ml fractions. Protein concentrations were measured by the Bradford quantification method, and purity analysis was performed by Coomassie staining after electrophoresis.

›Example 4: Selection of Polyphages and Monophages by Phage Display Method

Using the isolated and purified shFcRn (soluble human FcRn) as an antigen, polyphages that bind to the FcRn a chain at a pH between 6.0 and 7.4 in a pH-independent manner without binding to β2m were selected from a human antibody cDNA library (see FIG. 1 ), and among them, 8 monophages were used in the analysis of hit gene.

Specifically, a library having a diversity of 2.7×10 10 was cultured at 30° C. for 16 hours, concentrated in PEG (polyethyleneglycol), and then added to PBS buffer. Three-round panning was performed using shFcRn as an antigen, and in round 3, it was shown that the colony titer of the phages against the antigen was amplified by about 10-100 times. A group of monoclonal phage antibodies was prepared from a group of polyclonal phage antibodies resulting from round 3. The ability of each of the antibodies to bind to the antigen was analyzed, and monoclonal phage antibodies were obtained by fingerprinting and sequencing. The cells obtained from the library cells by the three-round panning were transfected with a helper phage and cultured, and poly ScFv-phages present in the supernatant were analyzed by ELSIA using an immuno-plate reader. As a result, it was found that the poly ScFv-phages had an enhanced ability to bind to the antigen (see FIG. 1 ).

To sequence each of the monophage clones confirmed by fingerprinting with BstN1, DNA was isolated from the monoclonal cells and sequenced. The V H and V L CDR regions of the selected antibodies were analyzed, and the similarity between these antibodies and a germ line antibody group was examined using the Ig BLAST program of NCBI (http://www.ncbi.nlm.nih.gov/igblast/). As a result, 8 kinds of shFcRn-specific phage antibodies could be selected. The variable region sequences of the 8 selected antibodies and the nucleotide sequences that encode the variable region sequences are shown in Tables 2 and 3 below. In addition, the CDR sequences in each of the variable regions are shown in Table 4 below.

›Example 5: Construction and Production of Human Antibodies

Each of the heavy-chain and light-chain variable regions from the selected monoclonal scFv phages was amplified by PCR, and then cloned into a pNATAB vector for human antibody expression. The pNATAB vector for heavy-chain expression had Fc gene already constructed therein, and the pNATAB vector for light-chain expression had a light-chain constant region already constructed therein, and thus the Fc gene and the light-chain constant region were ligated with the cloned variable region gene and expressed in the form of whole human IgG. A human antibody was obtained by transiently transfecting 293E cells with two kinds of plasmids, which express the heavy chain region and the light chain region, and purifying an antibody secreted into the medium using a protein A column.

Specifically, before a day of transfection, 5×10 6 293E cells were seeded into a 100-mm culture dish. When the cells reached a confluence of 90%, transfection was performed. 5 g of each of heavy-chain and light-chain plasmid DNAs was prepared and added to 500 μl of serum-free DMEM medium. 20 μg of polyethylenimine (polyscience, cat#. 23966) as a transfection reagent was added to the plasmid DNA-containing medium and well mixed with a pipette, followed by incubation at room temperature for 15 minutes. Next, a DNA/transfection reagent mixture was added to the medium in which 293E cells have grown. The next day, the medium was replaced with fresh serum-free medium, and then the medium was harvested while the medium was replaced at 2-day intervals. The antibody-containing medium was concentrated using a Pellicon 3 filter (Millipore, cat#. P3C030C01), and then the human antibody was purified using a Hi-Trap protein A FF column (GE healthcare, cat#. 17-5079-01) in an AKTA purifier system. The antibody eluted with 100 mM glycine-HCl (pH3.3) buffer was dialyzed with PBS and quantified by measuring the absorbance at a wavelength of 280 nm.

›Example 6: Measurement of Binding Ability of Antibody by SPR

Measurement of the binding ability of antibody by SPR was performed by immobilizing shFcRn as a ligand onto a Proteon GLC chip (Bio-Rad) and measuring affinity.

To determine the K D of anti-FcRn 161 antibody that bind to FcRn, SPR analysis was performed using Proteon XPR36 (Bio-Rad). The analysis of ligand and analyte was performed using a Proteon GLC chip, and the interaction was analyzed at a pH of 6.0 and a pH of 7.4. Immobilization of the ligand was activated by injecting a 1:1 mixture of 1×EDAC (EDC) and 1× Surfo-NHS for 5 minutes. shFcRn was diluted in 10 mM sodium acetate (pH 4.5) at a concentration of 25 μg/ml and added to the ligand at a flow rate of 30 μl/min for 5 minutes. Deactivation was performed with ethanolamine HCl at a flow rate of 30 μl/min for 5 minutes, and it could be seen that shFcRn was immobilized at a level of about 1200-1500 RU. The analyte antibody was allowed to flow on the immobilized chip at a flow rate of 30 μl/min. The analyte antibody was diluted in 0.05% Tween 20/PBS (pH 6.0 or pH 7.4) at concentrations of 100 nM, 50 nM, 20 nM, 10 nM, 5 nM and 2.5 nM before injection. The association time of the analyte antibody was 240 seconds, and the dissociation time was 600 seconds. Regeneration of the chip was performed by injecting 10 mM glycine (pH 2.5) at a flow rate of 100 μl/min for 18 seconds. Based on sensorgrams resulting from six concentrations of the analyte, kinetics analysis was performed using Proteon XPR36 software. The kinetic parameters of the antibody, obtained by the SPR analysis, are shown in Table 5 below.

›Example 7: Construction of Full-Length FcRn Expression Vector

In order to examine whether the eight antibodies bind to hFcRn on the human cell surface and inhibit the interaction between hFcRn and IgG Fc and to examine the cross-reactivity of the antibodies with FcRn of each of humans, monkeys, mice and rats, an expression vector for constructing a cell line of each species that overexpresses FcRn on the cell surface was constructed.

1) Human FcRn

A clone (αFcRn: hMU008093/β2m: hMU005156) was purchased from the Korea Research Institute of Bioscience and Biotechnology, and plasmid DNA was extracted from the clone. 2 μl of 200 ng template, 2 μl of 10 pmole N-primer, 2 μl of 10 pmole C-primer, 25 μl of 2× Solgent mixture and 19 μl of distilled water were mixed with each other to make 50 μl of a reaction solution. The primer sequences used in the experiment are shown in Table 1. The PCR reaction was performed under the following conditions: initial denaturation at 95° C. for 2 min, and then 25 cycles of denaturation at 95° C. at 20 sec, primer annealing at 60° C. for sec and elongation at 72° C. for 1 min, followed by final enzymatic reaction at 72° C. for 5 min. The αFcRn gene amplification product was treated with NheI and XhoI enzymes at 37° C. for at least 4 hours, and the β2m gene amplification product was treated with NheI and XbaI enzymes at 37° C. for at least 4 hours, and the pcDNA3.1(+) vector was treated with each of NheI/XhoI and NheI/XbaI enzymes at 37° C. for at least hours, followed by electrophoresis. Each of the DNA fragments was electrophoresed on agarose gel to confirm its size and recovered using an agarose gel extraction kit. The DNA fragment and the vector fragment were mixed with each other at a ratio of 1:5 to form a total of 10 ul of a mixture, and 10 μl of NEB ligase buffer and 1 μl of ligase were added thereto, followed by incubation at room temperature for 2 hours. 5 μl of the ligation mixture was added to DH5α competent cells and transformed into the cells by heat shock at 42° C. for 1 minute, and the cells were stationary cultured in ampicillin-containing LB solid medium to obtain colonies. The colonies were cultured in ampicillin-containing LB liquid medium at 37° C. for 24 hours, and plasmid DNA was isolated therefrom and sequenced. The results of the DNA sequencing indicated that each of the αFcRn and β2m genes was cloned into pcDNA3.1(+).

2) Construction of Mouse, Rat and Monkey Full-Length FcRn Expression Vectors

Mouse, rat and monkey cDNA libraries used in this Example were purchased from BioChain. Mouse cDNA (C1334149), rat cDNA (C1434149) and monkey cDNA (C1534150-cy) were used as templates. 1 μl of template, 2 μl of 10 pmole N-primer shown in Table 1, 2 μl of 10 pmole C-primer shown in Table 1, 25 μl of 2× Solgent mixture and 20 μl of distilled water were mixed with each other to make 50 μl of a reaction solution. The nucleotide sequences of the primers used in the experiment are shown in Table 1. PCR reaction was performed under the following conditions: initial denaturation at 95° C. for 2 min, and then 25 cycles of denaturation at 95° C. for 20 sec, primer annealing at 56° C. for 40 sec and extension at 72° C. for 1 min, followed by final enzymatic reaction at 72° C. for 5 min. The αFcRn and β2m gene amplification products were treated with Kpn and Xho enzymes at 37° C. for at least 4 hours, and the pcDNA3.1(+) vector was treated with Kpn/Xho enzymes, followed by electrophoresis. Each of the DNA fragments was electrophoresed on agarose gel to confirm its size and recovered using an agarose gel extraction kit. The DNA fragment and the vector fragment were mixed with each other at a ratio of 1:5 to form a total of 10 ul of a mixture, and 10 μl of NEB ligase buffer and 1 μl of ligase were added thereto, followed by incubation at room temperature for 2 hours. 5 μl of the ligation mixture was added to DH5α competent cells and transformed into the cells by heat shock at 42° C. for 1 minute, and the cells were stationary cultured in ampicillin-containing LB solid medium to obtain colonies. The colonies were cultured in ampicillin-containing LB liquid medium at 37° C. for 24 hours, and plasmid DNA was isolated therefrom and sequenced. The results of the DNA sequencing indicated that each of the αFcRn and β2m genes was cloned into pcDNA3.1(+). PCR was performed using the two plasmid DNAs cloned into the pcDNA3.1(+) vector as a template together with PCR primers having an attB site inserted into the 5′ and 3′ ends, using a Jump-In™ fast gateway cloning kit according to the manufacturer's instructions. In this way, expression vectors having the hGH leader and the αFcRn/β2m genes of different species in pJTI™ FastDEST vector were constructed. The genes in the constructed expression vectors were sequenced.

›Example 8: Construction of Cell Lines Expressing Full-Length FcRn

Because plasmid DNA to be used for transfection should have high concentration and purity, QIAGEN plasmid purification was performed. The bacterial clone of the sequenced hGH leader FcRn pJTI™ FastDEST vector was inoculated into a 100-ml LB flask containing ampicillin. The bacterial cells were recovered by centrifugation at 3600 rpm for 15 minutes. After removal of the medium, the pellet was completely dissolved in 10 ml of P1 solution by vortexing, and then 10 ml of P2 solution was added thereto. The mixture was gently inverted five times and incubated at room temperature for 5 minutes. Then, 10 ml of P3 solution was added to the mixture, which was then inverted five times and incubated on ice for 30 minutes. After completion of incubation, the solution was centrifuged at 4° C. and 15,000 rpm for 30 minutes. The supernatant was transferred into a 50-ml fresh centrifuge tube and additionally centrifuged for minutes. The supernatant was loaded into a column equilibrated with 10 ml of QBT solution. When loading of the solution by gravity was completed, the column was washed twice with 30 ml of QC solution. A 50-ml centrifuge tube was placed below the column, and then elution with 15 ml of QF solution was performed. 10.5 ml of isopropanol was added to the eluate and centrifuged at 4° C. and 15,000 rpm for 30 minutes. After the DNA pellet was visually observed, the supernatant was carefully removed, and 5 ml of 70% ethanol was added to the pellet. Then, the solution was centrifuged for 15 minutes, and the supernatant was removed in such a manner that the pellet was not detached, after which the pellet was dissolved in 150 μl of LAR water. After the pellet was completely dissolved, the solution was filtered through a 0.22 μm filter. The DNA concentration was analyzed by a Nanodrop spectrophotometer, and the DNA measured to have a purity corresponding to an A260 value of 0.1-1.0 was used for transfection.

Cell lines, which express human FcRn, rat FcRn and monkey FcRn, respectively, were constructed in the following manner. The HEK293 cell line for human FcRn, the 3T3L1 cell line for mouse FcRn, Rat-2 fibroblasts for rat FcRn, and the COS-7 cell line for monkey FcRn were used. 24 hours before transfection, each of the cell lines was seeded into T75 flask and grown to a confluence of 80%. After 24 hours, the medium was replaced with fresh medium.

5 μg of each of a FcRn DEST vector and a phiC31 Integrase vector was diluted in 500 μl of OptiMEM medium. Then, 20 μl of Lipofectamine 2000 was diluted in 500 μl of OptiMEM medium, and allowed to stand at room temperature for 5 minutes. Next, the two dilutions were mixed with each other and allowed to stand at room temperature for 30 minutes so that a complex of DNA and Lipofectamine could be formed. Next, the mixture was added to a flask containing cells. The cells were cultured in a 5% CO 2 incubator at 37° C. for 6 hours, and then the medium was replaced with refresh 10% FBS/DMEM medium, and the cells were further cultured.

To select cells comprising the FcRn expression vector permanently integrated into the chromosome, the following process was performed. Through this process, the expression level of FcRn could be increased by selectively killing non-integrated cells. After 48 hours of transfection, hygromycin B was added to the cells to perform selection. Medium replacement and antibiotic treatment were performed at 3-day intervals during cell culture, and the formed colonies were detached at various time points and cultured. From the selected cell groups, stable monoclonal cell lines were selected by clonal selection.

Confirmation of the selected stable cell lines was performed by FACS analysis. Alexa488-labeled hIgG1 was bound to the human FcRn-expressing stable cell line at a pH of 6.0 to measure a shift in population. Likewise, Alexa488-labeled Cynomolgus monkey IgG1 was bound to the monkey FcRn-expressing stable cell line at a pH of 6.0 to measure a shift in population. In the case of the mouse FcRn-expressing stable cell line, mouse IgG1 was bound to the cell line at a pH of 6.0 for 1 hour, the level of bound mouse IgG1 was measured by FACS using FITC-labeled anti-mouse IgG1, thereby measuring a shift in population. In the case of the rat FcRn-expressing stable cell line, anti-rat FcRn mouse antibody was bound to the cell line at a pH of 7.4 for 1 hour, and then the level of bound rat IgG was measured by FACS using FITC-labeled anti-rat IgG antibody, thereby measuring a shift in population.

›Example 9: Analysis of Binding of Antibody to FcRn by FACS

In stable HEK293 cells expressing human FcRn, the degrees of binding of antibody to FcRn at various pHs were analyzed using a FACS system. Specifically, 100,000 stable HEK293 cells were washed with PBS and centrifuged in a table top microcentrifuge at 4500 rpm for 5 minutes to obtain pellets. 1 μg of antibody was added to 100 μl of pH 6.0 or pH 7.4 PBS/10 mM EDTA. The cell pellets were resuspended in 100 μl of the antibody solution and incubated on ice for 60 minutes. The cells were washed once with 150 μl of buffer having pH difference, and then pellets were obtained therefrom. Alexa488-labeled anti-human antibody goat antibody (1 mg/ml) was diluted at 1:20 in buffer having pH difference, and the pellets were resuspended in 100 μl of the buffer, and then cultured on ice for 60 minutes. The cells were washed once with 150 μl of buffer having pH difference, and pellets were obtained therefrom and resuspended in buffer having pH difference. The suspension was transferred into a tube for FACS analysis. These cells were analyzed by FACS using BD FACSDiva™ v6.1.3 software (BD Bioscience). The results of the analysis were expressed as Mean Fluorescence Intensity (MFI) (see FIG. 2 ). It was shown that, among the eight selected antibodies, HL161-1A, HL161-11G and HL161-11H did strongly bind to hFcRn on the cell surface compared to the comparative substance IgG1.

›Example 10: Analysis of Blocking Function of Antibody by FACS

HEK293 cells expressing hFcRn on the surface were treated with the eight antibodies confirmed to have the ability to bind to hFcRn on the cell surface, and whether the binding of Alexa-Fluo-488-labeled hIgG1 decreased was analyzed to examine the blocking function of the antibodies.

The analysis process was performed in the following manner.

1) Labeling of Human IgG1 with Alexa-Fluor-488

Human IgG1 (Calbiochem, cat#.400120) was labeled by a Alexa Fluor 488 labeling kit (Molecular Probed/Invitrogen, Carlsbad, Calif.) according to the manufacturer's protocol. Specifically, 50 μl of 1 M sodium bicarbonate (pH 9.0) was added to 500 μl of 2 mg/ml solution of IgG in PBS. This protein solution was added to Alexa-Fluor-488 succinimidyl ester (dry powder) and incubated with stirring at room temperature for 1 hour. The protein was purified by size-exclusion chromatography using the kit component column (Bio-Rad BioGel P-30 Fine size exclusion purification resin). The sample was loaded onto the column and eluted with PBS. The first colored band contained the labeled protein. The degree of labeling was determined by measuring the absorbance of the eluted IgG at A280 (absorbance at 280 nm) and A494 (absorbance at 494 nm). The protein molar concentration was determined using the following formula:

( M )=[ A 280−( A 494×0.11)×dilution factor]/203,000.

In addition, the formula used to derive the moles of dye per mole of protein was as follows:

( M )= A 494×dilution factor/71,000×protein concentration.

Typically, 4-5 moles of Alexa-Fluor 488 were incorporated per mole of IgG.

2) Cell Competition Assay Using FcRn-Expressing Cells

In stable HEK293 cells expressing human FcRn, the blocking of the antibody against FcRn was analyzed by FACS. The antibody was diluted in binding buffer (PBS pH 6.0, 10 mM EDTA) at concentrations of 2,000 nM, 400 nM and 80 nM to make 50 μl of dilutions, which were dispensed into tubes. To each of the tubes, 10 μl of 1 uM Alexa488-labeled hIgG1 (pH 6.0) was added. Stable HEK293 cells were diluted in binding buffer at a concentration of 2,500,000 cells/ml, and 40 μl of the cell dilution was added to each of the labeled antibody-containing tubes. Thus, a final volume of 100 μl contained 100,000 cells, 100 nM labeled antibody and 1000 nM, 500 nM or 250 nM competitor antibody. The cells were washed once with 150 μl of buffer (pH 6.0), and pellets were obtained therefrom and resuspended in 150 μl of buffer having pH difference. The suspension was transferred into a tube for FACS analysis. The cells were analyzed by FACS using BD FACSDiva™ v6.1.3 software (BD Bioscience). The results of the analysis were expressed as mean fluorescence intensity (MFI).

The MFI of the test group was processed after subtracting the MFI (background signal) measured in cells alone. The ratio of the MFI of the competitor-containing tube relative to the MFI (taken as 100%) of the control tube (Alexa Fluor 488 alone and without competitor) was calculated.

If MFI was lower than the MFI of the human IgG1 competitor-containing tube, it was determined that the binding of the competitor antibody was high. The results in FIG. 3 indicated that HL161-1A, HL161-11G and HL161-11H have blocking functions.

›Example 11: Analysis of Cross-Reactivity by FACS

In order to examine whether the three human antibodies having blocking functions bind to FcRn of other species to block the binding of IgG to FcRn of each species, cross-reactivity between species was analyzed in the following manner.

1) Analysis of Cross-Reactivity with Mouse FcRn

3T3-L1 cells stably expressing mouse FcRn were cultured in 10% FCS DMEM medium, and then detached from the culture plate by trypsin treatment. The cells were washed three times with cold binding buffer (PBS, pH 6.0 10 mM EDTA), and then diluted in binding buffer at a concentration of 10 5 cells/ml. 100 μl of the cell dilution was dispensed into each 1.5-ml tube in such a manner that each tube contained 10 4 cells, and 1 μl of HL161 antibody (1 mg/ml) was added to the dispensed cells. Next, the cells were incubated on ice. As control antibodies, 1 μl of each of rabbit antibody (Santacruz, sc-66893) and human IgG (Abcam, cat#. 409120), which bind to mouse FcRn, was used. The cells were recovered by centrifugation at 4° C. and 4000 rpm for 5 minutes, after which the cells were washed once with binding buffer and resuspended in 100 μl of binding buffer. As FITC-conjugated secondary antibody, 1 μl of anti-human IgG goat antibody (Invitrogen, Cat*. A11013) was added to the cells. In the case of the experiment using anti-mouse FcRn rabbit antibody, the anti-rabbit antibody was incubated with the cells on ice for 1 hour, and then the cells were recovered by centrifugation at 4° C. and 700 g for 5 minutes, washed once with binding buffer, resuspended in 400 ul of binding buffer and analyzed by FACS to examine the cross-reactivity of the HL161 antibodies with mouse FcRn (see FIG. 4 ). An experiment at a pH of 7.4 was performed using binding buffer at a pH of 7.4 in the same manner as the experiment using binding buffer at a pH of 6.0. The degree of the binding of each antibody to mouse FcRn was presented as relative MFI based on human IgG. At both a pH of 6.0 and a pH of 7.4, the HL161-1A and h1161-11G antibodies did bind to mouse FcRn, but HL161-11H did not bind to mouse FcRn (see FIG. 4 ).

2) Analysis of Cross-Reactivity with Rat FcRn

Rat-2 (KCTC #AC28203), rat fibroblasts stably expressing rat FcRn, were cultured in 10% FBS DMEM medium, and then detached from the culture plate by trypsin treatment. The cells were washed three times with cold binding buffer (PBS pH 6.0, 10 mM EDTA), and then diluted in binding buffer at a concentration of 10 5 cells/ml. 100 μl of the cell dilution was dispensed into each 1.5-ml tube in such a manner that each tube contained 10 4 cells, and 1 μl of HL161 antibody (1 mg/ml) was added to the dispensed cells. Next, the cells were incubated on ice. As control antibodies, 1 μl of each of mouse 1G3 antibody and human IgG antibody (Abcam, cat#. 409120), which bind to rat FcRn, was used. The 1G3 antibody was produced and purified from mouse hybridoma cells (ATCC CRL2434). The cells were recovered by centrifugation at 4° C. and 4000 rpm for 5 minutes, after which the cells were washed once with binding buffer and resuspended in 100 μl of binding buffer. As FITC-conjugated secondary antibody, 1 μl of anti-human IgG goat antibody (Invitrogen, cat#. A11013) was added to the cells. In the case of the experiment using anti-rat FcRn mouse antibody, the anti-mouse IgG goat antibody (Invitrogen, cat#. A11001) was incubated with the cells on ice for 1 hour, and then the cells were recovered by centrifugation at 4° C. and 4000 rpm for 5 minutes, washed once with binding buffer, resuspended in 400 μl of binding buffer and analyzed by FACS to examine the cross-reactivity of the HL161 antibodies with rat FcRn (see FIG. 4 ). An experiment at a pH of 7.4 was performed using binding buffer at a pH of 7.4 in the same manner as the experiment using binding buffer at a pH of 6.0. The degree of the binding of each antibody to rat FcRn was presented as relative MFI based on human IgG. At both a pH of 6.0 and a pH of 7.4, the HL161-1A and h1161-11G antibodies did bind to rat FcRn, but HL161-11H did not bind to rat FcRn (see FIG. 4 ).

3) Analysis of Cross-Reactivity with Monkey FcRn

Cos-7 cells stably expressing monkey FcRn were cultured in 10% FBS DMEM medium, and then detached from the culture plate by trypsin treatment. The cells were washed three times with cold binding buffer (PBS pH 6.0, 10 mM EDTA), and then diluted in binding buffer at a concentration of 10 5 cells/ml. 100 μl of the cell dilution was dispensed into each 1.5-ml tube in such a manner that each tube contained 10 4 cells, and 1 μl of each HL161 antibody (1 mg/ml) was added to the dispensed cells. Next, the cells were incubated on ice. As control antibodies, 1 μl of each of Cynomolgus monkey IgG (Equitech-Bio Inc, cat#. SLCM66 0100) and human IgG (Abcam, cat#. 409120) was used. The cells were recovered by centrifugation at 4° C. and 700 g for 5 minutes, after which the cells were washed once with binding buffer and resuspended in 100 μl of binding buffer. As FITC-conjugated secondary antibody, 1 μl of anti-human IgG goat antibody (Invitrogen, cat#. A11013) was added to the cells, which were then incubated with on ice for 1 hour. Next, the cells were recovered by centrifugation at 4° C. and 700 g for 5 minutes, washed once with binding buffer, resuspended in 400 J of binding buffer, and then analyzed by FACS to examine the cross-reactivity of the HL161 antibodies with monkey FcRn (see FIG. 4 ). An experiment at a pH of 7.4 was performed using binding buffer at a pH of 7.4 in the same manner as the experiment using binding buffer at a pH of 6.0. The degree of the binding of each antibody to monkey FcRn was presented as relative MFI based on human IgG. At both a pH of 6.0 and a pH of 7.4, the HL161-1A, h1161-11G and HL161-11H antibodies did bind to monkey FcRn (see FIG. 4 ).

›Example 12: Test for Effect of Human Antibody in mFcRn−/−hFCRN Transgenic 276 Mice

Among the three human antibodies determined by FACS analysis to bind to hFcRn to block the binding of hIgG1, two antibodies were selected. Tg276 (hFcRn+/+, h2m+/+, mFcRn−/−, m2m−/−) mice (Jackson Laboratory) expressing hFcRn were injected with human IgG, and then HL161_1A or HL161_11H and human IgG were administered to the mice to examine whether the antibody influences the catabolism of human IgG. Each of two HL161 candidates (HL161_1A and HL161_11H) and human IgG (Greencross, IVglobulinS) was diluted at a concentration of 1 mg/mL, and each dilution was dispensed and stored for 4-day administration. As a vehicle, PBS (phosphate buffered saline; pH 7.4) was used. hFcRn Tg276 mice were acclimated for about 7 days and allowed access to water and feed ad libitum and housed at a temperature of 23±2° C.) and a humidity of (55±5%) with a 12-hr light/12-hr dark cycle. The mice were grouped into three test groups, each consisting of three mice, and a vehicle group consisting of one mouse. In order to use human IgG as a tracer, biotin-conjugated hIgG was prepared using a kit (Pierce, Cat No. 21327) according to the manufacturer's protocol. The prepared biotin-IgG was injected intraperitoneally into the mice at a dose of 5 mg/kg. At 24, 48, 72 and 96 hours after injection of biotin-IgG, the antibody was injected intraperitoneally into the mice at a dose of 10 mg/kg. The mice were gently anesthetized with Forane (Isoflurane, JW pharmaceutical), and then blood was collected from the Retro-orbital plexus using a heparinized micro-hematocrit capillary tube (Fisher) at 6, 12, 24, 48, 72, 96, 120 and 168 hours after injection of biotin-IgG. At 24, 48, 72 and 96 hours after blood collection, the antibody was administered after blood collection. 0.1 mL of the whole blood was received in an Eppendorf tube, and then immediately, plasma was separated by centrifugation and stored in a deep freezer (Thermo) at −70° C. until use in analysis.

The level of biotin-hIgG1 in the collected blood was analyzed by an ELISA assay in the following manner. 100 μl of neutravidin (Pierce, 31000) was seeded into each well of a 96-well plate (Costar, Cat. No: 2592) at a concentration of 1.0 g/ml, and then immobilized at 4° C. for 16 hours. The plate was washed three times with buffer A (0.05% Tween-20, 10 mM PBS, pH 7.4), and then incubated in 1% BSA-containing PBS (pH 7.4) at room temperature for 2 hours. After washing the plate three times with buffer A, a neutravidin plate was prepared at a concentration of 1 μg/ml using 0.5% BSA-containing PBS (pH 7.4). The blood sample was 500-1000-fold serially diluted with buffer B (100 mM MES, 150 mM NaCl, 0.5% BSA IgG-free, 0.05% Tween-20, pH 6.0), and 150 μl of each of the dilutions was injected into each well. The injected sample was allowed to react at room temperature for 1 hour. The plate was washed three times with buffer A, and then 200 j of 1 nM HRP-conjugated anti-human IgG goat antibody was injected into each well and allowed to react at 37° C. for 2 hours. The plate was washed three times with ice-cold buffer B, and then 100 μl of 3,3,5,5-tetramethylbenzidine (RnD, Cat. No: DY999) as a substrate was injected into each well and allowed to react at room temperature for 15 minutes. 50 μl of 1.0M sulfuric acid solution (Samjeon, Cat. No: 52129) was injected into each well to stop the reaction, and then the absorbance at 450 nm was measured.

The concentration of biotin-IgG at 6 hours (approximate T max of biotin-IgG in mice, before the catabolism of biotin-IgG occurred) was set at 100%, and the ratios (%) of biotin-IgG concentrations at other time points relative to the concentration at 6 hours. The results are shown in FIG. 5 .

The half-life of the vehicle group was 97.55 hours, and the half-life of the hIgG group used to examine the IVIG effect was 75 hours. The half-lives of the two HL161 candidates HL161-1A and HL161-11H were 72 hours and 57 hours, respectively. The half-life of HL161-1A was shorter than that of the vehicle group by at least 25 hours, but was similar to that of the hIgG group. The half-life of HL161-11H was shorter than that of the vehicle group by at least 40 hours and shorter than that of the hIgG group by about 20 hours or more. These results indicate that the pH-independent, Fc-competitive antibody specific for hFcRn has the effect of increasing the catabolism of endogenous antibody.

Part II: Optimization of FcRn-Specific Antibody by Affinity Maturation

›Examples4

›Example 13: Optimization of Candidate Antibody by Affinity Maturation · 1 of 2

13-1: Primary Affinity Maturation

In order to perform primary affinity maturation, HL161-1A and HL161-11H determined to have the best effect in Examples 1 to 12 using the isolated and purified shFcRn (soluble human FcRn) as an antigen were used as antibodies for affinity maturation. In addition, primary affinity maturation was performed based on 1Ag and 11Hg obtained by modifying the amino acid sequences of HL161-1A and HL161-11H into amino acid sequences that are frequently found in human germ lines. 1Ag and 11Hg have the variable region sequences and CDR sequences shown in Tables 6 and 7 below.

For affinity maturation, antibodies that bind in a pH-independent manner in the pH range from 6.0 to 7.4 were selected from the scFv format library and sequenced, and then 25 specific antibodies were isolated and purified. Next, the affinities of the antibodies were measured by SPR, and antibodies determined to have enhanced affinity and specificity were selected as templates for use in secondary affinity maturation. A detailed method for affinity maturation is as follows.

(1) Construction of Library

The CDR-H3 of each of 1Ag and 11Hg was subjected to saturated randomization at one position in order to minimize the activity of binding to antigen or a change in surface protein in the randomization process. Some residues that are frequently found were not modified or were randomized in a limited manner. The CDR-L3 was subjected to randomization so that it could contain amino acids that were frequently found at positions as a result of analysis of human germ line antibody genes. Oligonucleotides for randomized sites were synthesized, and randomized scFv genes were obtained by PCR. The scFv genes were ligated into pComb3X vectors using a Sfi-I restriction enzyme, and then transformed into an E. coli ER2537, thereby constructing a library having a diversity of 8.0×10 6 for 1Ag and a diversity of 5.0×10 6 for 11Hg (see FIG. 6 ).

(2) Panning

In a panning strategy, in order to select clones that strongly bind to antigen at a pH of 6.0 (low KD) and are not easily detached at a pH of 7.4 (low K off ), biotinylated hFcRn (100 ng) was used as antigen, and hFcRn-expressing HEK293 cells (60-mm, 80% confluence) were used. When HEK293-hFcRn cells were used, the cells were fixed with 3.7% formaldehyde, followed by panning. In the case of 1Ag, fixed soluble cells were used, and in the case of 11Hg, fixed adhesion cells were used. For enhancement of K off , the washing time was increased and shFcRn was added. When protein was used, shFcRn was added for 24 hours except for 1 st round, followed by washing, and when cells were used, washing was performed 15 times (about 2 hours). When output titer increased as panning progressed, it was considered to be enriched.

(3) ELISA and Dot-Blot Screening

For ELISA and dot-blot screening, each colony was cultured with 0.15 mL of SB medium and induced overnight with mM IPTG, and then a periplasmic extract was obtained therefrom using 0.1 mL of TES. ELISA was performed using TMB reagent after binding periplasmic extract by direct coating with 30 ng, 10 ng and 5 ng of hFcRn and binding anti-HA-HRP. For dot-blot screening, the periplasmic extract was diluted at 1:3 to 1:5 in PBS, and 1 mL of the dilution was dotted onto a nitrocellulose membrane, after which anti-HA-HRP was bound to the membrane which was then analyzed using AbSignal (Abclon, Korea). For numerical comparison with ELISA, a periplasmic extract of parental scFv was serially diluted at 1:2 and used as a standard. For selection of high-affinity binders, based on the dot-blot and ELISA values of parental scFv, clones having lower expression levels and ELISA values higher than parental scFv were selected. In the case of 1Ag, ELISA and dot-blot screening were performed on 855 Strategy-1 4 th output colonies, 1425 Strategy-2 3 rd output colonies, and 855 Strategy-2 5 th output colonies. In order to select binders having high affinity at pH 7.4 and pH 6.0, scFv levels were compared by ELISA for three concentrations of shFcRn. As a result, 40 colonies were selected from Strategy-1 4 th outputs, 41 colonies were selected from Strategy-2 3 rd outputs, and 40 colonies were selected from Strategy-2 5 th outputs.

(4) Nucleotide Sequencing

121 colonies selected from the library based on 1Ag were sequenced, thereby selecting 74 unique sequence clones. Among these sequence clones, 30 clones having no putative glycosylation site were selected.

88 colonies selected from the library based on 11Hg were sequenced, thereby selecting 37 unique clones. Among these clones, 25 clones having no putative glycosylation site were selected.

(5) Purification of 1Ag and 11Hg-Derived Candidate Antibodies Having Improved Affinity

In order to perform ELISA, cELISA and the measurement of SPR K off , scFv was purified. Specifically, cells were incubated in 20-50 mL of SB and then induced overnight with 1 mM IPTG, after which these cells were extracted with 1:5-1:8 volumes of TES buffer to obtain a periplasmic extract. Purification of scFv was performed by affinity chromatography using Ni-NTA. For measurement of K off , 17 clones derived from 1Ag and 8 clones derived from 11Hg were purified.

(6) Measurement of Binding Affinity by ELISA and SPR

ELISA was performed at a pH of 6.0 and a pH of 7.4, and all buffers and samples were used at a pH of 6.0 and a pH of 7.4. shFcRn was diluted in PBS (pH 6.0 or pH 7.4) at a concentration of 2 g/mL, and 100 μl of the dilution was added to each well of a 96-well plate and coated at room temperature for 2 hours (or O/N coated at 4° C.). The plate was washed three times with washing buffer (pH 6.0 or pH 7.4), and then solution was removed from each well by suction. Next, 200 μl of blocking buffer (pH 6.0 or pH 7.4) was added to each well which was then blocked at room temperature for 2 hours. After completion of blocking, the plate was washed three times with washing buffer, and 100 μl of scFv solution at 100 ng/mL for the 1Ag-derived variant or at 150 ng/mL for the 11Hg-derived variant was added to each well of the 96-well plate and incubated for 2 hours. Then, the plate was washed three times with washing buffer. To detect antibody bound to shFcRn, anti-HA-HRP antibody (anti-HA-HRP antibody) (1:2,000, pH 6.0 or pH 7.4) was added to each well and incubated at room temperature for 2 hours. Each well was washed three times with washing buffer (pH 6.0 or pH 7.4), and then 100 μl of TMB solution was added to each well and incubated at room temperature for 10 minutes. After 10 minutes, 50 μl of stop solution (H 2 SO 4 solution) was added to each well to stop the reaction, and then the absorbance at 450 nm was measured.

›Example 13: Optimization of Candidate Antibody by Affinity Maturation · 2 of 2

The K off rate of scFv was measured using the Biorad-XPR36 system according to the manual. shFcRn was immobilized on a GLC chip, and scFv was added thereto at one concentration to obtain a sensorgram.

As shown in Tables 8 and 9 above, among the randomly mutated CDR-3 clones, eight clones (A11-007, A11-G06, A12-009, A12-D55, A12-E01, A12-E04, A12-F02 and A12-H04) were determined to have increased affinity compared to the templates, as a result of the ELISA and SPR tests. Thus, these eight clones were selected as templates for use in secondary affinity maturation. In addition, 11Hg-derived clones showed no increase in affinity compared to the templates, and any of these clones was not selected as a template for use in secondary affinity maturation.

›Example 13-2: Secondary Affinity Maturation · 1 of 2

From the scFv format library for secondary affinity maturation of the 1Ag template antibodies and 11Hg selected in Example 13-1 using the isolated and purified shFcRn (soluble human FcRn) as antigen, antibodies that bind to the antigen in a pH-independent manner in the pH range from 6.0 to 7.4 were selected and sequenced. Then, antigen-specific antibodies were isolated and purified, and the binding affinities of the purified antibodies were measured by SPR, thereby selecting 56 optimized complete human antibodies. A detailed method for affinity maturation is as follows.

(1) Construction of Library

In the case of 1Ag, a sub-library was constructed by randomizing the CDR-1 and CDR-2 of eight clones (A11-007, A11-G06, A12-009, A12-D55, A12-E01, A12-E04, A12-F02, and A12-H04) having improved affinity as a result of randomization of CDR-3. In the case of 11Hg, a sub-library was constructed by randomizing three positions of CDR-H3 and CDR-1/2 while maintaining CDR-L3 at the template sequence.

Amino acids appearing at positions of each of CDR-1 and CDR-2 of the human antibody as a result of sequencing were analyzed, and based on the results of the analysis, CDR-1 and CDR-2 were randomized so as to have a diversity similar to the original diversity. Oligonucleotides for the randomized sites were synthesized, and randomized scFv genes were obtained by PCR and ligated into pComb3X vectors using the restriction enzyme Sfi-I. Next, the vectors were transformed into an E. coli ER2537 strain, thereby obtaining 1.0×10 7 transformants. 83 colonies were sequenced, and as a result, it was found that 29 colonies had the normal scFv sequences and that the diversities of the resulting sub-library were 3.5×10 6 for 1Ag and 1.3×10 7 for 11Hg.

(2) Panning

In a panning strategy, in order to select clones that strongly bind to antigen at a pH of 6.0 (low KD) and are not easily detached at a pH of 7.4 (low K off ), biotinylated hFcRn (biotin-hFcRn) and hFcRn-expressing HEK293 cells (293-hFcRn) were used. When HEK293-hFcRn cells were used, these cells were converted to single cells using trypsin-EDTA and fixed with 3.7% formaldehyde, followed by panning.

(2-a) Panning of 1Ag Sub-Library

Panning was performed according to the method shown in Table 10 below. In Strategy-1 and Strategy-3, only biotin-shFcRn (100 ng) was used, and in Strategy-4 and Strategy-5, biotin-hFcRn was used in rounds 1 and 2, 293-hFcRn cells (1.0×10 6 cells) were used in rounds 3 and 4. In Strategy-3, Strategy-4 and Strategy-5, soluble parental IgG was used as a competitor in binding. Binding was performed using 1.0×10 12 phages at a pH of 6.0 at room temperature for 2 hours after quantification using a phage titration kit. To increase the K off rate, the washing time was increased and shFcRn was added. After binding, the cells were washed 10 times with PBS-T to remove unbound phages and cultured with rotation in shFcRn-containing PBS-T at 37° C. for 20 hours. Next, the cells were washed 10 times with PBS-T and treated with 100 mM TEA (triethylamine) to elute phages. The phages obtained from the sub-library were quantified and analyzed by ELISA, and as a result, it was concluded that the ELISA signal was not lower than that of the template. Thus, parental IgG was used as a competitor in binding from round 1.

The obtained output phages were quantified using a phage titration kit, and then ELISA was performed using the same amount of phages. Among output colonies from round 4 of Strategy-1, Strategy-3 and Strategy-4, 95 colonies were randomly selected, and the activities thereof were analyzed by ELISA, and as a result, it was found that 90% of the colonies in all the strategies had binding activity.

(2-b) Panning of 11Hg Sub-Library

Panning was performed according to the method shown in Table 11 below. In Strategy-1 and Strategy-3, only biotin-shFcRn (100 ng) was used, and in Strategy-4 and Strategy-5, biotin-hFcRn was used in rounds 1 and 2, 293-hFcRn cells (1.0×10 6 cells) were used in rounds 3 and 4. In Strategy-3, Strategy-4 and Strategy-5, soluble parental IgG was used as a competitor in binding. Binding was performed using 1.0×10 12 phages at a pH of 6.0 at room temperature for 2 hours after quantification using a phage titration kit. To increase the K off rate, the washing time was increased and shFcRn was added. After binding, the cells were washed 10 times with PBS-T to remove unbound phages and cultured with rotation in shFcRn-containing PBS-T at 37° C. for 20 hours. Next, the cells were washed 10 times with PBS-T and treated with 100 mM TEA (triethylamine) to elute phages. The phages obtained from the sub-library were quantified and analyzed by ELISA, and as a result, it was shown that the ELISA signal was not low. Thus, parental IgG was not used as a competitor in round 1 of Strategy-3, Strategy-4 and Strategy-5 and was used from round 2.

The obtained output phages were quantified using a phage titration kit, and then ELISA was performed using the same amount of phages. In strategy-1 and strategy-3 performed using biotin-hFcRn as antigen, the ELISA-positive ratio was shown to be about 80%, and thus colonies resulting from panning were subjected to ELISA screening.

(3) ELISA Screening

scFv in the periplasmic extract was quantified by an ELISA method that recognizes HA, and ELISA was performed using the same amount of scFv. Next, clones having an absorbance value higher than that of the template scFv were selected.

(3-a) Screening of 1Ag Clones

280 colonies from each of Strategy-1 and Strategy-3 were cultured in 0.15 mL of SB medium and induced with 1 mM IPTG, after which the cells were treated with 0.1 mL of TES to obtain a periplasmic extract. scFv in the periplasmic extract was quantified by ELISA, and scFv was diluted in PBS-T (pH 7.4 or pH 6.0) to final concentrations of 1000 ng/mL and 3000 ng/mL, and shFcRn was coated at a concentration of 1 μg/mL. In this way, ELISA was performed.

As a result of ELISA, colonies having an absorbance higher than that of the template scFv at a pH of 7.4 and a pH of 6.0 were selected. The clones having an absorbance higher than that of the template at a pH of 6.0 mostly showed an absorbance higher than that of the template at a pH of 7.4. Based on the ELISA values for a total of 456 colonies, 200 higher-ranked colonies having an ELISA signal higher than that of the template at a pH of 7.4 were sequenced, and as a result, 77 unique clones were selected. The 77 selected clones had the same H-CDR3 sequence (A11-007), and L-CDR3 from the template clones had various sequences.

›Example 13-2: Secondary Affinity Maturation · 2 of 2

(3-b) Screening of 11Hg-Derived Clones

Screening of 11Hg-derived clones was performed in the same manner as described above with respect to ELISA screening of 1Ag-derived clones. As a result of ELISA screening, the number of colonies having an absorbance higher than that of the template scFv at a pH of 7.4 was 64/456 (14.0%), and the number of colonies having an absorbance higher than that of the template scFv at a pH of 6.0 was 32 (7.0%). Based on the ELISA values for a total of 456 colonies, the colonies were ranked based on folds of the ELISA signal compared to the template at a pH of 7.4, and 50 higher-ranked colonies were sequenced. As a result, 10 unique sequence clones were selected.

(4) Purification of Improved 1Ag- and 11Hg-Derived Candidate Antibodies

(4-a) Purification of 1Ag-Derived Clones

Among 77 unique clones, scFv for 48 clones excluding 29 clones having a putative N-glycosylation site (derived from the template) was purified from periplasmic extracts. Specifically, cells were cultured in 100-400 mL of SB medium and then induced overnight with 1 mM IPTG, after the cells treated with treated with a 1:5 volume of TES buffer to obtain periplasmic extracts. scFv was purified from the periplasmic extracts using Ni-NTA resin, and then concentrated with PBS, and the buffer was replaced. The scFv was quantified by the Bradford assay, and 1 g of the scFv was separated by SDS-PAGE and stained with Coomassie blue, thereby determining the concentration and purity of the scFv.

(4-b) Purification of 11Hg-Derived Clones

scFvs for 7 clones among 10 unique clones and for 1Ag, 11Hg and H11-B04 were purified from periplasmic extracts in the same manner as described above with respect to purification of 1Ag.

(5) Measurement of Binding Affinity by ELISA and SPR

Binding affinity was measured according to the above-described Example, and the results of the measurement are shown in Tables 12 and 13.

The amino acid sequences of the variable regions of the antibodies, selected by the above-described primary and secondary affinity maturations and having increased affinity and specificity for FcRn, and nucleotide sequences encoding the amino acid sequences, are shown in Tables 14 and 15 below. In addition, the CDR sequences of the variable regions are shown in Tables 16 and 17 below.

›Tables in the description — 17

TABLE 1 — Primer sequences used in construction of vector

	Forward-primer	Reverse-primer
Common	Leader	1 st	5′-
primer	sequence		CTCTGCCTGCCCTGGCTTCAAGAGGGC
			AGTGCC-3′
		2 nd	5′-
			TGGCTTTTGGCCTGCTCTGCCTGCCCT
			GGCTTCAAG-3′
		3 rd	5′-
			GGACGTCCCTGCTCCTGGCTTTTGGCC
			TGCTCTGCC-3′
		4 th	5′-
			ACCATGGCTACAGGCTCCCGGACGTCC
			CTGCTCCTGGCT-3′
Human	Soluble	αFcRn	5′-TTC AAG AGG GCA GTG CCG	5′-GCT CGA GTC AGG CGG
FcRn	FcRn		CAG AAA GCC ACC TCT CCC TC-	TGG CTG GAA TC-3′
			3′
		β2M	5′-TTC AAG AGG GCA GTG CCA	5′-GTC TAG ATT ACA TGT
			TCC AGC GTA CTC CAA AGA TT-	CTC GAT CCC ACT T-3′
			3′
	Full	αFcRn	5′-GGC TAG CAT GGG GGT CCC	5′-GCT CGA GTC AGG CGG
	length		GCG-3′	TGG CTG GAA TC-3′
	FcRn
		β2M	5′-GGC TAG CAT GTC TCG CTC	5′-GTC TAG ATT ACA TGT
			CGT GGC C-3′	CTC GAT CCC ACT T-3′
Mouse	Full	αFcRn	5′-GGG TAC CAT GGG GAT GCC	5′-GCT CGA GTC AGG AAG
FcRn	length		ACT GCC-3′	TGG CTG GAA A-3′
	FcRn	β2M	5′-GGG TAC CAT GGC TCG CTC	5′-GCT CGA GTC ACA TGT
			GGT GAC-3′	CTC GAT CCC A-3′
Rat	Full	αFcRn	5′-GGG TAC CAT GGG GAT GTC	5′-GCT CGA GTC AGG AAG
FcRn	length		CCA GCC-3′	TGG CCG GAA A-3′
	FcRn	β2M	5′-GGG TAC CAT GGC TCG CTC	5′-GCT CGA GTT ACA TGT
			GGT GAC-3′	CTC GGT CCC AG-3′
Monkey	Full	αFcRn	5′-GGG ATC CAT GAG GGT CCC	5′-GCT CGA GTC AGG CAG
FcRn	length		GCG G-3′	TGG CTG GG-3′
	FcRn	β2M	5′-GGG TAC CAT GTC TCC CTC	5′-GCT CGA GTT ACA TGT
			AGT GGC-3′	CTC GAT CCC A-3′
Common	pJTI ™FA	αFcRn	5′-GGG GAC AAG TTT GTA CAA	5′-GGG GAC AAC TTT TGT
primer	STDEST		AAA AGC AGG CTC CGT TGA CAT	ATA CAA AGT TGT CCA TAG
	vector		TGA TTA TTG ACT AGT T-3′	AGC CCA CCG CAT CCC CAG-
				3′
		β2M	5′-GGG GAC AAC TTT GTA TAC	5′-GGG GAC CAC TTT GTA
			AAA AGT TGC CGT TGA CAT TGA	CAA GAA AGC TGG GTA CCA
			TTA TTG ACT AGT T-3′	TAG AGC CCA CCG CAT CCC
				CAG-3′

TABLE 2 — Amino acid sequences of heavy-chain and light- chain variable regions of selected antibodies

	Sequences of heavy-chain	Sequences of light-chain
	variable regions	variable regions
Antibody		Amino acid		Amino acid
name	SEQ ID NO:	sequences	SEQ ID NO:	sequences
HL161-1A	2	QVQLVQSGGG	146	NFMLTQPASV
		LVQPGRSLRL		SGSPGQTITI
		SCAASGFSFG		SCTGSSSDVG
		EYGMHWVRQA		GYNYVSWYQQ
		PGKGLEWVSG		HPGKAPQLII
		VSWNSGSIAY		YDVTKRPSGV
		ADSVRGRFTI		SNRFSGSKSG
		SRDNSKNSLY		NSASLTISGL
		LQMNSLRAED		QAEDEADYYC
		TAVYYCARGR		SSYSSSTFYV
		SMDVWGQGTT VTVSS		FGTGTKVTVL
HL161-2A	4	QMQLVQSGAE	148	QLVLTQPPST
		VKKPGSSVKV		SETPGQRVTI
		SCKASGGTFN		SCSGSSSNIG
		NYAVSWVRQA		SNYVYWYQQL
		PGQGLEWMGR		PGTAPKLLIY
		IIPILGIANY		RNNQRPSGVP
		AQTFQGRVTI		DRFSGSKSGT
		TADKSTTTAY		SASLAISGLR
		MELSSLRSED		SEDEADYYCA
		TAVYYCARDR		SWDDSLSGVV
		YGMDVWGQGT TVTVSS		FGGGTKLTVL
HL161-2D	6	QVQLVESGGG	150	NFMLTQPHSV
		LVQPGRSLRL		SESPGKTVTI
		SCTASGFTFG		SCTRSSGSIA
		DYAMSWVRQA		ANYVHWYQQR
		PGKGLEWVGF		PGSPPTTVIY
		IRSKAYGGTT		NDNQRPSGVP
		EYAASVKGRF		DRFSGSIDRS
		TISRDDSKSI		SNSASLTISG
		AYLQMNSLRA		LKTEDEADYY
		EDTAVYYCAR		CQSYDSTTYA
		EGLFLPLGGF		FGGGTKLTVL
		DLWGLGTMVT VSS
HL161-6C	8	QVQLVESGAE	152	DIQMTQSPSS
		VKKPGASVKV		VSASVGDRVT
		SCKASGYTFT		ITCRASQGIS
		SYYMHWVRQA		NWVAWYQQKP
		PGQGLEWMGI		GKAPKLLIYA
		INPSGGSTSY		ASSLQSGVPS
		AQKFQGRVTM		RFSGSGSGTD
		TRDTSTSTVY		FTLTISSLQP
		MELSSLRSED		EDFAIYYCQQ
		TAVYYCARGG		GHSFPYTFGQ GTKVEIK
		GAFDIWGQGT MVTVSS
HL161-9F	10	QVQLVESGGG	154	NFMLTQPHSV
		LVQSGRSLRL		SESPGKTVTI
		SCTASGFTFG		SCTRSSGSIA
		DYAMSWVRQA		ANYVHWYQQR
		PGKGLEWVGF		PGSPPTTVIY
		IRSKAYGGTT		NDNQRPSGVP
		EYAASVKGRF		DRFSGSIDRS
		TISRDDSKSI		SNSASLTISG
		AYLQMNSLRA		LKTEDEADYY
		EDTAVYYCAR		CQSYDSTTYA
		EGLFLPLGGF		FGGGTKLTVL
		DLWGLGTMVT VSS
HL161 10E	12	QVQLVESGGG	156	SYELTQPLSV
		LVQPGGSLRL		SMSPGQTARI
		SCAASGFRFS		TCSGDALSKQ
		NFAMTWVRQA		YASWYQLKPG
		PGKGLEWVST		QAPVVVMYKD
		LSGSGGSIHH		TERPSGIPDR
		ADSVKGRFTI		FSGSSSGTTV
		SRDNSKNTLY		TLTISGVQAE
		LQMNSLRAED		DEADYYCQSI
		TAVYYCAKGP		TDKSGTDVIF
		LRGQPAYLDP		GGGTKLTVL
		WGQGTLVTVS S
HL161-11G	14	QMQLVESGGG	158	NFMLTQPASV
		VVQPGRSLRL		SGSPGQSITI
		SCVGSGFNFN		SCTGSSSDVG
		SYGIHWVRQA		GYNYVSWYQQ
		PGKGLEWVGG		HPGKAPQLII
		IFYDGSQVKY		YDVTKRPSGV
		ADSVKGRVSI		SNRFSGSKSG
		SRDNSKNTAY		NSASLTISGL
		LQMNSLRAED		QAEDEADYYC
		TAVYYCARRN		SSYSSSTFYV
		LLDYWGQGTV VTVSS		FGTGTKVTVL
HL161-11H	16	QMQLVESGGG	160	DIQMTQSPST
		LVQPGRSLRL		LSASVGDRVT
		SCAASGFTFS		ITCRASQSIS
		SYAMHWVRQA		SRLAWYQQKP
		PGKGLEWVAV		GKAPKLLIYK
		ISYDGSNKYY		ASSLETGVPS
		ADSVKGRFTI		RFSGSGSGTE
		SRDNSKNTLY		FTLTISSLQP
		LQMNSLRSED		DDFATYYCQQ
		TAVYYCSRGS		TNSFPLTFGG GTKVEIK
		GGRDAFDVWG
		QGTMITVSS

TABLE 3 — Polynucleotide sequences of heavy-chain and light-chain variable regions of selected antibodies

	Sequences of heavy-chain	Sequences of light-chain
	variable regions	variable regions
Antibody	SEQ ID	Polynucleotide		Polynucleotide
name	NO:	sequences	SEQ ID NO:	sequences
HL161-1A	1	CAGGTGCAGC	145	AATTTTATGC
		TGGTGCAGTC		TGACTCAGCC
		TGGGGGAGGC		CGCCTCCGTG
		TTGGTACAGC		TCTGGGTCTC
		CTGGCAGGTC		CTGGACAGAC
		CCTGAGACTC		GATCACCATC
		TCCTGTGCAG		TCCTGCACTG
		CCTCTGGTTT		GAAGCAGCAG
		CAGTTTTGGT		CGACGTTGGT
		GAATATGGCA		GGTTATAACT
		TGCACTGGGT		ATGTCTCCTG
		CCGGCAAGCT		GTACCAACAG
		CCAGGGAAGG		CACCCAGGCA
		GCCTGGAGTG		AAGCCCCCCA
		GGTCTCAGGT		ACTCATCATT
		GTTAGTTGGA		TATGATGTCA
		ACAGTGGTAG		CTAAGCGGCC
		CATTGCCTAT		CTCAGGGGTT
		GCGGACTCTG		TCTAATCGCT
		TGAGGGGCCG		TCTCCGGCTC
		ATTCACCATC		CAAGTCTGGC
		TCCAGAGACA		AACTCGGCCT
		ACAGCAAAAA		CCCTGACCAT
		CTCCCTGTAT		CTCTGGACTC
		CTGCAAATGA		CAGGCTGAGG
		ACAGTCTGAG		ACGAGGCTGA
		AGCCGAGGAC		TTATTACTGC
		ACGGCCGTGT		AGCTCATACA
		ATTACTGTGC		GCAGCAGCAC
		GAGAGGTAGA		TTTTTACGTC
		AGTATGGACG		TTCGGAACTG
		TCTGGGGCCAA		GGACCAAGGT
		GGGACCACG		CACCGTCCTA
		GTCACCGTCT CCTCA
HL161-2A	3	CAGATGCAGC	147	CAGCTCGTGC
		TGGTGCAGTC		TGACTCAGCC
		TGGGGCTGAG		ACCCTCAACG
		GTGAAGAAGC		TCTGAGACCC
		CTGGGTCCTC		CCGGGCAGAG
		GGTGAAGGTC		GTCACCATC
		TCCTGCAAGG		TCTTGTTCTG
		CTTCTGGAGG		GAAGCAGCTC
		CACCTTCAAC		CAACATCGGA
		AACTATGCTG		AGTAATTATG
		TCAGCTGGGT		TATACTGGTA
		GCGACAGGCC		CCAGCAACTC
		CCTGGACAAG		CCAGGAACGG
		GGCTTGAGTG		CCCCCAAACT
		GATGGGAAGG		CCTCATCTAT
		ATCATCCCTA		AGGAATAATC
		TCCTTGGTAT		AGCGGCCCTC
		AGCAAACTAC		AGGGGTCCCT
		GCACAGACAT		GACCGATTCT
		TCCAGGGCAG		CTGGCTCCAA
		AGTCACGATT		GTCTGGCACT
		ACCGCGGACA		TCAGCCTCCC
		AATCCACGAC		TGGCCATCAG
		CACAGCCTAC		TGGGCTCCGG
		ATGGAGCTGA		TCCGAGGATG
		GCAGCCTGAG		AGGCTGATTA
		ATCTGAGGAC		TTACTGTGCA
		ACGGCCGTGT		TCATGGGATG
		ATTACTGTGC		ACAGCCTGAG
		AAGAGATCGT		TGGTGTGGTT
		TACGGTATGG		TTCGGCGGAG
		ACGTCTGGGG		GGACCAAGCT
		CCAAGGGACC		GACCGTCCTA
		ACGGTCACCG TCTCCTCA
HL161-2D	5	CAGGTGCAGC	149	AATTTTATGC
		TGGTGGAGTC		TGACTCAGCC
		TGGGGGAGGC		CCACTCTGTG
		TTGGTACAGC		TCGGAGTCTC
		CAGGGCGGTC		CGGGGAAGAC
		CCTGAGACTC		GGTCACCATC
		TCCTGTACAG		TCCTGCACCC
		CTTCTGGATT		GCAGCAGTGG
		CACCTTTGGT		CAGCATTGCC
		GATTATGCTA		GCCAACTATG
		TGAGCTGGGT		TGCACTGGTA
		CCGCCAGGCT		CCAACAGCGC
		CCAGGGAAGG		CCGGGCAGTC
		GGCTGGAGTG		CCCCCACCAC
		GGTAGGTTTC		TGTCATCTAT
		ATTAGAAGCA		AACGATAACC
		AAGCTTATGG		AAAGACCCTC
		TGGGACAACA		TGGAGTCCCT
		GAATACGCCG		GATCGGTTCT
		CGTCTGTGAA		CTGGGTCCAT
		AGGCAGATTC		CGACAGGTCC
		ACCATCTCAA		TCCAACTCTG
		GAGATGATTC		CCTCCCTCAC
		CAAAAGCATC		CATCTCTGGA
		GCCTATCTGC		CTGAAGACTG
		AAATGAACAG		AGGACGAGGC
		TCTGAGAGCC		TGACTACTAC
		GAGGACACGG		TGTCAGTCCT
		CCGTGTATTA		ACGATAGTAC
		CTGTGCGAGA		CACTTATGCA
		GAGGGGCTGT		TTCGGCGGAG
		TCCTGCCCCT		GGACCAAGCT
		GGGAGGTTTT		GACCGTCCTA
		GATTTATGGG
		GCCTAGGGAC
		AATGGTCACC
		GTCTCCTCA
HL161-6C	7	CAGGTGCAGC	151	GACATCCAGA
		TGGTGGAGTC		TGACCCAGTC
		TGGGGCTGAG		TCCATCTTCC
		GTGAAGAAGC		GTGTCTGCAT
		CTGGGGCCTC		CTGTAGGAGA
		AGTGAAGGTT		CAGAGTCACC
		TCCTGCAAGG		ATCACTTGTC
		CATCTGGATA		GGGCGAGTCA
		CACCTTCACC		GGGTATCAGC
		AGCTACTATA		AACTGGGTAG
		TGCACTGGGT		CCTGGTATCA
		GCGACAGGCC		GCAGAAACCA
		CCTGGACAAG		GGCAAAGCCC
		GGCTTGAGTG		CTAAGCTCCT
		GATGGGAATA		GATCTATGCT
		ATCAACCCTA		GCATCCAGTT
		GTGGTGGTAG		TGCAAAGTGG
		CACAAGCTAC		GGTCCCATCA
		GCACAGAAGT		AGGTTCAGCG
		TCCAGGGCAG		GCAGTGGATC
		AGTCACCATG		TGGGACAGAC
		ACCAGGGACA		TTCACTCTCA
		CGTCCACGAG		CCATCAGCAG
		CACAGTCTAC		CCTGCAGCCT
		ATGGAGCTGA		GAAGATTTTG
		GCAGCCTGAG		CAATTTACTA
		ATCTGAGGAC		TTGTCAACAG
		ACGGCCGTGT		GGTCACAGTT
		ATTACTGTGC		TCCCGTACAC
		AAGAGGGGGG		TTTTGGCCAA
		GGGGCTTTTG		GGGACCAAGG
		ATATCTGGGG		TGGAAATCAA A
		CCAAGGGACA
		ATGGTCACCG TCTCCTCA
HL161-9F	9	CAGGTGCAGC	153	AATTTTATGC
		TGGTGGAGTC		TGACTCAGCC
		TGGGGGAGGC		CCACTCTGTG
		TTGGTACAGT		TCGGAGTCTC
		CAGGGCGGTC		CGGGGAAGAC
		CCTGAGACTC		GGTCACCATC
		TCCTGTACAG		TCCTGCACCC
		CTTCTGGATT		GCAGCAGTGG
		CACCTTTGGT		CAGCATTGCC
		GATTATGCTA		GCCAACTATG
		TGAGCTGGGT		TGCACTGGTA
		CCGCCAGGCT		CCAACAGCGC
		CCAGGGAAGG		CCGGGCAGTC
		GGCTGGAGTG		CCCCCACCAC
		GGTAGGTTTC		TGTCATCTAT
		ATTAGAAGCA		AACGATAACC
		AAGCTTATGG		AAAGACCCTC
		TGGGACAACA		TGGAGTCCCT
		GAATACGCCG		GATCGGTTCT
		CGTCTGTGAA		CTGGGTCCAT
		AGGCAGATTC		CGACAGGTCC
		ACCATCTCAA		TCCAACTCTG
		GAGATGATTC		CCTCCCTCAC
		CAAAAGCATC		CATCTCTGGA
		GCCTATCTGC		CTGAAGACTG
		AAATGAACAG		AGGACGAGGC
		TCTGAGAGCC		TGACTACTAC
		GAGGACACGG		TGTCAGTCCT
		CCGTGTATTA		ACGATAGTAC
		CTGTGCGAGA		CACTTATGCA
		GAGGGGCTGT		TTCGGCGGAG
		TCCTGCCCCT		GGACCAAGCT
		GGGAGGTTTT		GACCGTCCTA
		GATTTATGGG
		GCCTAGGGAC
		AATGGTCACC
		GTCTCCTCA
HL161 10E	11	CAGGTGCAGC	155	TCCTATGAGC
		TGGTGGAGTC		TGACACAGCC
		TGGGGGAGGC		ACTCTCGGTG
		TTAGTACAGC		TCAATGTCCC
		CTGGGGGGTC		CAGGACAAAC
		CCTGAGACTC		GGCCAGGATC
		TCCTGTGCAG		ACCTGTTCTG
		CCTCTGGCTT		GAGATGCTTT
		CAGATTCAGC		GTCAAAGCAA
		AACTTTGCCA		TATGCTTCTT
		TGACCTGGGT		GGTACCAGCT
		CCGCCAGGCT		GAAGCCAGGC
		CCAGGGAAGG		CAGGCCCCTG
		GGCTGGAGTG		TGGTGGTGAT
		GGTCTCAACT		GTATAAAGAC
		CTTAGTGGTA		ACTGAGAGGC
		GTGGTGGTAG		CCTCAGGGAT
		TATACACCAC		CCCTGACCGA
		GCAGACTCCG		TTCTCTGGCT
		TGAAGGGCCG		CCAGCTCCGG
		ATTCACCATC		GACAACAGTC
		TCCAGAGACA		ACGTTGACCA
		ATTCCAAGAA		TCAGTGGAGT
		CACGCTGTAT		CCAGGCAGAA
		CTGCAAATGA		GACGAGGCTG
		ACAGTCTGAG		ATTATTACTG
		AGCCGAGGAC		TCAATCAATA
		ACGGCCGTGT		ACAGACAAGA
		ATTACTGTGC		GTGGTACTGA
		GAAAGGGCCC		TGTGATCTTC
		TTGAGGGGAC		GGCGGAGGGA
		AGCCGGCCTA		CCAAGCTGAC CGTCCTA
		CCTTGACCCC
		TGGGGCCAGG
		GAACCCTGGT
		CACCGTCTCC TCA
HL161-11G	13	CAGATGCAGC	157	AATTTTATGC
		TGGTGGAGTC		TGACTCAGCC
		GGGGGGAGGC		CGCCTCCGTG
		GTGGTCCAGC		TCTGGGTCCC
		CTGGGAGGTC		CTGGACAGTC
		TCTGAGACTC		GATCACCATC
		TCCTGTGTAG		TCCTGCACTG
		GGTCTGGATT		GAAGCAGCAG
		CAACTTCAAC		CGACGTTGGT
		AGTTATGGCA		GGTTATAACT
		TACACTGGGT		ATGTCTCCTG
		CCGCCAGGCT		GTACCAACAG
		CCAGGCAAGG		CACCCAGGCA
		GGCTGGAGTG		AAGCCCCCCA
		GGTGGGAGGA		ACTCATCATT
		ATATTTTATG		TATGATGTCA
		ATGGAAGTCA		CTAAGCGGCC
		AGTAAAGTAT		CTCAGGGGTT
		GCAGACTCCG		TCTAATCGAT
		TGAAGGGCCG		TCTCCGGCTC
		AGTCTCCATC		CAAGTCTGGC
		TATGCCATGA		AACTCGGCCT
		ATTCCAAGAA		CCCTGACCAT
		CACAGCGTAT		CTCTGGACTC
		CTGCAAATGA		CAGGCTGAGG
		ACAGTCTGAG		ACGAGGCTGA
		AGCCGAGGAC		TTATTACTGC
		ACGGCCGTGT		AGCTCATACA
		ATTACTGTGC		GCAGCAGCAC
		GCGACGAAAC		TTTTTACGTC
		CTCCTGGACT		TTCGGAACTG
		ACTGGGGCCA		GGACCAAGGT
		GGGAACGGTG		CACCGTCCTA
		GTCACCGTCT CCTCA
HL161-11H	15	CAGATGCAGC	159	GACATCCAGA
		TGGTAGAGTC		TGACCCAGTC
		TGGGGGAGGT		TCCTTCCACC
		TTGGTACAGC		CTGTCTGCAT
		CGGGCAGGTC		CTGTAGGAGA
		CCTGAGACTC		CAGAGTCACC
		TCCTGTGCAG		ATCACTTGCC
		CCTCTGGATT		GGGCCAGTCA
		CACCTTCAGT		GAGTATTAGT
		AGCTATGCTA		AGCCGGTTGG
		TGCACTGGGT		CCTGGTATCA
		CCGCCAGGCT		GCAGAAACCA
		CCAGGCAAGG		GGGAAAGCCC
		GGCTGGAGTG		CTAAGCTCCT
		GGTGGCAGTT		GATCTATAAG
		ATATCATATG		GCATCTAGCT
		ATGGAAGCAA		TAGAAACTGG
		TAAATACTAC		GGTCCCATCA
		GCAGACTCCG		AGGTTCAGCG
		TGAAGGGCCG		GCAGTGGATC
		ATTCACCATC		TGGGACAGAA
		TCCAGAGACA		TTCACTCTCA
		ATTCCAAGAA		CCATCAGCAG
		CACGCTGTAT		CCTGCAGCCT
		CTGCAAATGA		GATGATTTTG
		ACAGCCTGAG		CAACTTACTA
		ATCTGAGGAC		TTGTCAACAG
		ACGGCCGTGT		ACGAACAGTT
		ATTACTGTGC		TCCCTCTCAC
		GAGAGGTAGT		TTTCGGCGGA
		GGTGGTCGTG		GGGACCAAGG
		ACGCTTTTGA		TGGAGATCAA A
		TGTCTGGGGC
		CAAGGAACAA
		TGATCACCGT CTCCTCA

TABLE 4 — CDR sequences of heavy-chain and light-chain variable regions of selected antibodies CDR sequences of heavy-

	chain variable regions	CDR sequences of light-chain
	SEQ		variable regions
Antibody	ID				SEQ ID
name	NO:	CDR1	CDR2	CDR3	NO:	CDR1	CDR2	CDR3
HL161-	2	EYGMH	GVSWNSGS	GRSMDV	146	GPLRGQPAYL	DVTKRPS	SSYSSST
1A			IAYADSVRG			DP		FYV
HL161-	4	NYAVS	RIIPILGI	DRYGMDV	148	SGSSSNIGSN	RNNQRPS	ASWDDSL
2A			ANYAQTFQG			YVY		SGVV
HL161-	6	DYAMS	FIRSKAYG	EGLFLP	150	TRSSGSIAAN	NDNQRPS	QSYDSTT
2D			GTTEYAAS	LGGFDL		YVH		YAFGGGT
			VKG					KLTVLG
HL161-	8	SYYMH	IINPSGGS	GGGAFDI	152	RASQGISNWVA	AASSLQS	QQGHSFP
6C			TSYAQKFQG					YT
HL161-	10	DYAMS	FIRSKAYG	EGLFLP	154	TRSSGSIAAN	NDNQRPS	QSYDSTT
9F			GTTEYAAS	LGGFDL		YVH		YA
			VKG
HL161	12	NFAMT	TLSGSGGS	GPLRGQ	156	TRSSGSIAAN	DNQRPS	QSYDSTT
10E			IHHADSVKG	PAYLDP		YVH		YA
HL161-	14	SYGIH	GIFYDGSQ	RNLLDY	158	TGSSSDVGGY	DVTKRPS	SSYSSST
11G			VKYADSVKG			NYVS		FYV
HL161-	16	SYAMH	VISYDGSN	GSGGRD	160	RASQSISSRLA	KASSLET	QQTNSFP
11H			KYYADSVKG	AFDV				LT

TABLE 5 — Results of SPR analysis by FcRn immobilization shFcRn immobilization

Antibody	SPR (pH 6.0)	SPR (pH 7.4)
name	k on (M −1 s −1 )	k off (s −1 )	K D (M)	k on (M −1 s −1 )	k off (s −1 )	K D (M)
HL161-1A	4.0 × 10 6	3.2 × 10 −3	8.0 × 10 −10	1.1 × 10 6	9.3 × 10 −3	8.5 × 10 −9
HL161-2A	6.9 × 10 5	1.1 × 10 −3	1.6 × 10 −9	4.2 × 10 5	6.7 × 10 −4	1.6 × 10 −9
HL161-2D	6.9 × 10 5	6.8 × 10 −4	9.8 × 10 −10	3.8 × 10 5	1.7 × 10 −3	4.5 × 10 −9
HL161-6C	1.0 × 10 6	1.9 × 10 −3	1.9 × 10 −9	4.7 × 10 5	3.1 × 10 −3	6.6 × 10 −9
HL161-9F	7.5 × 10 5	7.0 × 10 −4	9.3 × 10 −10	4.5 × 10 5	1.6 × 10 −3	3.6 × 10 −9
HL161-10E	1.2 × 10 6	4.6 × 10 −3	3.8 × 10 −9	3.1 × 10 5	8.2 × 10 −3	2.6 × 10 −8
HL161-11G	1.2 × 10 6	1.9 × 10 −4	1.6 × 10 −10	5.2 × 10 5	1.2 × 10 −4	2.3 × 10 −10
HL161-11H	9.7 × 10 5	3.4 × 10 −4	3.5 × 10 −10	5.0 × 10 5	4.5 × 10 −4	9.0 × 10 −10
hIgG 1	3.2 × 10 5	4.6 × 10 −4	1.4 × 10 −9	No	No	No
				binding	binding	binding

TABLE 6 — Variable region sequences of 1Ag and 11Hg

	Heavy-chain	Light-chain
	variable regions	variable regions
Clone		Amino acid		Amino acid
name	SEQ ID NO:	sequences	SEQ ID NO:	sequences
1Ag	289	EVQLVESGGGLVQPGRSLRLSC	290	QSALTQPASVSGSPGQS
		AASGFTFDEYGMHWVRQAPGKG		ITISCTGSSSDVGGYNY
		LEWVSGVSWNSGSIAYADSVRG		VSWYQQHPGKAPKLMIY
		RFTISRDNAKNSLYLQMNSLRA		DVTKRPSGVSNRFSGSK
		EDTALYYCARGRYSDVWGQGTT		SGNTASLTISGLQAEDE
		VTVSSASTKGPSVFPLAPSSKS		ADYYCSSYSSSTFYVFG
		TSGGTAALGCLVKDYFPEPVTV		TGTKVTVLGRSVAAPSV
		SWNSGALTSGVHTFPAVLQSSG		FIFPPSDEQLKSGTASV
		LYSLSSVVTVPSSSLGTQTYIC		VCLLNNFYPREAKVQWK
		NVNHKPSNTKVDKKVEPKSCDK		VDNALQSGNSQESVTEQ
		THTCPPCPAPELLGGPSVFLFP		DSKDSTYSLSSTLTLSK
		PKPKDILMISRIPEVICVVVDV		ADYEKHKVYACEVTHQG
		SHEDPEVKFNWYVDGVEVHNAK		LSSPVTKSFNRGEC
		TKPREEQYNSTYRVVSVLTVLH
		QDWLNGKEYKCKVSNKALPAPI
		EKTISKAKGQPREPQVYTLPPS
		REEMTKNQVSLTCLVKGFYPSD
		IAVEWESNGQPENNYKTTPPVL
		DSDGSFFLYSKLTVDKSRWQQG
		NVFSCSVMHEALHNHYTQKSLS
		LSPGK
11Hg	291	QVQLVESGGGVVQPGRSLRLSC	292	DIQMTQSPSTLSASVGD
		AASGFTFSSYAMHWVRQAPGKG		RVTITCRASQSISSRLA
		LEWVAVISYDGSNKYYADSVKG		WYQQKPGKAPKLLIYKA
		RFTISRDNSKNTLYLQMNSLRA		SSLETGVPSRFSGSGSG
		EDTAVYYCARGSGGRDAFDVWG		TEFTLTISSLQPDDFAT
		QGTMITVSSASTKGPSVFPLAP		YYCQQTNSFPLTFGGGT
		SSKSTSGGTAALGCLVKDYFPE		KVEIKRSVAAPSVFIFP
		PVTVSWNSGALTSGVHTFPAVL		PSDEQLKSGTASVVCLL
		QSSGLYSLSSVVTVPSSSLGTQ		NNFYPREAKVQWKVDNA
		TYICNVNHKPSNTKVDKKVEPK		LQSGNSQESVTEQDSKD
		SCDKTHTCPPCPAPELLGGPSV		STYSLSSTLTLSKADYE
		FLFPPKPKDILMISRIPEVICV		KHKVYACEVTHQGLSSP
		VVDVSHEDPEVKFNWYVDGVEV		VTKSFNRGEC
		HNAKTKPREEQYNSTYRVVSVL
		TVLHQDWLNGKEYKCKVSNKAL
		PAPIEKTISKAKGQPREPQVYT
		LPPSREEMTKNQVSLTCLVKGF
		YPSDIAVEWESNGQPENNYKTT
		PPVLDSDGSFFLYSKLTVDKSR
		WQQGNVFSCSVMHEALHNHYTQ
		KSLSLSPGK

TABLE 7 — CDR sequences of 1Ag and 11Hg

	Heavy-chain variable regions	Light-chain variable regions
Clone	SEQ ID						SEQ ID
name	NO:	CDR1		SEQ ID NO:	CDR1		NO:	CDR1
1Ag	289	EYGMH	GVSWNSGSIAYADSVRG	GRSMDV	290	TGSSSDVGGYNYVS	DVTKRPS	SSYSSSTFYV
11Hg	291	SYAMH	VISYDGSNKYYADSVKG	GSGGRDAFDV	292	RASQSISSRLA	KASSLET	QQTNSFPLT

TABLE 8 — Results of ELISA and SPR analysis of 1Ag CDR-3 random mutations scFv

	ELISA	SPR Koff
	(OD450)	values
Clone name	(pH 6.0)	(pH 7.4)	(pH 6.0)	(pH 7.4)
B04	0.22	0.08	3.41E−04	3.10E−04
1Ag (parent)	0.35	0.38	2.22E−04	2.12E−04
A11-A01	1.31	0.86	1.49E−04	2.13E−03
A11-C07	3.50	2.40	3.93E−04	2.48E−03
A11-G06	1.48	0.99	2.25E−04	4.96E−04
A11-A02	0.93	0.80	1.69E−04	8.50E−04
A12-A03	0.60	0.86	3.43E−04	4.81E−04
A12-A05	0.87	0.56	6.57E−05	3.07E−04
A12-B02	1.06	0.74	1.29E−04	3.07E−04
A12-B03	1.03	0.86	1.58E−04	6.07E−04
A12-B04	ND	ND	2.73E−04	3.46E−03
A12-C01	0.59	0.46	2.93E−04	3.52E−04
A12-C04	0.95	0.71	2.88E−04	3.62E−04
A12-C09	1.63	1.30	1.77E−04	9.09E−04
A12-D02	0.64	0.60	1.61E−04	4.70E−04
A12-D04	0.42	0.44	8.51E−05	8.79E−04
A12-D05	1.21	1.16	1.31E−04	9.64E−04
A12-E01	1.71	1.05	5.99E−05	1.15E−03
A12-E04	1.59	1.29	1.32E−04	1.37E−03
A12-E05	2.06	1.80	2.16E−04	2.22E−03
A12-F02	2.17	2.40	3.05E−04	2.25E−04
A12-F05	0.43	0.42	1.29E−04	4.92E−04
A12-F08	1.08	0.74	1.08E−04	9.31E−04
A12-G05	0.68	0.50	7.01E−05	3.72E−04
A12-G07	0.74	0.71	1.05E−04	5.89E−04
A12-G08	0.74	0.64	1.33E−04	4.01E−04
A12-H01	0.49	0.40	3.38E−04	3.31E−04
A12-H04	2.26	1.57	2.20E−04	2.35E−03
A12-H06	1.13	0.99	2.76E−04	5.72E−04
A12-H08	0.93	0.84	2.44E−04	4.79E−04
A12-H09	1.26	1.30	3.88E−04	2.54E−04
A12-H51	0.59	0.68	2.72E−05	1.12E−03

TABLE 9 — Results of affinity maturation by 11Hg CDR-3 random mutations scFv

	ELISA	SPR K off
	(OD450)	values
Clone Name	(pH 6.0)	(pH 7.4)	(pH 6.0)	(pH 7.4)
B04	0.32	0.15	3.41E−04	3.10E−04
11Hg (parent)	0.24	0.42	4.34E−04	4.33E−04
H11-A02	0.29	0.36	2.29E−04	4.18E−04
H11-A03	0.38	0.68	2.44E−04	4.17E−04
H11-A05	0.27	0.27	3.45E−04	3.38E−04
H11-A07	0.22	0.70	2.17E−04	5.52E−04
H11-B03	0.28	0.39	4.30E−04	7.81E−04
H11-B04	0.16	0.09	5.43E−04	5.46E−04
H11-B07	0.21	0.45	6.99E−04	6.04E−04
H11-B08	0.19	0.12	1.15E−03	6.57E−04
H11-D07	0.33	0.47	1.60E−04	1.15E−03
H11-D08	0.20	0.62	3.81E−04	5.97E−04
H11-E03	0.17	0.07	3.65E−04	5.13E−04
H11-E05	0.23	0.20	5.46E−04	7.02E−04
H11-E08	0.20	0.80	2.59E−04	5.15E−04
H11-F04	0.18	0.21	9.02E−04	5.93E−04
H11-H05	0.15	0.04	3.01E−04	4.52E−04
H11-H06	0.15	0.09	5.25E−04	5.45E−04
H12-A01	0.26	0.36	4.57E−04	4.23E−04
H12-A09	0.21	0.54	1.50E−04	6.34E−04
H12-A11	0.22	0.24	3.72E−04	5.54E−04
H12-A12	0.14	0.11	2.62E−04	5.27E−04
H12-B01	0.22	0.12	3.24E−04	4.46E−04
H12-B09	0.26	0.49	2.96E−04	3.81E−04
H12-B11	0.15	0.58	3.63E−04	4.54E−04
H12-C09	0.16	0.16	2.83E−04	4.35E−04
H12-C10	ND	ND	ND	3.31E−03
H12-D12	0.17	0.12	5.90E−04	6.79E−04
H12-E12	ND	ND	2.57E−04	3.72E−04
H12-F09	0.40	0.58	1.40E−03	4.18E−04
H12-F10	ND	ND	2.39E−04	4.48E−04

TABLE 10 — Panning strategy of 1Ag sub-library

Strategy	Step	Factor	1 st Round	2 nd Round	3 rd Round	4 th Round
Strategy-1	Binding	Antigen	Biotin-	Biotin-	Biotin-	Biotin-
			hFcRn	hFcRn	hFcRn	hFcRn
		Competitor	—	—	—	—
		pH	6.0	6.0	6.0	6.0
	Wash	Competitor	shFcRn	shFcRn	shFcRn	shFcRn
		pH	7.4	7.4	7.4	7.4
Strategy-3	Binding	Antigen	Biotin-	Biotin-	Biotin-	Biotin-
			hFcRn	hFcRn	hFcRn	hFcRn
		Competitor	IgG	IgG	IgG	IgG
		pH	6.0	6.0	6.0	6.0
	Wash	Competitor	shFcRn	shFcRn	shFcRn	shFcRn
		pH	7.4	7.4	7.4	7.4
Strategy-4	Binding	Antigen	Biotin-	Biotin-	293-hFcRn	293-hFcRn
			hFcRn	hFcRn
		Competitor	IgG	IgG	IgG	IgG
		pH	6.0	6.0	6.0	6.0
	Wash	Competitor	shFcRn	shFcRn	shFcRn	shFcRn
		pH	7.4	7.4	7.4	7.4
Strategy-5	Binding	Antigen	Biotin-	Biotin-	293-hFcRn	293-hFcRn
			hFcRn	hFcRn
		Competitor	IgG	IgG	—	—
		pH	6.0	6.0	6.0	6.0
	Wash	Competitor	shFcRn	shFcRn	shFcRn	shFcRn
		pH	7.4	7.4	7.4	7.4

TABLE 11 — Panning strategy of 11Hg sub-library

Strategy	Step	Factor	1 st Round	2 nd Round	3 rd Round	4 th Round
Strategy-1	Binding	Antigen	Biotin-	Biotin-hFcRn	Biotin-	Biotin-
			hFcRn		hFcRn	hFcRn
		Competitor	—	—	—	—
		pH	6.0	6.0	6.0	6.0
	Wash	Competitor	shFcRn	shFcRn	shFcRn	shFcRn
		pH	7.4	7.4	7.4	7.4
Strategy-3	Binding	Antigen	Biotin-	Biotin-hFcRn	Biotin-	Biotin-
			hFcRn		hFcRn	hFcRn
		Competitor	—	IgG	IgG	IgG
		pH	6.0	6.0	6.0	6.0
	Wash	Competitor	shFcRn	shFcRn	shFcRn	shFcRn
		pH	7.4	7.4	7.4	7.4
Strategy-4	Binding	Antigen	Biotin-	Biotin-hFcRn	293-hFcRn	293-hFcRn
			hFcRn
		Competitor	—	IgG	IgG	IgG
		pH	6.0	6.0	6.0	6.0
	Wash	Competitor	shFcRn	shFcRn	shFcRn	shFcRn
		pH	7.4	7.4	7.4	7.4
Strategy-5	Binding	Antigen	Biotin-	Biotin-hFcRn	293-hFcRn	293-hFcRn
			hFcRn
		Competitor	—	IgG	—	—
		pH	6.0	6.0	6.0	6.0
	Wash	Competitor	shFcRn	shFcRn	shFcRn	shFcRn
		pH	7.4	7.4	7.4	7.4

TABLE 12 — Results of affinity maturation by 1Ag CDR-1 and CDR-2 mutations Partially purified scFv K off values (fold)

			pH 6.0	pH 7.4
ELISA (fold)		Two state	Two state
Clone name	pH 6.0	pH 7.4	kd1	kd1
B04	1.7	1.5	10.7	33.7
1Ag	1.0	1.0	1.0	1.0
A23-3H04	25.4	25.8	27.3	11.6
A21-4C03	21.8	18.8	41.6	14.6
A24-1G10	18.0	26.2	37.7	16.7
A24-1F07	17.5	24.7	29.2	16.5
A21-4B10	17.4	25.9	36.3	19.9
A21-4G04	17.1	24.0	11.2	5.7
A23-3H05	15.0	20.1	20.9	10.0
A21-3A09	14.2	25.2	18.8	10.8
A21-4B06	13.7	17.4	7.2	3.8
A24-1B05	12.8	20.8	26.2	11.6
A23-3A08	11.1	24.0	32.6	18.3
A21-4C08	10.5	19.6	12.1	6.9
A23-4D09	10.4	15.5	24.1	10.5
A23-3D03	10.1	19.8	21.3	9.3
A21-4B03	9.1	16.1	11.2	6.7
A21-3D10	8.5	18.3	19.5	13.1
A21-3A10	7.9	25.6	23.3	14.5
A21-4H04	7.2	23.8	11.8	8.1
A21-4F11	5.7	19.6	13.1	5.9
A23-3G05	5.5	25.0	53.2	22.7
A23-3A10	5.0	15.9	9.3	5.4
A25-1H04	5.0	20.4	47.0	2.6
A23-3B06	4.8	22.8	41.8	10.5
A23-4A09	4.7	17.1	28.4	7.2
A25-1D09	4.5	26.6	42.1	43.0
A21-4E10	4.0	24.3	21.9	12.0
A23-3C04	3.8	20.3	24.8	7.7
A23-3G06	3.1	6.0	12.9	4.6
A24-1E09	3.1	14.8	11.2	5.9
A23-3F03	3.1	20.7	17.9	11.2
A21-4F07	2.9	16.2	8.7	4.1
A24-1A03	2.8	11.5	5.9	3.8
A24-1H11	2.7	21.7	19.5	10.5
A21-3D09	2.5	16.9	11.8	7.2
A24-1D10	2.3	18.6	32.6	8.9
A21-4B04	2.3	9.3	24.5	8.0
A23-4C12	2.2	23.8	16.7	9.5
A21-4G06	2.1	17.3	9.4	5.4
A23-3E04	2.0	12.9	10.4	5.4
A24-1C09	2.0	13.1	5.1	2.8
A24-1C04	2.0	8.9	3.4	2.9
A25-1H10	1.9	15.1	11.9	6.5
A21-4D08	1.6	5.5	9.0	4.8
A24-1D08	1.4	9.4	5.9	5.0
A24-1A08	1.4	4.1	5.1	2.3
A21-4A07	1.3	9.1	7.0	3.9
A24-1B09	1.2	9.6	5.8	3.7
A24-1E07	1.2	3.3	4.8	2.2

TABLE 13 — Results of affinity maturation by 11Hg CDR-1 and CDR-2 mutations Partially purified scFv K off values (fold)

			pH 6.0	pH 7.4
ELISA (fold)		Two state	Two state
Clone name	pH 6.0	pH 7.4	kd1	kd1
H11-B04	1.3	1.6	1.372	9.611
11Hg	1.0	1.0	1.000	1.000
H21-3A07	1.0	4.2	1.075	1.499
H21-4D11	0.7	3.6	0.001	0.000
H21-3C11	1.9	10.9	1.363	1.468
H21-3A09	0.7	0.2	0.174	0.002
H21-4H04	0.9	5.7	0.893	1.233
H23-3D08	3.7	7.0	2.891	1.893
H21-4D09	ND	ND	NA	NA
H24-1D11	1.0	1.0	NA	NA

TABLE 14 — Amino acid sequences of heavy-chain and light- chain variable regions of selected antibodies

	Heavy-chain	Light-chain
	variable regions	variable regions
Antibody	SEQ ID	Amino acid		Amino acid
name	NO:	sequences	SEQ ID NO:	Sequences
A11-007	18	EVQLVESGGGLVQPGRSLR	162	QSALTQPASVSGSPGQSI
		LSCAASGFTFDEYGMHWVR		TISCTGSSSDVGGYNYVS
		QAPGKGLEWVSGVSWNSGS		WYQQHPGKAPKLMIYDVT
		IAYADSVRGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYA
		CAKGRYSDVWGQGTTVTVS		SYSSNTFYVFGTGTKVTV
		S		LG
A11-G06	20	EVQLVESGGGLVQPGRSLR	164	QSALTQPASVSGSPGQSI
		LSCAASGFTFDEYGMHWVR		TISCTGSSSDVGGYNYVS
		QAPGKGLEWVSGVSWNSGS		WYQQHPGKAPKLMIYDVT
		IAYADSVRGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYG
		CAKGRLMDVWGQGTTVTVS		SYNNNTFYVFGTGTKVTV
		S		LG
A12-C09	22	EVQLVESGGGLVQPGRSLR	166	QSALTQPASVSGSPGQSI
		LSCAASGFTFDEYGMHWVR		TISCTGSSSDVGGYNYVS
		QAPGKGLEWVSGVSWNSGS		WYQQHPGKAPKLMIYDVT
		IAYADSVRGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYG
		CAKGRTMDVWGQGTTVTVS		SYSSNTFYVFGTGTKVTV
		S		LG
A12-E05	24	EVQLVESGGGLVQPGRSLR	168	QSALTQPASVSGSPGQSI
		LSCAASGFTFDEYGMHWVR		TISCTGSSSDVGGYNYVS
		QAPGKGLEWVSGVSWNSGS		WYQQHPGKAPKLMIYDVT
		IAYADSVRGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYG
		CAKGRILDVWGQGTTVTVS		SYNNSTFYVFGTGTKVTV
		S		LG
A12-E01	26	EVQLVESGGGLVQPGRSLR	170	QSALTQPASVSGSPGQSI
		LSCAASGFTFDEYGMHWVR		TISCTGSSSDVGGYNYVS
		QAPGKGLEWVSGVSWNSGS		WYQQHPGKAPKLMIYDVT
		IAYADSVRGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYG
		CAKSRSMDVWGQGTTVTVS		SYSNNNFYVFGTGTKVTV
		S		LG
A12-E04	28	EVQLVESGGGLVQPGRSLR	172	QSALTQPASVSGSPGQSI
		LSCAASGFTFDEYGMHWVR		TISCTGSSSDVGGYNYVS
		QAPGKGLEWVSGVSWNSGS		WYQQHPGKAPKLMIYDVT
		IAYADSVRGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYG
		CAKGRLFDVWGQGTTVTVS		SYSNSNFYVFGTGTKVTV
		S		LG
A12-F02	30	EVQLVESGGGLVQPGRSLR	174	QSALTQPASVSGSPGQSI
		LSCAASGFTFDEYGMHWVR		TISCTGSSSDVGGYNYVS
		QAPGKGLEWVSGVSWNSGS		WYQQHPGKAPKLMIYDVT
		IAYADSVRGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYG
		CAKGRYLDVWGQGTTVTVS		SYDSNTFYVFGTGTKVTV
		S		LG
A12-H04	32	EVQLVESGGGLVQPGRSLR	176	QSALTQPASVSGSPGQSI
		LSCAASGFTFDEYGMHWVR		TISCTGSSSDVGGYNYVS
		QAPGKGLEWVSGVSWNSGS		WYQQHPGKAPKLMIYDVT
		IAYADSVRGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYG
		CAKGRLLDVWGQGTTVTVS		AYSNTNFYVFGTGTKVTV
		S		LG
A23-3H04	34	EVQLVESGGGLVQPGRSLR	178	QSALTQPASVSGSPGQSI
		LSCAASGFTFDTYGMNWVR		TISCGGSSSDVGGYNYVS
		QAPGKGLEWVSGISYNSGT		WYQQHPGKAPKLMIYDVN
		TAYADSVRGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYDSNTFYVFGTGTKVT
		S		VLG
A21-4C03	36	EVQLVESGGGLVQPGRSLR	180	QSALTQPASVSGSPGQSI
		LSCAASGFTFDAYGMNWVR		TISCTGSSSDIGGYNYVS
		QAPGKGLEWVSGISYNSGT		WYQQHPGKAPKLMIYDVS
		IAYADSVKGRFTISRDNAK		DRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYSSNTFYVFGTGTKVT
		S		VLG
A24-1G10	38	EVQLVESGGGLVQPGRSLR	182	QSALTQPASVSGSPGQSI
		LSCAASGFTFDAYGMHWVR		TISCGGSSSNIGGYNYVS
		QAPGKGLEWVSGISYNSGT		WYQQHPGKAPKLMIYDVN
		KAYADSVKGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		ASYSNSNFYVFGTGTKVT
		S		VLG
A24-1F07	40	EVQLVESGGGLVQPGRSLR	184	QSALTQPASVSGSPGQSI
		LSCAASGFTFDAYGMHWVR		TISCSGSSSNVGSYNYVS
		QAPGKGLEWVSGVSYNSGT		WYQQHPGKAPKLMIYDVT
		TAYADSVRGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYSNSNFYVFGTGTKVT
		S		VLG
A21-4B10	42	EVQLVESGGGLVQPGRSLR	186	QSALTQPASVSGSPGQSI
		LSCAASGFTFDEYGMHWVR		TISCSGSSSNIGGYNYVS
		QAPGKGLEWVSGISYNSGN		WYQQHPGKAPKLMIYDVS
		KAYADSVRGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYDSNTFYVFGTGTKVT
		S		VLG
A21-4G04	44	EVQLVESGGGLVQPGRSLR	188	QSALTQPASVSGSPGQSI
		LSCAASGFTFDSYGMHWVR		TISCSGSSSNIGGYNYVS
		QAPGKGLEWVSGISYNGGN		WYQQHPGKAPKLMIYDVN
		TAYADSVRGRFTISRDNAK		ERPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYSNNNFYVFGTGTKVT
		S		VLG
A23-3H05	46	EVQLVESGGGLVQPGRSLR	190	QSALTQPASVSGSPGQSI
		LSCAASGFTFDAYGMNWVR		TISCGGSSSNVGGYNYVS
		QAPGKGLEWVSGISYNSGT		WYQQHPGKAPKLMIYDVS
		IAYADSVKGRFTISRDNAK		NRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYSNSNFYVFGTGTKVT
		S		VLG
A21-3A09	48	EVQLVESGGGLVQPGRSLR	192	QSALTQPASVSGSPGQSI
		LSCAASGFTFDNYGMNWVR		TISCSGSSSDIGGYNYVS
		QAPGKGLEWVSGISYNSGT		WYQQHPGKAPKLMIYDVN
		KAYADSVKGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		ASYSSNTFYVFGTGTKVT
		S		VLG
A21-4B06	50	EVQLVESGGGLVQPGRSLR	194	QSALTQPASVSGSPGQSI
		LSCAASGFTFDSYGMHWVR		TISCSGSSSNIGSYNYVS
		QAPGKGLEWVSGISYNGGS		WYQQHPGKAPKLMIYDVT
		KAYADSVRGRFTISRDNAK		DRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYSSNTFYVFGTGTKVT
		S		VLG
A24-1B05	52	EVQLVESGGGLVQPGRSLR	196	QSALTQPASVSGSPGQSI
		LSCAASGFTFDKYGMNWVR		TISCAGSSSDIGGYNYVS
		QAPGKGLEWVSGISYNSGN		WYQQHPGKAPKLMIYDVS
		TAYADSVRGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYDSNTFYVFGTGTKVT
		S		VLG
A23-3A08	54	EVQLVESGGGLVQPGRSLR	198	QSALTQPASVSGSPGQSI
		LSCAASGFTFDAYGMHWVR		TISCAGSSSNIGGYNYVS
		QAPGKGLEWVSGISYNSGT		WYQQHPGKAPKLMIYDVS
		TAYADSVKGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYSNSNFYVFGTGTKVT
		S		VLG
A21-4C08	56	EVQLVESGGGLVQPGRSLR	200	QSALTQPASVSGSPGQSI
		LSCAASGFTFDTYGMHWVR		TISCSGSSSNVGSYNYVS
		QAPGKGLEWVSGISYNAGN		WYQQHPGKAPKLMIYDVN
		KAYADSVRGRFTISRDNAK		NRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYSSNTFYVFGTGTKVT
		S		VLG
A23-4D09	58	EVQLVESGGGLVQPGRSLR	202	QSALTQPASVSGSPGQSI
		LSCAASGFTFDAYGMHWVR		TISCSGSSSNIGSYNYVS
		QAPGKGLEWVSGVSYDAGN		WYQQHPGKAPKLMIYDVT
		TAYADSVRGRFTISRDNAK		DRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYSSNTFYVFGTGTKVT
		S		VLG
A23-3D03	60	EVQLVESGGGLVQPGRSLR	204	QSALTQPASVSGSPGQSI
		LSCAASGFTFDAYGMNWVR		TISCTGSSSDVGGYNYVS
		QAPGKGLEWVSGISYNAGS		WYQQHPGKAPKLMIYDVT
		TAYADSVRGRFTISRDNAK		NRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYDSNTFYVFGTGTKVT
		S		VLG
A21-1B03	62	EVQLVESGGGLVQPGRSLR	206	QSALTQPASVSGSPGQSI
		LSCAASGFTFDAYGMNWVR		TISCSGSSSNIGSYNYVS
		QAPGKGLEWVSGISYNAGN		WYQQHPGKAPKLMIYDVN
		KAYADSVRGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		ASYSSNTFYVFGTGTKVT
		S		VLG
A21-3D10	64	EVQLVESGGGLVQPGRSLR	208	QSALTQPASVSGSPGQSI
		LSCAASGFTFDNYGMHWVR		TISCGGTSSNIGSYNYVS
		QAPGKGLEWVSGISYDAGT		WYQQHPGKAPKLMIYDVT
		TAYADSVKGRFTISRDNAK		NRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYSNTNFYVFGTGTKVT
		S		VLG
A21-3A10	66	EVQLVESGGGLVQPGRSLR	210	QSALTQPASVSGSPGQSI
		LSCAASGFTFDAYGMHWVR		TISCAGSSSNIGGYNYVS
		QAPGKGLEWVSGISYNAGN		WYQQHPGKAPKLMIYDVS
		KAYADSVRGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYSNSNFYVFGTGTKVT
		S		VLG
A21-4H04	68	EVQLVESGGGLVQPGRSLR	212	QSALTQPASVSGSPGQSI
		LSCAASGFTFDSYGMHWVR		TISCSGTSSDIGGYNYVS
		QAPGKGLEWVSGISYNSGN		WYQQHPGKAPKLMIYDVS
		KAYADSVKGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYSNNNFYVFGTGTKVT
		S		VLG
A21-4F11	70	EVQLVESGGGLVQPGRSLR	214	QSALTQPASVSGSPGQSI
		LSCAASGFTFDAYGMNWVR		TISCGGTSSNIGGYNYVS
		QAPGKGLEWVSGISYNGGT		WYQQHPGKAPKLMIYDVN
		KAYADSVRGRFTISRDNAK		DRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		ASYSSNTFYVFGTGTKVT
		S		VLG
A23-3G05	72	EVQLVESGGGLVQPGRSLR	216	QSALTQPASVSGSPGQSI
		LSCAASGFTFDTYGMHWVR		TISCAGSSSNIGSYNYVS
		QAPGKGLEWVSGISYNSGT		WYQQHPGKAPKLMIYDVS
		IAYADSVRGRFTISRDNAK		NRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYDSNTFYVFGTGTKVT
		S		VLG
A23-3A10	74	EVQLVESGGGLVQPGRSLR	218	QSALTQPASVSGSPGQSI
		LSCAASGFTFDKYGMHWVR		TISCAGSSSNIGGYNYVS
		QAPGKGLEWVSGISYNAGS		WYQQHPGKAPKLMIYDVS
		KAYADSVKGRFTISRDNAK		DRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYDSNTFYVFGTGTKVT
		S		VLG
A25-1H04	76	EVQLVESGGGLVQPGRSLR	220	QSALTQPASVSGSPGQSI
		LSCAASGFTFDAYGMNWVR		TISCAGSSSDIGGYNYVS
		QAPGKGLEWVSGISYNSGN		WYQQHPGKAPKLMIYDVS
		TAYADSVRGRFTISRDNAK		ERPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYDSNTFYVFGTGTKVT
		S		VLG
A23-3B06	78	EVQLVESGGGLVQPGRSLR	222	QSALTQPASVSGSPGQSI
		LSCAASGFTFDAYGMHWVR		TISCSGSSSDVGGYNYVS
		QAPGKGLEWVSGISYNSGS		WYQQHPGKAPKLMIYDVS
		KAYADSVKGRFTISRDNAK		ERPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYDSNTFYVFGTGTKVT
		S		VLG
A23-4A09	80	EVQLVESGGGLVQPGRSLR	224	QSALTQPASVSGSPGQSI
		LSCAASGFTFDNYGMNWVR		TISCGGSSSNIGGYNYVS
		QAPGKGLEWVSGISYDSGN		WYQQHPGKAPKLMIYDVT
		KAYADSVKGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		ASYSSNTFYVFGTGTKVT
		S		VLG
A25-1D09	82	EVQLVESGGGLVQPGRSLR	226	QSALTQPASVSGSPGQSI
		LSCAASGFTFDAYGMHWVR		TISCGGTSSDVGSYNYVS
		QAPGKGLEWVSGISYNGGT		WYQQHPGKAPKLMIYDVN
		IAYADSVKGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYSNSNFYVFGTGTKVT
		S		VLG
A21-4E10	84	EVQLVESGGGLVQPGRSLR	228	QSALTQPASVSGSPGQSI
		LSCAASGFTFDAYGMNWVR		TISCTGSSSNVGGYNYVS
		QAPGKGLEWVSGVSYNAGN		WYQQHPGKAPKLMIYDVS
		KAYADSVRGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYSSNTFYVFGTGTKVT
		S		VLG
A23-3C04	86	EVQLVESGGGLVQPGRSLR	230	QSALTQPASVSGSPGQSI
		LSCAASGFTFDTYGMHWVR		TISCSGTSSDIGGYNYVS
		QAPGKGLEWVSGISYDSGT		WYQQHPGKAPKLMIYDVT
		TAYADSVKGRFTISRDNAK		EPPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		ASYSSNTFYVFGTGTKVT
		S		VLG
A23-3G06	88	EVQLVESGGGLVQPGRSLR	232	QSALTQPASVSGSPGQSI
		LSCAASGFTFDAYGMNWVR		TISCAGTSSNIGGYNYVS
		QAPGKGLEWVSGISYNSGN		WYQQHPGKAPKLMIYDVN
		IAYADSVRGRFTISRDNAK		DRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYDSNTFYVFGTGTKVT
		S		VLG
A24-1E09	90	EVQLVESGGGLVQPGRSLR	234	QSALTQPASVSGSPGQSI
		LSCAASGFTFDKYGMHWVR		TISCTGSSSNIGGYNYVS
		QAPGKGLEWVSGVSYNAGT		WYQQHPGKAPKLMIYDVT
		TAYADSVRGRFTISRDNAK		NRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYSNSNFYVFGTGTKVT
		S		VLG
A23-3F03	92	EVQLVESGGGLVQPGRSLR	236	QSALTQPASVSGSPGQSI
		LSCAASGFTFDTYGMHWVR		TISCGGSSSNIGSYNYVS
		QAPGKGLEWVSGISYNSGN		WYQQHPGKAPKLMIYDVT
		IAYADSVKGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYDSNTFYVFGTGTKVT
		S		VLG
A21-4F07	94	EVQLVESGGGLVQPGRSLR	238	QSALTQPASVSGSPGQSI
		LSCAASGFTFDAYGMNWVR		TISCSGTSSNVGGYNYVS
		QAPGKGLEWVSGISYNAGN		WYQQHPGKAPKLMIYDVS
		KAYADSVKGRFTISRDNAK		DRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYSNSNFYVFGTGTKVT
		S		VLG
A24-1A03	96	EVQLVESGGGLVQPGRSLR	240	QSALTQPASVSGSPGQSI
		LSCAASGFTFDAYGMNWVR		TISCGGSSSNVGGYNYVS
		QAPGKGLEWVSGISYNAGN		WYQQHPGKAPKLMIYDVS
		TAYADSVKGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYSNSNFYVFGTGTKVT
		S		VLG
A24-1H11	98	EVQLVESGGGLVQPGRSLR	242	QSALTQPASVSGSPGQSI
		LSCAASGFTFDAYGMHWVR		TISCTGSSSDVGGYNYVS
		QAPGKGLEWVSGISYNSGT		WYQQHPGKAPKLMIYEVN
		TAYADSVRGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		ASYSSNTFYVFGTGTKVT
		S		VLG
A21-3D09	100	EVQLVESGGGLVQPGRSLR	244	QSALTQPASVSGSPGQSI
		LSCAASGFTFDNYGMNWVR		TISCSGTSSNVGGYNYVS
		QAPGKGLEWVSGISYNSGT		WYQQHPGKAPKLMIYDVN
		KAYADSVKGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYSNSNFYVFGTGTKVT
		S		VLG
A24-1D10	102	EVQLVESGGGLVQPGRSLR	246	QSALTQPASVSGSPGQSI
		LSCAASGFTFDNYGMHWVR		TISCSGSSSDIGGYNYVS
		QAPGKGLEWVSGISYNSGN		WYQQHPGKAPKLMIYDVT
		KAYADSVKGRFTISRDNAK		DRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYSNNNFYVFGTGTKVT
		S		VLG
A21-4B04	104	EVQLVESGGGLVQPGRSLR	248	QSALTQPASVSGSPGQSI
		LSCAASGFTFDAYGMHWVR		TISCAGTSSNIGGYNYVS
		QAPGKGLEWVSGISYDAGN		WYQQHPGKAPKLMIYDVS
		IAYADSVRGRFTISRDNAK		NRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		ASYSSNTFYVFGTGTKVT
		S		VLG
A23-4C12	106	EVQLVESGGGLVQPGRSLR	250	QSALTQPASVSGSPGQSI
		LSCAASGFTFDAYGMNWVR		TISCSGTSSDVGGYNYVS
		QAPGKGLEWVSGVSYNSGN		WYQQHPGKAPKLMIYDVT
		KAYADSVRGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYSSNTFYVFGTGTKVT
		S		VLG
A21-4G06	108	EVQLVESGGGLVQPGRSLR	252	QSALTQPASVSGSPGQSI
		LSCAASGFTFDTYGMNWVR		TISCAGSSSNVGGYNYVS
		QAPGKGLEWVSGISYNAGT		WYQQHPGKAPKLMIYDVT
		KAYADSVRGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYSNSNFYVFGTGTKVT
		S		VLG
A23-3E04	110	EVQLVESGGGLVQPGRSLR	254	QSALTQPASVSGSPGQSI
		LSCAASGFTFDEYGMHWVR		TISCTGSSSDVGGYNYVS
		QAPGKGLEWVSGVSWNSGS		WYQQHPGKAPKLMIYDVT
		IAYADSVRGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		SSYSSSTFYVFGTGTKVT
		S		VLG
A24-1C09	112	EVQLVESGGGLVQPGRSLR	256	QSALTQPASVSGSPGQSI
		LSCAASGFTFDAYGMNWVR		TISCTGTSSNVGSYNYVS
		QAPGKGLEWVSGISYNGGN		WYQQHPGKAPKLMIYDVN
		KAYADSVRGRFTISRDNAK		DRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYDSNTFYVFGTGTKVT
		S		VLG
A24-1C04	114	EVQLVESGGGLVQPGRSLR	258	QSALTQPASVSGSPGQSI
		LSCAASGFTFDGYGMHWVR		TISCTGTSSNIGGYNYVS
		QAPGKGLEWVSGISYNSGS		WYQQHPGKAPKLMIYDVT
		TAYADSVRGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYSNSNFYVFGTGTKVT
		S		VLG
A25-1H10	116	EVQLVESGGGLVQPGRSLR	260	QSALTQPASVSGSPGQSI
		LStABLE		TISCGGSSSDVGGYNYVS
		14ASGFTFDAYGMHWVRQA		WYQQHPGKAPKLMIYEVS
		PGKGLEWVSGVSYNAGTTA		NRPSGVSNRFSGSKSGNT
		YADSVRGRFTISRDNAKNS		ASLTISGLQAEDEADYYC
		LYLQMNSLRAEDTALYYCA		GSYSNSNFYVFGTGTKVT
		KGRSMDVWGQGTTVTVSS		VLG
A21-4D08	118	EVQLVESGGGLVQPGRSLR	262	QSALTQPASVSGSPGQSI
		LSCAASGFTFDTYGMHWVR		TISCGGTSSDVGGYNYVS
		QAPGKGLEWVSGVSYNSGN		WYQQHPGKAPKLMIYDVN
		KAYADSVKGRFTISRDNAK		DRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYSNNNFYVFGTGTKVT
		S		VLG
A24-1D08	120	EVQLVESGGGLVQPGRSLR	264	QSALTQPASVSGSPGQSI
		LSCAASGFTFDNYGMHWVR		TISCAGSSSNVVSYNYVS
		QAPGKGLEWVSGVSYNSGN		WYQQHPGKAPKLMIYDVN
		TGYADSVRGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYDSNTFYVFGTGTKVT
		S		VLG
A24-1A08	122	EVQLVESGGGLVQPGRSLR	266	QSALTQPASVSGSPGQSI
		LSCAASGFTFDAYGMHWVR		TISCTGSSSNIGGYNYVS
		QAPGKGLEWVSGISYDAGN		WYQQHPGKAPKLMIYEVN
		TAYADSVRGRFTISRDNAK		NRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		ASYSSNTFYVFGTGTKVT
		S		VLG
A21-4A07	124	EVQLVESGGGLVQPGRSLR	268	QSALTQPASVSGSPGQSI
		LSCAASGFTFDTYGMHWVR		TISCAGSSSNIGGYNYVS
		QAPGKGLEWVSGVSYNSGS		WYQQHPGKAPKLMIYDVN
		KAYADSVKGRFTISRDNAK		DRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYSNSNFYVFGTGTKVT
		S		VLG
A24-1B09	126	EVQLVESGGGLVQPGRSLR	270	QSALTQPASVSGSPGQSI
		LSCAASGFTFDRYGMHWVR		TISCTGTSSNIGSYNYVS
		QAPGKGLEWVSGVSYDGGT		WYQQHPGKAPKLMIYDVN
		TAYADSVRGRFTISRDNAK		KRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYDSNTFYVFGTGTKVT
		S		VLG
A24-1E07	128	EVQLVESGGGLVQPGRSLR	272	QSALTQPASVSGSPGQSI
		LSCAASGFTFDEYGMHWVR		TISCAGSSSNVGGYNYVS
		QAPGKGLEWVSGISYDAGS		WYQQHPGKAPKLMIYEVS
		TAYADSVRGRFTISRDNAK		NRPSGVSNRFSGSKSGNT
		NSLYLQMNSLRAEDTALYY		ASLTISGLQAEDEADYYC
		CARGRYSDVWGQGTTVTVS		GSYDSNTFYVFGTGTKVT
		S		VLG
H21-3A07	130	QVQLVESGGGVVQPGRSLR	274	DIQMTQSPSTLSASVGDR
		LSCAASGFTFSNYYMNWVR		VTITCRASQSISNRLAWY
		QAPGKGLEWVTVSYDSGNK		QQKPGKAPKLLIYKASNL
		YYADSVKGRFTISRDNSKN		ESGVPSRFSGSGSGTEFT
		TLYLQMNSLRAEDTAVYYC		LTISSLQPDDFATYYCQQ
		ARGSRRDAFDVWGQGTMVT		TNSFPLTFGGGTKVEIKR
		VSSA		TV
H21-4D11	132	QVQLVESGGGVVQPGRSLR	276	DIQMTQSPSTLSASVGDR
		LSCAASGFTFSNYAMNWVR		VTITCQASQGISNRLAWY
		QAPGKGLEWVIISYDSSSK		QQKPGKAPKLLIYKASNL
		YYADSVKGRFTISRDNSKN		QSGVPSRFSGSGSGTEFT
		TLYLQMNSLRAEDTAVYYC		LTISSLQPDDFATYYCQQ
		ARGSGKRDAFDVWGQGTMV		TNSFPLTFGGGTKVEIKR
		TVSSA		TV
H21-3C11	134	QVQLVESGGGVVQPGRSLR	278	DIQMTQSPSTLSASVGDR
		LSCAASGFTFSNYAMHWVR		VTITCRASQSISNRLAWY
		QAPGKGLEWVVVSYDGGNI		QQKPGKAPKLLIYKASSL
		YYADSVKGRFTISRDNSKN		QSGVPSRFSGSGSGTEFT
		TLYLQMNSLRAEDTAVYYC		LTISSLQPDDFATYYCQQ
		ARGSGRRDAFDVWGQGTMV		TNSFPLTFGGGTKVEIKR
		TVSSA		TV
H21-3A09	136	QVQLVESGGGVVQPGRSLR	280	DIQMTQSPSTLSASVGDR
		LSCAASGFTFSNYDIHWVR		VTITCRASQSISNRLAWY
		QAPGKGLEWVVVSYDGSNT		QQKPGKAPKLLIYKASNL
		YYADSVKGRFTISRDNSKN		QSGVPSRFSGSGSGTEFT
		TLYLQMNSLRAEDTAVYYC		LTISSLQPDDFATYYCQQ
		ARGSGKRDAFDVWGQGTMV		TNSFPLTFGGGTKVEIKR
		TVSSA		TV
H21-4H04	138	QVQLVESGGGVVQPGRSLR	282	DIQMTQSPSTLSASVGDR
		LSCAASGFTFSSYAIHWVR		VTITCQASQSISSRLAWY
		QAPGKGLEWVVVSYDGGSK		QQKPGKAPKLLIYKASSL
		YYADSVKGRFTISRDNSKN		QSGVPSRFSGSGSGTEFT
		TLYLQMNSLRAEDTAVYYC		LTISSLQPDDFATYYCQQ
		ARGSGRRDAFDVWGQGTMV		TNSFPLTFGGGTKVEIKR
		TVSSA		TV
H23-3D08	140	QVQLVESGGGVVQPGRSLR	284	DIQMTQSPSTLSASVGDR
		LSCAASGFTFSDYDMHWVR		VTITCQASQGISNRLAWY
		QAPGKGLEWVVISYDGGSK		QQKPGKAPKLLIYKASNL
		YYADSVKGRFTISRDNSKN		ETGVPSRFSGSGSGTEFT
		TLYLQMNSLRAEDTAVYYC		LTISSLQPDDFATYYCQQ
		ARGSGQRDAFDVWGQGTMV		TNSFPLTFGGGTKVEIKR
		TVSSA		TV
H21-4D09	142	QVQLVESGGGVVQPGRSLR	286	DIQMTQSPSTLSASVGDR
		LSCAASGFTFSNYYINWVR		VTITCQASQGIRNRLAWY
		QAPGKGLEWVSVSYDGGSI		QQKPGKAPKLLIYKASNL
		YYADSVKGRFTISRDNSKN		QSGVPSRFSGSGSGTEFT
		TLYLQMNSLRAEDTAVYYC		LTISSLQPDDFATYYCQQ
		ARGSGRRDAFDVWGQGTMV		TNSFPLTFGGGTKVEIKR
		TVSSA		TV
H24-1D11	144	QVQLVESGGGVVQPGRSLR	288	DIQMTQSPSTLSASVGDR
		LSCAASGFTFSSYAMHWVR		VTITCRASQSISSRLAWY
		QAPGKGLEWVAVISYDGSN		QQKPGKAPKLLIYKASSL
		KYYADSVKGRFTISRDNSK		ETGVPSRFSGSGSGTEFT
		NTLYLQMNSLRAEDTAVYY		LTISSLQPDDFATYYCQQ
		CARGSGGRDAFDVWGQGTM		TNSFPLTFGGGTKVEIKR
		VTVSSA		TV

TABLE 15 — Polynucleotide sequences of heavy-chain and light-chain variable regions of selected antibodies

	heavy-chain	light-chain
	variable regions	variable regions
Antibody	SEQ ID	Polynucleotide	SEQ ID	Polynucleotide
name	NO:	sequences	NO:	sequences
A11-C07	17	GAAGTGCAGCTGGTCGAG	161	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCA
		AGCGGGTTCACCTTTGAC		CGGGATCAAGTAGCGA
		GAATATGGCATGCACTGG		TGTGGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCGTTTCATGGAAT		CCCCCAAACTGATGATT
		TCTGGTAGCATTGCGTAC		TACGACGTAACAAAGC
		GCTGACTCTGTGAGAGGC		GCCCCTCAGGGGTCTCC
		AGATTCACTATCTCCAGA		AATCGCTTTTCTGGCAG
		GATAACGCCAAAAACAGC		TAAAAGCGGAAACACA
		TTATACCTGCAGATGAAT		GCCTCCCTGACTATCAG
		TCACTGAGAGCCGAGGAC		CGGCCTCCAAGCTGAA
		ACAGCCCTGTACTATTGT		GACGAGGCTGATTATTA
		GCTAGAGGAAGATATTCG		TTGTGCTTCTTACTCTA
		GATGTGTGGGGCCAGGGA		GCAACACTTTTTACGTT
		ACTACAGTTACCGTCTCC		TTCGGAACCGGGACAA
		TCA		AGGTGACCGTCTTGGGC
A11-G06	19	GAAGTGCAGCTGGTCGAG	163	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCA
		AGCGGGTTCACCTTTGAC		CGGGATCAAGTAGCGA
		GAATATGGCATGCACTGG		TGTGGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCGTTTCATGGAAT		CCCCCAAACTGATGATT
		TCTGGTAGCATTGCGTAC		TACGACGTAACAAAGC
		GCTGACTCTGTGAGAGGC		GCCCCTCAGGGGTCTCC
		AGATTCACTATCTCCAGA		AATCGCTTTTCTGGCAG
		GATAACGCCAAAAACAGC		TAAAAGCGGAAACACA
		TTATACCTGCAGATGAAT		GCCTCCCTGACTATCAG
		TCACTGAGAGCCGAGGAC		CGGCCTCCAAGCTGAA
		ACAGCCCTGTACTATTGT		GACGAGGCTGATTATTA
		GCTAAAGGAAGAATGTTG		TTGTGGTTCTTACAATA
		GATGTGTGGGGCCAGGGA		ACAACACTTTTTACGTT
		ACTACAGTTACCGTCTCC		TTCGGAACCGGGACAA
		TCA		AGGTGACCGTCTTGGGC
A12-C09	21	GAAGTGCAGCTGGTCGAG	165	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCA
		AGCGGGTTCACCTTTGAC		CGGGATCAAGTAGCGA
		GAATATGGCATGCACTGG		TGTGGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCGTTTCATGGAAT		CCCCCAAACTGATGATT
		TCTGGTAGCATTGCGTAC		TACGACGTAACAAAGC
		GCTGACTCTGTGAGAGGC		GCCCCTCAGGGGTCTCC
		AGATTCACTATCTCCAGA		AATCGCTTTTCTGGCAG
		GATAACGCCAAAAACAGC		TAAAAGCGGAAACACA
		TTATACCTGCAGATGAAT		GCCTCCCTGACTATCAG
		TCACTGAGAGCCGAGGAC		CGGCCTCCAAGCTGAA
		ACAGCCCTGTACTATTGT		GACGAGGCTGATTATTA
		GCTAAAGGAAGAACGAT		TTGTGGTTCTTACTCTA
		GGATGTGTGGGGCCAGGG		GCAACACTTTTTACGTT
		AACTACAGTTACCGTCTC		TTCGGAACCGGGACAA
		CTCA		AGGTGACCGTCTTGGGC
A12-E05	23	GAAGTGCAGCTGGTCGAG	167	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGCGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCA
		AGCGGGTTCACCTTTGAC		CGGGATCAAGTAGCGA
		GAATATGGCATGCACTGG		TGTGGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCGTTTCATGGAAT		CCCCCAAACTGATGATT
		TCTGGTAGCATTGCGTAC		TACGACGTAACAAAGC
		GCTGACTCTGTGAGAGGC		GCCCCTCAGGGGTCTCC
		AGATTCACTATCTCCAGA		AATCGCTTTTCTGGCAG
		GATAACGCCAAAAACAGC		TAAAAGCGGAAACACA
		TTATACCTGCAGATGAAT		GCCTCCCTGACTATCAG
		TCACTGAGAGCCGAGGAC		CGGCCTCCAAGCTGAA
		ACAGCCCTGTACTATTGT		GACGAGGCTGATTATTA
		GCTAGAGGAAGAATGATC		TTGTGGTTCTTACAATA
		GATGTGTGGGGCCAGGGA		GCAACACTTTTTACGTT
		ACTACAGTTACCGTCTCC		TTCGGAACCGGGACAA
		TCA		AGGTGACCGTCTTGGGC
A12-E01	25	GAAGTGCAGCTGGTCGAG	169	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGCAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCA
		AGCGGGTTCACCTTTGAC		CGGGATCAAGTAGCGA
		GAATATGGCATGCACTGG		TGTGGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCGTTTCATGGAAT		CCCCCAAACTGATGATT
		TCTGGTAGCATTGCGTAC		TACGACGTAACAAAGC
		GCTGACTCTGTGAGAGGC		GCCCCTCAGGGGTCTCC
		AGATTCACTATCTCCAGA		AATCGCTTTTCTGGCAG
		GATAACGCCAAAAACAGC		TAAAAGCGGAAACACA
		TTATACCTGCAGATGAAT		GCCTCCCTGACTATCAG
		TCACTGAGAGCCGAGGAC		CGGCCTCCAAGCTGAA
		ACAGCCCTGTACTATTGT		GACGAGGCTGATTATTA
		GCTAAAGGAAGACTTTTG		TTGTTCTTCTTACTCTA
		GATGTGTGGGGCCAGGGA		ACAACACTTTTTACGTT
		ACTACAGTTACCGTCTCC		TTCGGAACCGGGACAA
		TCA		AGGTGACCGTCTTGGGC
A12-E04	27	GAAGTGCAGCTGGTCGAG	171	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCA
		AGCGGGTTCACCTTTGAC		CGGGATCAAGTAGCGA
		GAATATGGCATGCACTGG		TGTGGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCGTTTCATGGAAT		CCCCCAAACTGATGATT
		TCTGGTAGCATTGCGTAC		TACGACGTAACAAAGC
		GCTGACTCTGTGAGAGGC		GCCCCTCAGGGGTCTCC
		AGATTCACTATCTCCAGA		AATCGCTTTTCTGGCAG
		GATAACGCCAAAAACAGC		TAAAAGCGGAAACACA
		TTATACCTGCAGATGAAT		GCCTCCCTGACTATCAG
		TCACTGAGAGCCGAGGAC		CGGCCTCCAAGCTGAA
		ACAGCCCTGTACTATTGT		GACGAGGCTGATTATTA
		GCTAAAGGAAGAATGATG		TTGTGCTTCTTACAATA
		GATGTGTGGGGCCAGGGA		ACTCCACTTTTTACGTT
		ACTACAGTTACCGTCTCC		TTCGGAACCGGGACAA
		TCA		AGGTGACCGTCTTGGGC
A12-F02	29	GAAGTGCAGCTGGTCGAG	173	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCA
		AGCGGGTTCACCTTTGAC		CGGGATCAAGTAGCGA
		GAATATGGCATGCACTGG		TGTGGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCGTTTCATGGAAT		CCCCCAAACTGATGATT
		TCTGGTAGCATTGCGTAC		TACGACGTAACAAAGC
		GCTGACTCTGTGAGAGGC		GCCCCTCAGGGGTCTCC
		AGATTCACTATCTCCAGA		AATCGCTTTTCTGGCAG
		GATAACGCCAAAAACAGC		TAAAAGCGGAAACACA
		TTATACCTGCAGATGAAT		GCCTCCCTGACTATCAG
		TCACTGAGAGCCGAGGAC		CGGCCTCCAAGCTGAA
		ACAGCCCTGTACTATTGT		GACGAGGCTGATTATTA
		GCTAAAGGAAGATATTTG		TTGTGGTTCTTACGATA
		GATGTGTGGGGCCAGGGA		GCAACACTTTTTACGTT
		ACTACAGTTACCGTCTCC		TTCGGAACCGGGACAA
		TCA		AGGTGACCGTCTTGGGC
A12-H04	31	GAAGTGCAGCTGGTCGAG	175	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCA
		AGCGGGTTCACCTTTGAC		CGGGATCAAGTAGCGA
		GAATATGGCATGCACTGG		TGTGGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCGTTTCATGGAAT		CCCCCAAACTGATGATT
		TCTGGTAGCATTGCGTAC		TACGACGTAACAAAGC
		GCTGACTCTGTGAGAGGC		GCCCCTCAGGGGTCTCC
		AGATTCACTATCTCCAGA		AATCGCTTTTCTGGCAG
		GATAACGCCAAAAACAGC		TAAAAGCGGAAACACA
		TTATACCTGCAGATGAAT		GCCTCCCTGACTATCAG
		TCACTGAGAGCCGAGGAC		CGGCCTCCAGGCTGAA
		ACAGCCCTGTACTATTGT		GACGAGGCTGATTATTA
		GCTAAAGGAAGACTTTTG		TTGTGGTGCTTACTCTA
		GATGTGTGGGGCCAGGGA		ACACCAATTTTTACGTT
		ACTACAGTTACCGTCTCC		TTCGGAACCGGGACAA
		TCA		AGGTGACCGTCTTGGGC
A23-3H04	33	GAAGTGCAGCTGGTCGAG	177	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCG
		AGCGGGTTCACCTTTGAC		GCGGATCAAGTAGCGA
		ACCTATGGGATGAACTGG		TGTCGGTGGCTATAATT
		G TGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		A A GGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATAAT		CCCCCAAACTGATGATT
		GGTGGTACCACAGCGTAC		TACGACGTTAACAAGC
		GCTGACTCTGTGAGAGGC		GCCCCTCAGGGGTCTCC
		AGATTCACTATCTCCAGA		AATCGCTTTTCTGGCAG
		GATAACGCCAAAAACAGC		TAAAAGCGGAAACACA
		TTATACCTGCAGATGAAT		GCCTCCCTGACTATCAG
		TCACTGAGAGCCGAGGAC		CGGCCTCCAAGCTGAA
		ACAGCCCTGTACTATTGT		GACGAGGCTGATTATTA
		GCTAGAGGAAGATATTCG		TTGTGGTTCTTACGATA
		GATGTGTGGGGCCAGGGA		GCAACACTTTTTACGTT
		ACTACAGTTACCGTCTCC		TTCGGAACCGGGACAA
		TCA		AGGTGACCGTCTTGGGC
A21-4C03	35	GAAGTGCAGCTGGTCGAG	179	CAGTCTGCACTTACTCA
		AGTGGGGAGGCTTGGTAC		GCCAGCCAGTGTGTCTG
		AACCTGGAAGATCCCTTA		GGAGTCCTGGACAGTC
		GACTCTCTTGCGCAGCAA		GATCACCATTTCCTGCA
		GCGGGTTCACCTTTGACG		CCGGATCAAGTAGCGA
		CATATGGGATGAACGGGT		TATCGGTGGCTATAATT
		GAGACAGGCTCCAGGAA		ATGTGTCCTGGTACCAG
		GGGTCTGGAGTGGGTGTC		CAGCACCCAGGCAAGG
		TGGCATTTCATATAATTCT		CCCCCAAACTGATGATT
		GGTACCATAGCGTACGCT		TACGACGTTAGCGATCG
		GACTCTGTGAAAGGCAGA		CCCCTCAGGGGTCTCCA
		TTCACTATCTCCAGAGAT		ATCGCTTTTCTGGCAGT
		AACGCCAAAAACAGCTTA		AAAAGCGGAAACACAG
		TACCTGCAGATGAATTCA		CCTCCCTGACTATCAGC
		CTGAGAGCCGGGACACAG		GGCCTCCAAGCTGAAG
		CCCTGTACTATTGTGCTA		ACGAGGCTGATTATTAT
		GAGGAAGATATTCGGATG		TGTGGTTCTTACTCTAG
		TGTGGGGCCAGGGAACTA		CAACACTTTTTACGTTT
		CAGTTACCGTCTCCTCA		TCGGAACCGGGACAAA
				GGTGACCGTCTTGGGC
A24-1G10	37	GAAGTGCAGCTGGTCGAG	181	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCG
		AGCGGGTTCACCTTTGAC		GCGGATCAAGTAGCAA
		GCCTATGGGATGCACTGG		TATCGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATAATT		CCCCCAAACTGATGATT
		CTGGTACCAAAGCGTACG		TACGACGTTAACAAGC
		CTGACTCTGTGAAAGGCA		GCCCCTCAGGGGTCTCC
		GATTCACTATCTCCAGAG		AATCGCTTTTCTGGCAG
		ATAACGCCAAAAACAGCT		TAAAAGCGGAAACACA
		TATACCTGCAGATGAATT		GCCTCCCTGACTATCAG
		CACTGAGAGCCGAGGACA		CGGCCTCCAAGCTGAA
		CAGCCCTGTACTATTgTGC		GACGAGGCTGATTATTA
		TAGAGGAAGATATTCGGA		TTGTGCTTCTTACTCTA
		TGTGTGGGGCCAGGGAAC		ACTCCAATTTTTACGTT
		TACAGTTACCGTCTCCTCA		TTCGGAACCGGGACAA
				AGGTGACCGTCTTGGGC
A24-1F07	39	GAAGTGCAGCTGGTCGAG	183	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGgAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCA
		AGCGGGTTCACCTTTGAC		GCGGATCAAGTAGCAA
		GCCTATGGGATGCACTGG		TGTCGGTAGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCGTTTCATATAATT		CCCCCAAACTGATGATT
		CTGGTACCACAGCGTACG		TACGACGTTACCAAGC
		CTGACTCTGTGAGAGGCA		GCCCCTCAGGGGTCTCC
		GATTCACTATCTCCAGAG		AATCGCTTTTCTGGCAG
		ATAACGCCAAAAACAGCT		TAAAAGCGGAAACACA
		TATACCTGCAGATGAATT		GCCTCCCTGACTATCAG
		CACTGAGAGCCGAGGACA		CGGCCTCCAAGCTGAA
		CAGCCCTGTACTATTGTG		GACGAGGCTGATTATTA
		CTAGAGGAAGATATTCGG		TTGTGGTTCTTACTCTA
		ATGTGTGGGGCCAGGGAA		ACTCCAATTTTTACGTT
		CTACAGTTACCGTCTCCTCA		TTCGGAACCGGGACAA
				AGGTGACCGTCTTGGGC
A21-4B10	41	GAAGTGCAGCTGGTCGAG	185	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCA
		AGCGGGTTCACCTTTGAC		GCGGATCAAGTAGCAA
		GAATATGGGATGCACTGG		TATCGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATAATT		CCCCCAAACTGATGATT
		CTGGTAACAAAGCGTACG		TACGACGTTAGCAAGC
		CTGACTCTGTGAGAGGCA		GCCCCTCAGGGGTCTCC
		GATTCACTATCTCCAGAG		AATCGCTTTTCTGGCAG
		ATAACGCCAAAAACAGCT		TAAAAGCGGAAACACA
		TATACCTGCAGATGAATT		GCCTCCCTGACTATCAG
		CACTGAGAGCCGAGGACA		CGGCCTCCAAGCTGAA
		CAGCCCTGTACTATTGTG		GACGAGGCTGATTATTA
		CTAGAGGAAGATATTCGG		TTGTGGTTCTTACGATA
		ATGTGTGGGGCCAGGGAA		GCAACACTTTTTACGTT
		CTACAGTTACCGTCTCCTCA		TTCGGAACCGGGACAA
				AGGTGACCGTCTTGGGC
A21-4G04	43	GAAGTGCAGCTGGTC	187	CAGTCTGCACTTACTCA
		GAGAGTGGGGGAGGCTTG		GCCAGCCAGTGTGTCTG
		GTACAACCTG		GGAGTCCTGGACAGTC
		GAAGATCCCTTAG		GATCACCATTTCCTGCA
		ACTCTCTTGCGCAGCAAG		GCGGATCAAGTAGCAA
		CGGGTTCACCTTTGACAG		TATCGGTGGCTATAATT
		CTATGGGATGCACTGGGT		ATGTGTCCTGGTACCAG
		GAGACAGGCTCCAGGGA		CAGCACCCAGGCAAGG
		AGGGTCTGGAGTGGGTGT		CCCCCAAACTGATGATT
		CTGGCATTTCATATAATG		TACGACGTTAACGAGC
		GTGGTAACACAGCGTACG		GCCCCTCAGGGGTCTCC
		CTGACTCTGTGAGAGGCA		AATCGCTTTTCTGGCAG
		GATTCACTATCTCCAGAG		TAAAAGCGGAAACACA
		ATAACGCCAAAAACAGCT		GCCTCCCTGACTATCAG
		TATACCTGCAGATGAATT		CGGCCTCCAAGCTGAA
		CACTGAGAGCCGAGGACA		GACGAGGCTGATTATTA
		CAGCCCTGTACTATTGTG		TTGTGGTTCTTACTCTA
		CTAGAGGAAGATATTCGG		ACAACAATTTTTACGTT
		ATGTGTGGGGCCAGGGAA		TTCGGAACCGGGACAA
		CTACAGTTACCGTCTCTTCA		AGGTGACCGTCTTGGGC
A23-3H05	45	GAAGTGCAGCTGGTCGAG	189	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCG
		AGCGGGTTCACCTTTGAC		GCGGATCAAGTAGCAA
		GCATATGGGATGAACTGG		TGTCGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATAATT		CCCCCAAACTGATGATT
		CTGGTACCATAGCGTACG		TACGACGTTAGCAATCG
		CTGACTCTGTGAAAGGCA		CCCCTCAGGGGTCTCCA
		GATTCACTATCTCCAGAG		ATCGCTTTTCTGGCAGT
		ATAACGCCAAAAACAGCT		AAAAGCGGAAACACAG
		TATACCTGCAGATGAATT		CCTCCCTGACTATCAGC
		CACTGAGAGCCGAGGACA		GGCCTCCAAGCTGAAG
		CAGCCCTGTACTATTGTG		ACGAGGCTGATTATTAT
		CTAGAGGAAGATATTCGG		TGTGGTTCTTACTCTAA
		ATGTGTGGGGCCAGGGAA		CTCCAATTTTTACGTTT
		CTACAGTTACCGTCTCCTCA		TCGGAACCGGGACAAA
				GGTGACCGTCTTGGGC
A21-3A09	47	GAAGTGCAGCTGGTCGAG	191	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCA
		AGCGGGTTCACCTTTGAC		GCGGATCAAGTAGCGA
		AACTATGGGATGAACTGG		TATCGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATAATT		CCCCCAAACTGATGATT
		CTGGTACCAAAGCGTACG		TACGACGTTAACAAGC
		CTGACTCTGTGAAAGGCA		GCCCCTCAGGGGTCTCC
		GATTCACTATCTCCAGAG		AATCGCTTTTCTGGCAG
		ATAACGCCAAAAACAGCT		TAAAAGCGGAAACACA
		TATACCTGCAGATGAATT		GCCTCCCTGACTATCAG
		CACTGAGAGCCGAGGACA		CGGCCTCCAAGCTGAA
		CAGCCCTGTACTATTGTG		GACGAGGCTGATTATTA
		CTAGAGGAAGATATTCGG		TTGTGCTTCTTACTCTA
		ATGTGTGGGGCCAGGGAA		GCAACACTTTTTACGTT
		CTACAGTTACCGTCTCCTCA		TTCGGAACCGGGACAA
				AGGTGACCGTCTTGGGC
A21-4B06	49	GAAGTGCAGCTGGTCGAG	193	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCA
		AGCGGGTTCACCTTTGAC		GCGGATCAAGTAGCAA
		AGCTATGGGATGCACTGG		TATCGGTAGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATAAT		CCCCCAAACTGATGATT
		GGTGGTAGCAAAGCGTAC		TACGACGTTACCGATCG
		GCTGACTCTGTGAGAGGC		CCCCTCAGGGGTCTCCA
		AGATTCACTATCTCCAGA		ATCGCTTTTCTGGCAGT
		GATAACGCCAAAAACAGC		AAAAGCGGAAACACAG
		TTATACCTGCAGATGAAT		CCTCCCTGACTATCAGC
		TCACTGAGAGCCGAGGAC		GGCCTCCAAGCTGAAG
		ACAGCCCTGTACTATTGT		ACGAGGCTGATTATTAT
		GCTAGAGGAAGATATTCG		TGTGGTTCTTACTCTAG
		GATGTGTGGGGCCAGGGA		CAACACTTTTTACGTTT
		ACTACAGTTACCGTCTCC		TCGGAACCGGGACAAA
		TCA		GGTGACCGTCTTGGGC
A24-1B05	51	GAAGTGCAGCTGGTCGAG	195	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCG
		AGCGGGTTCACCTTTGAC		CCGGATCAAGTAGCGA
		AAATATGGGATGAACTGG		TATCGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATAATT		CCCCCAAACTGATGATT
		CTGGTAACACAGCGTACG		TACGACGTTAGCAAGC
		CTGACTCTGTGAGAGGCA		GCCCCTCAGGGGTCTCC
		GATTCACTATCTCCAGAG		AATCGCTTTTCTGGCAG
		ATAACGCCAAAAACAGCT		TAAAAGCGGAAACACA
		TATACCTGCAGATGAATT		GCCTCCCTGACTATCAG
		CACTGAGAGCCGAGGACA		CGGCCTCCAAGCTGAA
		CAGCCCTGTACTATTGTG		GACGAGGCTGATTATTA
		CTAGAGGAAGATATTCGG		TTGTGGTTCTTACGATA
		ATGTGTGGGGCCAGGGAA		GCAACACTTTTTACGTT
		CTACAGTTACCGTCTCCTCA		TTCGGAACCGGGACAA
				AGGTGACCGTCTTGGGC
A23-3A08	53	GAAGTGCAGCTGGTCGAG	197	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCG
		AGCGGGTTCACCTTTGAC		CCGGATCAAGTAGCAA
		GCATATGGGATGCACTGG		TATCGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATAATT		CCCCCAAACTGATGATT
		CTGGTACCACAGCGTACG		TACGACGTTAGCAAGC
		CTGACTCTGTGAAAGGCA		GCCCCTCAGGGGTCTCC
		GATTCACTATCTCCAGAG		AATCGCTTTTCTGGCAG
		ATAACGCCAAAAACAGCT		TAAAAGCGGAAACACA
		TATACCTGCAGATGAATT		GCCTCCCTGACTATCAG
		CACTGAGAGCCGAGGACA		CGGCCTCCAAGCTGAA
		CAGCCCTGTACTATTGTG		GACGAGGCTGATTATTA
		CTAGAGGAAGATATTCGG		TTGTGGTTCTTACTCTA
		ATGTGTGGGGCCAGGGAA		ACTCCAATTTTTACGTT
		CTACAGTTACCGTCTCCTCA		TTCGGAACCGGGACAA
				AGGTGACCGTCTTGGGC
A21-4C08	55	GAAGTGCAGCTGGTCGAG	199	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCA
		AGCGGGTTCACCTTTGAC		GCGGATCAAGTAGCAA
		ACATATGGGATGCACTGG		TGTCGGTAGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATAAT		CCCCCAAACTGATGATT
		GCCGGTAACAAAGCGTAC		TACGACGTTAACAATCG
		GCTGACTCTGTGAGAGGC		CCCCTCAGGGGTCTCCA
		AGATTCACTATCTCCAGA		ATCGCTTTTCTGGCAGT
		GATAACGCCAAAAACAGC		AAAAGCGGAAACACAG
		TTATACCTGCAGATGAAT		CCTCCCTGACTATCAGC
		TCACTGAGAGCCGAGGAC		GGCCTCCAAGCTGAAG
		ACAGCCCTGTACTATTGT		ACGAGGCTGATTATTAT
		GCTAGAGGAAGATATTCG		TGTGGTTCTTACTCTAG
		GATGTGTGGGGCCAGGGA		CAACACTTTCTACGTTT
		ACTACAGTTACCGTCTCC		TCGGAACCGGGACAAA
		TCA		GGTGACCGTCTTGGGC
A23-4D09	57	GAAGTGCAGCTGGTCGAG	201	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCA
		AGCGGGTTCACCTTTGAC		GCGGATCAAGTAGCAA
		GCCTATGGGATGCACTGG		TATCGGTAGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCGTTTCATATGAT		CCCCCAAACTGATGATT
		GCTGGTAACACAGCGTAC		TACGACGTTACCGATCG
		GCTGACTCTGTGAGAGGC		CCCCTCAGGGGTCTCCA
		AGATTCACTATCTCCAGA		ATCGCTTTTCTGGCAGT
		GATAATGCCAAAAACAGC		AAAAGCGGAAACACAG
		TTATACCTGCAGATGAAT		CCTCCCTGACTATCAGC
		TCACTGAGAGCCGAGGAC		GGCCTCCAAGCTGAAG
		ACAGCCCTGTACTATTGT		ACGAGGCTGATTATTAT
		GCTAGAGGAAGATATTCG		TGTGGTTCTTACTCTAG
		GATGTGTGGGGCCAGGGA		CAACACTTTTTACGTTT
		ACTACAGTTACCGTCTCC		TCGGAACCGGGACAAA
		TCA		GGTGACCGTCTTGGGC
A23-3D03	59	GAAGTGCAGCTGGTCGAG	203	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCA
		AGCGGGTTCACCTTTGAC		CCGGATCAAGTAGCGA
		GCATATGGGATGAACTGG		TGTCGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATAAT		CCCCCAAACTGATGATT
		GCTGGTAGCACAGCGTAC		TACGACGTTACCAATCG
		GCTGACTCTGTGAGAGGC		CCCCTCAGGGGTCTCCA
		AGATTCACTATCTCCAGA		ATCGCTTTTCTGGCAGT
		GATAACGCCAAAAACAGC		AAAAGCGGAAACACAG
		TTATACCTGCAGATGAAT		CCTCCCTGACTATCAGC
		TCACTGAGAGCCGAGGAC		GGCCTCCAAGCTGAAG
		ACAGCCCTGTACTATTGT		ACGAGGCTGATTATTAT
		GCTAGAGGAAGATATTCG		TGTGGTTCTTACGATAG
		GATGTGTGGGGCCAGGGA		CAACACTTTTTACGTTT
		ACTACAGTTACCGTCTCC		TCGGAACCGGGACAAA
		TCA		GGTGACCGTCTTGGGC
A21-4B03	61	GAAGTGCAGCTGGTCGAG	205	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCA
		AGCGGGTTCACCTTTGAC		GCGGATCAAGTAGCAA
		GCATATGGGATGAACTGG		TATCGGTAGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATAAT		CCCCCAAACTGATGATT
		GCTGGTAACAAAGCGTAC		TACGACGTTAACAAGC
		GCTGACTCTGTGAGAGGC		GCCCCTCAGGGGTCTCC
		AGATTCACTATCTCCAGA		AATCGCTTTTCTGGCAG
		GATAACGCCAAAAACAGC		TAAAAGCGGAAACACA
		TTATACCTGCAGATGAAT		GCCTCCCTGACTATCAG
		TCACTGAGAGCCGAGGAC		CGGCCTCCAAGCTGAA
		ACAGCCCTGTACTATTGT		GACGAGGCTGATTATTA
		GCTAGAGGAAGATATTCG		TTGTGCTTCTTACTCTA
		GATGTGTGGGGCCAGGGA		GCAACACTTTTTACGTT
		ACTACAGTTACCGTCTCC		TTCGGAACCGGGACAA
		TCA		AGGTGACCGTCTTGGGC
A21-3D10	63	GAAGTGCAGCTGGTCGAG	207	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCG
		AGCGGGTTCACCTTTGAC		GCGGAACAAGTAGCAA
		AACTATGGGATGCACTGG		TATCGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATGAT		CCCCCAAACTGATGATT
		GCTGGTACCACAGCGTAC		TACGACGTTACCAATCG
		GCTGACTCTGTGAAAGGC		CCCCTCAGGGGTCTCCA
		AGATTCACTATCTCCAGA		ATCGCTTTTCTGGCAGT
		GATAACGCCAAAAACAGC		AAAAGCGGAAACACAG
		TTATACCTGCAGATGAAT		CCTCCCTGACTATCAGC
		TCACTGAGAGCCGAGGAC		GGCCTCCAAGCTGAAG
		ACAGCCCTGTACTATTGT		ACGAGGCTGATTATTAT
		GCTAAAGGAAGATATTCG		TGTGGTTCTTACTCTAA
		GATGTGTGGGGCCAGGGA		CACCAATTTTTACGTTT
		ACTACAGTTACCGTCTCC		TCGGAACCGGGACAAA
		TCA		GGTGACCGTCTTGGGC
A21-3A10	65	GAAGTGCAGCTGGTCGAG	209	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCtGGAAGATCCCTTA		GGAGTCCTGGACAGTC
		GACTCTCTTGCGCAGCAA		GATCACCATTTCCTGCG
		GCGGGTTCACCTTTGACG		CCGGATCAAGTAGCAA
		CATATGGGATGCACTGGG		TATCGGTGGCTATAATT
		TGAGACAGGCTCCAGGGA		ATGTGTCCTGGTACCAG
		AGGGTCTGGAGTGGGTGT		CAGCACCCAGGCAAGG
		CTGGCATTTCATATAATG		CCCCCAAACTGATGATT
		CTGGTAACAAAGCGTACG		TACGACGTTAGCAAGC
		CTGACTCTGTGAGAGGCA		GCCCCTCAGGGGTCTCC
		GATTCACTATCTCCAGAG		AATCGCTTTTCTGGCAG
		ATAACGCCAAAAACAGCT		TAAAAGCGGAAACACA
		TATACCTGCAGATGAATT		GCCTCCCTGACTATCAG
		CACTGAGAGCCGAGGACA		CGGCCTCCAAGCTGAA
		CAGCCCTGTACTATTGTG		GACGAGGCTGATTATTA
		CTAGAGGAAGATATTCGG		TTGTGGTTCTTACTCTA
		ATGTGTGGGGCCAGGGAA		ACTCCAATTTTTACGTT
		CTACAGTTACCGTCTCCTCA		TTCGGAACCGGGACAA
				AGGTGACCGTCTTGGGC
A21-4H04	67	GAAGTGCAGCTGGTCGAG	211	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCtggaAGATCCCTTAG		GGAGTCCTGGACAGTC
		ACTCTCTTGCGCAGCAAG		GATCACCATTTCCTGCA
		CGGGTTCACCTTTGACAG		GCGGAACAAGTAGCGA
		CTATGGGATGCACTGGGT		TATCGGTGGCTATAATT
		GAGACAGGCTCCAGGGA		ATGTGTCCTGGTACCAG
		AGGGTCTGGAGTGGGTGT		CAGCACCCAGGCAAGG
		CCGGCATTTCATATAATT		CCCCCAAACTGATGATT
		CTGGTAACAAAGCGTACG		TACGACGTTAGCAAGC
		CTGACTCTGTGAAAGGCA		GCCCCTCAGGGGTCTCC
		GATTCACTATCTCCAGAG		AATCGCTTTTCTGGCAG
		ATAACGCCAAAAACAGCT		TAAAAGCGGAAACACA
		TATACCTGCAGATGAATT		GCCTCCCTGACTATCAG
		CACTGAGAGCCGAGGACA		CGGCCTCCAAGCTGAA
		CAGCCCTGTACTATTGTG		GACGAGGCTGATTATTA
		CTAGAGGAAGATATTCGG		TTGTGGTTCTTACTCTA
		ATGTGTGGGGCCAGGGAA		ACAACAATTTTTACGTT
		CTACAGTTACCGTCTCCTCA		TTCGGAACCGGGACAA
				AGGTGACCGTCTTGGGC
A21-4F11	69	GAAGTGCAGCTGGTCGAG	213	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCG
		AGCGGGTTCACCTTTGAC		GCGGAACAAGTAGCAA
		GCATATGGGATGAACTGG		TATCGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATAAT		CCCCCAAACTGATGATT
		GGTGGTACCAAAGCGTAC		TACGACGTTAACGATCG
		GCTGACTCTGTGAGAGGC		CCCCTCAGGGGTCTCCA
		AGATTCACTATCTCCAGA		ATCGCTTTTCTGGCAGT
		GATAACGCCAAAAACAGC		AAAAGCGGAAACACAG
		TTATACCTGCAGATGAAT		CCTCCCTGACTATCAGC
		TCACTGAGAGCCGAGGAT		GGCCTCCAAGCTGAAG
		ACAGCCCTGTACTATTGT		ACGAGGCTGATTATTAT
		GCTAGAGGAAGATATTCG		TGTGCTTCTTACTCTAG
		GATGTGTGGGGCCAGGGA		CAACACTTTTTACGTTT
		ACTACAGTTACCGTCTCC		TCGGAACCGGGACAAA
		TCA		GGTGACCGTCTTGGGC
A23-3G05	71	GAAGTGCAGCTGGTCGAG	215	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCG
		AGCGGGTTCACCTTTGAC		CCGGATCAAGTAGCAA
		ACATATGGGATGCACTGG		TATCGGTAGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATAATT		CCCCCAAACTGATGATT
		CTGGTACCATAGCGTACG		TACGACGTTAGCAATCG
		CTGACTCTGTGAGAGGCA		CCCCTCAGGGGTCTCCA
		GATTCACTATCTCCAGAG		ATCGCTTTTCTGGCAGT
		ATAACGCCAAAAACAGCT		AAAAGCGGAAACACAG
		TATACCTGCAGATGAATT		CCTCCCTGACTATCAGC
		CACTGAGAGCCGAGGACA		GGCCTCCAAGCTGAAG
		CAGCCCTGTACTATTGTG		ACGAGGCTGATTATTAT
		CTAGAGGAAGATATTCGG		TGTGGTTCTTACGATAG
		ATGTGTGGGGCCAGGGAA		CAACACTTTTTACGTTT
		CTACAGTTACCGTCTCCTCA		TCGGAACCGGGACAAA
				GGTGACCGTCTTGGGC
A23-3A10	73	GAAGTGCAGCTGGTCGAG	217	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCG
		AGCGGGTTCACCTTTGAC		CCGGATCAAGTAGCAA
		AAATATGGGATGCACTGG		TATCGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATAAT		CCCCCAAACTGATGATT
		GCTGGTAGCAAAGCGTAC		TACGACGTTAGCGATCG
		GCTGACTCTGTGAAAGGC		CCCCTCAGGGGTCTCCA
		AGATTCACTATCTCCAGA		ATCGCTTTTCTGGCAGT
		GATAACGCCAAAAACAGC		AAAAGCGGAAACACAG
		TTATACCTGCAGATGAAT		CCTCCCTGACTATCAGC
		TCACTGAGAGCCGAGGAC		GGCCTCCAAGCTGAAG
		ACAGCCCTGTACTATTGT		ACGAGGCTGATTATTAT
		GCTAGAGGAAGATATTCG		TGTGGTTCTTACGATAG
		GATGTGTGGGGCCAGGGA		CAACACTTTTTACGTTT
		ACTACAGTTACCGTCTCC		TCGGAACCGGGACAAA
		TCA		GGTGACCGTCTTGGGC
A25-1H04	75	GAAGTGCAGCTGGTCGAG	219	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCG
		AGCGGGTTCACCTTTGAC		CCGGATCAAGTAGCGA
		GCATATGGGATGAACTGG		TATCGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATAATT		CCCCCAAACTGATGATT
		CTGGTAACACAGCGTACG		TACGACGTTAGCGAGC
		CTGACTCTGTGAGAGGCA		GCCCCTCAGGGGTCTCC
		GATTCACTATCTCCAGAG		AATCGCTTTTCTGGCAG
		ATAACGCCAAAAACAGCT		TAAAAGCGGAAACACA
		TATACCTGCAGATGAATT		GCCTCCCTGACTATCAG
		CACTGAGAGCCGAGGACA		CGGCCTCCAAGCTGAA
		CAGCCCTGTACTATTGTG		GACGAGGCTGATTATTA
		CTAGAGGAAGATATTCGG		TTGTGGTTCTTACGATA
		ATGTGTGGGGCCAGGGAA		GCAACACTTTTTACGTT
		CTACAGTTACCGTCTCCTCA		TTCGGAACCGGGACAA
				AGGTGACCGTCTTGGGC
A23-3B06	77	GAAGTGCAGCTGGTCGAG	221	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCA
		AGCGGGTTCACCTTTGAC		GCGGATCAAGTAGCGA
		GCCTATGGGATGCACTGG		TGTCGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATAATT		CCCCCAAACTGATGATT
		CTGGTAGCAAAGCGTACG		TACGACGTTAGCGAGC
		CTGACTCTGTGAAAGGCA		GCCCCTCAGGGGTCTCC
		GATTCACTATCTCCAGAG		AATCGCTTTTCTGGCAG
		ATAACGCCAAAAACAGCT		TAAAAGCGGAAACACA
		TATACCTGCAGATGAATT		GCCTCCCTGACTATCAG
		CACTGAGAGCCGAGGACA		CGGCCTCCAAGCTGAA
		CAGCCCTGTACTATTGTG		GACGAGGCTGATTATTA
		CTAGAGGAAGATATTCGG		TTGTGGTTCTTACGATA
		ATGTGTGGGGCCAGGGAA		GCAACACTTTTTACGTT
		CTACAGTTACCGTCTCCTCA		TTCGGAACCGGGACAA
				AGGTGACCGTCTTGGGC
A23-4A09	79	GAAGTGCAGCTGGTCGAG	223	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCG
		AGCGGGTTCACCTTTGAC		GCGGATCAAGTAGCAA
		AACTATGGGATGAACTGG		TATCGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATGATT		CCCCCAAACTGATGATT
		CTGGTAACAAAGCGTACG		TACGACGTTACCAAGC
		CTGACTCTGTGAAAGGCA		GCCCCTCAGGGGTCTCC
		GATTCACTATCTCCAGAG		AATCGCTTTTCTGGCAG
		ATAACGCCAAAAACAGCT		TAAAAGCGGAAACACA
		TATACCTGCAGATGAATT		GCCTCCCTGACTATCAG
		CACTGAGAGCCGAGGACA		CGGCCTCCAAGCTGAA
		CAGCCCTGTACTATTGTG		GACGAGGCTGATTATTA
		CTAGAGGAAGATATTCGG		TTGTGCTTCTTACTCTA
		ATGTGTGGGGCCAGGGAA		GCAACACTTTTTACGTT
		CTACAGTTACCGTCTCCTCA		TTCGGAACCGGGACAA
				AGGTGACCGTCTTGGGC
A25-1D09	81	GAAGTGCAGCTGGTCGAG	225	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCG
		AGCGGGTTCACCTTTTAC		GCGGAACAAGTAGCGA
		GCATATGGGATGCACTGG		TGTCGGTAGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATAAT		CCCCCAAACTGATGATT
		GGTGGTACCATAGCGTAC		TACGACGTTAACAAGC
		GCTGACTCTGTGAAAGGC		GCCCCTCAGGGGTCTCC
		AGATTCACTATCTCCAGA		AATCGCTTTTCTGGCAG
		GATAACGCCAAAAACAGC		TAAAAGCGGAAACACA
		TTATACCTGCAGATGAAT		GCCTCCCTGACTATCAG
		TCACTGAGAGCCGAGGAC		CGGCCTCCAAGCTGAA
		ACAGCCCTGTACTATTGT		GACGAGGCTGATTATTA
		GCTAGAGGAAGATATTCG		TTGTGGTTCTTACTCTA
		GATGTGTGGGGCCAGGGA		ACTCCAATTTTTACGTT
		ACTACAGTTACCGTCTCC		TTCGGAACCGGGACAA
		TCA		AGGTGACCGTCTTGGGC
A21-4E10	83	GAAGTGCAGCTGGTCGAG	227	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCA
		AGCGGGTTCACCTTTGAC		CCGGATCAAGTAGCAA
		GCCTATGGGATGAACTGG		TGTCGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCGTTTCATATAAC		CCCCCAAACTGATGATT
		GCTGGTAACAAAGCGTAC		TACGACGTTAGCAAGC
		GCTGACTCTGTGAGAGGC		GCCCCTCAGGGGTCTCC
		AGATTCACTATCTCCAGA		AATCGCTTTTCTGGCAG
		GATAACGCCAAAAACAGC		TAAAAGCGGAAACACA
		TTATACCTGCAGATGAAT		GCCTCCCTGACTATCAG
		TCACTGAGAGCCGAGGAC		CGGCCTCCAAGCTGAA
		ACAGCCCTGTACTATTGT		GACGAGGCTGATTATTA
		GCTAGAGGAAGATATTCG		TTGTGGTTCTTACTCTA
		GATGTGTGGGGCCAGGGA		GCAACACTTTTTACGTT
		ACTACAGTTACCGTCTCC		TTCGGAACCGGGACAA
		TCA		AGGTGACCGTCTTGGGC
A23-3C04	85	GAAGTGCAGCTGGTCGAG	229	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCC		GGAGTCCTGGACAGTC
		CTTAGACTCTCTTGCGCA		GATCACCATTTCCTGCA
		GCAAGCGGGTTCACCTTT		GCGGAACAAGTAGCGA
		GACACATATGGGATGCAC		TATCGGTGGCTATAATT
		TGGGTGAGACAGGCTCCA		ATGTGTCCTGGTACCAG
		GGGAAGGGTCTGGAGTGG		CAGCACCCAGGCAAGG
		GTGTCTGGCATTTCATAT		CCCCCAAACTGATGATT
		GATTCTGGTACCACAGCG		TACGACGTTACCGAGCC
		TACGCTGACTCTGTGAAA		CCCCTCAGGGGTCTCCA
		GGCAGATTCACTATCTCC		ATCGCTTTTCTGGCAGT
		AGAGATAACGCCAAAAA		AAAAGCGGAAACACAG
		CAGCTTATACCTGCAGAT		CCTCCCTGACTATCAGC
		GAATTCACTGAGAGCCGA		GGCCTCCAAGCTGAAG
		GGACACAGCCCTGTACTA		ACGAGGCTGATTATTAT
		TTGTGCTAGAGGAAGATA		TGTGCTTCTTACTCTAG
		TTCGGATGTGTGGGGCCA		CAACACTTTTTACGTTT
		GGGAACTACAGTTACCGT		TCGGAACCGGGACAAA
		CTCCTCA		GGTGACCGTCTTGGGC
A23-3G06	87	GAAGTGCAGCTGGTCGAG	231	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCC		GGAGTCCTGGACAGTC
		CTTAGACTCTCTTGCGCA		GATCACCATTTCCTGCG
		GCAAGCGGGTTCACCTTT		CCGGAACAAGTAGCAA
		GACGCATATGGGATGAAC		TATCGGTGGCTATAATT
		TGGGTGAGACAGGCTCCA		ATGTGTCCTGGTACCAG
		GGGAAGGGTCTGGAGTGG		CAGCACCCAGGCAAGG
		GTGTCTGGCATTTCATAT		CCCCCAAACTGATGATT
		AATTCTGGTAACATAGCG		TACGACGTTAACGATCG
		TACGCTGACTCTGTGAGA		CCCCTCAGGGGTCTCCA
		GGCAGATTCACTATCTCC		ATCGCTTTTCTGGCAGT
		AGAGATAACGCCAAAAA		AAAAGCGGAAACACAG
		CAGCTTATACCTGCAGAT		CCTCCCTGACTATCAGC
		GAATTCACTGAGAGCCGA		GGCCTCCAAGCTGAAG
		GGACACAGCCCTGTACTA		ACGAGGCTGATTATTAT
		TTGTGCTAGAGGAAGATA		TGTGGTTCTTACGATAG
		TTCGGATGTGTGGGGCCA		CAACACTTTTTACGTTT
		GGGAACTACAGTTACCGT		TCGGAACCGGGACAAA
		CTCCTCA		GGTGACCGTCTTGGGC
A24-1E09	89	GAAGTGCAGCTGGTCGAG	233	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCA
		AGCGGGTTCACCTTTGAC		CCGGATCAAGTAGCAA
		AAATATGGGATGCACTGG		TATCGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCGTTTCATATAAT		CCCCCAAACTGATGATT
		GCTGGTACCACAGCGTAC		TACGACGTTACCAATCG
		GCTGACTCTGTGAGAGGC		CCCCTCAGGGGTCTCCA
		AGATTCACTATCTCCAGA		ATCGCTTTTCTGGCAGT
		GATAACGCCAAAAACAGC		AAAAGCGGAAACACAG
		TTATACCTGCAGATGAAT		CCTCCCTGACTATCAGC
		TCACTGAGAGCCGAGGAC		GGCCTCCAGGCTGAAG
		ACAGCCCTGTACTATTGT		ACGAGGCTGATTATTAT
		GCTAGAGGAAGATATTCG		TGTGGTTCTTACTCTAA
		GATGTGTGGGGCCAGGGA		CTCCAATTTTTACGTTT
		ACTACAGTTACCGTCTCC		TCGGAACCGGGACAAA
		TCA		GGTGACCGTCTTGGGC
A23-3F03	91	GAAGTGCAGCTGGTCGAG	235	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCG
		AGCGGGTTCACCTTTGAC		GCGGATCAAGTAGCAA
		ACATATGGGATGCACTGG		TATCGGTAGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATAATT		CCCCCAAACTGATGATT
		CTGGTAACATAGCGTACG		TACGACGTAACAAAGC
		CTGACTCTGTGAAAGGCA		GCCCCTCAGGGGTCTCC
		GATTCACTATCTCCAGAG		AATCGCTTTTCTGGCAG
		ATAACGCCAAAAACAGCT		TAAAAGCGGAAACACA
		TATACCTGCAGATGAATT		GCCTCCCTGACTATCAG
		CACTGAGAGCCGAGGACA		CGGCCTCCAAGCTGAA
		CAGCCCTGTACTATTGTG		GACGAGGCTGATTATTA
		CTAGAGGAAGATATTCGG		TTGTGGTTCTTACGATA
		ATGTGTGGGGCCAGGGAA		GCAACACTTTTTACGTT
		CTACAGTTACCGTCTCCTCA		TTCGGAACCGGGACAA
				AGGTGACCGTCTTGGGC
A21-4F07	93	GAAGTGCAGCTGGTCGAG	237	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCA
		AGCGGGTTCACCTTTGAC		GCGGAACAAGTAGCAA
		GCCTATGGGATGAACTGG		TGTCGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATAAT		CCCCCAAACTGATGATT
		GCTGGTAACAAAGCGTAC		TACGACGTTAGCGATCG
		GCTGACTCTGTGAAAGGC		CCCCTCAGGGGTCTCCA
		AGATTCACTATCTCCAGA		ATCGCTTTTCTGGCAGT
		GATAACGCCAAAAACAGC		AAAAGCGGAAACACAG
		TTATACCTGCAGATGAAT		CCTCCCTGACTATCAGC
		TCACTGAGAGCCGAGGAC		GGCCTCCAAGCTGAAG
		ACAGCCCTGTACTATTGT		ACGAGGCTGATTATTAT
		GCTAGAGGAAGATATTCG		TGTGGTTCTTACTCTAA
		GATGTGTGGGGCCAGGGA		CTCCAATTTTTACGTTT
		ACTACAGTTACCGTCTCC		TCGGAACCGGGACAAA
		TCA		GGTGACCGTCTTGGGC
A24-1A03	95	GAAGTGCAGCTGGTCGAG	239	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCG
		AGCGGGTTCACCTTTGAC		GCGGATCAAGTAGCAA
		GCATATGGGATGAACTGG		TGTCGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATAAT		CCCCCAAACTGATGATT
		GCTGGTAACACAGCGTAC		TACGACGTTAGCAAGC
		GCTGACTCTGTGAAAGGC		GCCCCTCAGGGGTCTCC
		AGATTCACTATCTCCAGA		AATCGCTTTTCTGGCAG
		GATAACGCCAAAAACAGC		TAAAAGCGGAAACACA
		TTATACCTGCAGATGAAT		GCCTCCCTGACTATCAG
		TCACTGAGAGCCGAGGAC		CGGCCTCCAAGCTGAA
		ACAGCCCTGTACTATTGT		GACGAGGCTGATTATTA
		GCTAGAGGAAGATATTCG		TTGTGGTTCTTACTCTA
		GATGTGTGGGGCCAGGGA		ACTCCAATTTTTACGTT
		ACTACAGTTACCGTCTCC		TTCGGAACCGGGACAA
		TCA		AGGTGACCGTCTTGGGC
A24-1H11	97	GAAGTGCAGCTGGTCGAG	241	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCA
		AGCGGGTTCACCTTTGAC		CCGGATCAAGTAGCGA
		GCATATGGGATGCACTGG		TGTCGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATAATT		CCCCCAAACTGATGATT
		CTGGTACCACAGCGTACG		TACGAAGTTAACAAGC
		CTGACTCTGTGAGAGGCA		GCCCCTCAGGGGTCTCC
		GATTCACTATCTCCAGAG		AATCGCTTTTCTGGCAG
		ATAACGCCAAAAACAGCT		TAAAAGCGGAAACACA
		TATACCTGCAGATGAATT		GCCTCCCTGACTATCAG
		CACTGAGAGCCGAGGACA		CGGCCTCCAAGCTGAA
		CAGCCCTGTACTATTGTG		GACGAGGCTGATTATTA
		CTAGAGGAAGATATTCGG		TTGTGCTTCTTACTCTA
		ATGTGTGGGGCCAGGGAA		GCAACACTTTTTACGTT
		CTACAGTTACCGTCTCCTCA		TTCGGAACCGGGACAA
				AGGTGACCGTCTTGGGC
A21-3D09	99	GAAGTGCAGCTGGTCGAG	243	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCA
		AGCGGGTTCACCTTTGAC		GCGGAACAAGTAGCAA
		AACTATGGGATGAACTGG		TGTCGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATAATT		CCCCCAAACTGATGATT
		CTGGTACCAAAGCGTACG		TACGACGTTAACAAGC
		CTGACTCTGTGAAAGGCA		GCCCCTCAGGGGTCTCC
		GATTCACTATCTCCAGAG		AATCGCTTTTCTGGCAG
		ATAACGCCAAAAACAGCT		TAAAAGCGGAAACACA
		TATACCTGCAGATGAATT		GCCTCCCTGACTATCAG
		CACTGAGAGCCGAGGACA		CGGCCTCCAAGCTGAA
		CAGCCCTGTACTATTGTG		GACGAGGCTGATTATTA
		CTAGAGGAAGATATTCGG		TTGTGGTTCTTACTCTA
		ATGTGTGGGGCCAGGGAA		ACTCCAATTTTTACGTT
		CTACAGTTACCGTCTCCTCA		TTCGGAACCGGGACAA
				AGGTGACCGTCTTGGGC
A24-1D10	101	GAAGTGCAGCTGGTCGAG	245	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCA
		AGCGGGTTCACCTTTGAC		GCGGATCAAGTAGCGA
		AACTATGGGATGCACTGG		TATCGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATAATT		CCCCCAAACTGATGATT
		CTGGTAACAAAGCGTACG		TACGACGTTACCGATCG
		CTGACTCTGTGAAAGGCA		CCCCTCAGGGGTCTCCA
		GATTCACTATCTCCAGAG		ATCGCTTTTCTGGCAGT
		ATAACGCCAAAAACAGCT		AAAAGCGGAAACACAG
		TATACCTGCAGATGAATT		CCTCCCTGACTATCAGC
		CACTGAGAGCCGAGGACA		GGCCTCCAAGCTGAAG
		CAGCCCTGTACTATTGTG		ACGAGGCTGATTATTAT
		CTAGAGGAAGATATTCGG		TGTGGTTCTTACTCTAA
		ATGTGTGGGGCCAGGGAA		CAACAATTTTTACGTTT
		CTACAGTTACCGTCTCCTCA		TCGGAACCGGGACAAA
				GGTGACCGTCTTGGGC
A21-4B04	103	GAAGTGCAGCTGGTCGAG	247	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCG
		AGCGGGTTCACCTTTGAC		CCGGAACAAGTAGCAA
		GCCTATGGGATGCACTGG		TATCGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATGAT		CCCCCAAACTGATGATT
		GCTGGTAACATAGCGTAC		TACGACGTTAGCAATCG
		GCTGACTCTGTGAGAGGC		CCCCTCAGGGGTCTCCA
		AGATTCACTATCTCCAGA		ATCGCTTTTCTGGCAGT
		GATAACGCCAAAAACAGC		AAAAGCGGAAACACAG
		TTATACCTGCAGATGAAT		CCTCCCTGACTATCAGC
		TCACTGAGAGCCGAGGAC		GGCCTCCAAGCTGAAG
		ACAGCCCTGTACTATTGT		ACGAGGCTGATTATTAT
		GCTAGAGGAAGATATTCG		TGTGCTTCTTACTCTAG
		GATGTGTGGGGCCAGGGA		CAACACTTTTTACGTTT
		ACTACAGTTACCGTCTCC		TCGGAACCGGGACAAA
		TCA		GGTGACCGTCTTGGGC
A23-4C12	105	GAAGTGCAGCTGGTCGAG	249	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCA
		AGCGGGTTCACCTTTGAC		GCGGAACAAGTAGCGA
		GCATATGGGATGAACTGG		TGTCGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCGTTTCATATAATT		CCCCCAAACTGATGATT
		CTGGTAACAAAGCGTACG		TACGACGTTACCAAGC
		CTGACTCTGTGAGAGGCA		GCCCCTCAGGGGTCTCC
		GATTCACTATCTCCAGAG		AATCGCTTTTCTGGCAG
		ATAACGCCAAAAACAGCT		TAAAAGCGGAAACACA
		TATACCTGCAGATGAATT		GCCTCCCTGACTATCAG
		CACTGAGAGCCGAGGACA		CGGCCTCCAAGCTGAA
		CAGCCCTGTACTATTGTG		GACGAGGCTGATTATTA
		CTAGAGGAAGATATTCGG		TTGTGGTTCTTACTCTA
		ATGTGTGGGGCCAGGGAA		GCAACACTTTTTACGTT
		CTACAGTTACCGTCTCCTCA		TTCGGAACCGGGACAA
				AGGTGACCGTCTTGGGC
A21-4G06	107	GAAGTGCAGCTGGTCGAG	251	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCG
		AGCGGGTTCACCTTTGAC		CCGGATCAAGTAGCAA
		ACATATGGGATGAACTGG		TGTCGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAA
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATAAT		CCCCCAAACTGATGATT
		GCTGGTACCAAAGCGTAC		TACGACGTAACAAAGC
		GCTGACTCTGTGAGAGGC		GCCCCTCAGGGGTCTCC
		AGATTCACTATCTCCAGA		AATCGCTTTTCTGGCAG
		GATAACGCCAAAAACAGC		TAAAAGCGGAAACACA
		TTATACCTGCAGATGAAT		GCCTCCCTGACTATCAG
		TCACTGAGAGCCGAGGAC		CGGCCTCCAAGCTGAA
		ACAGCCCTGTACTATTGT		GACGAGGCTGATTATTA
		GCTAGAGGAAGATATTCG		TTGTGGTTCTTACTCTA
		GATGTGTGGGGCCAGGGA		ACTCCAATTTTTACGTT
		ACTACAGTTACCGTCTCC		TTCGGAACCGGGACAA
		TCA		AGGTGACCGTCTTGGGC
A23-3E04	109	GAAGTGCAGCTGGTCGAG	253	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGAT		GGAGTCCTGGACAGTC
		CCCTTAGACTCTCTTGCGC		GATCACCATTTCCTGCA
		AGCAAGCGGGTTCACCTT		CCGGATCAAGTAGCGA
		TGACAAATATGGGATGCA		TGTCGGTGGCTATAATT
		CTGGGTGAGACAGGCTCC		ATGTGTCCTGGTACCAG
		AGGGAAGGGTCTGGAGTG		CAGCACCCAGGCAAGG
		GGTGTCTGGCATTTCATA		CCCCCAAACTGATGATT
		TAATGCTGGTACCACAGC		TACGACGTTACCGATCG
		GTACGCTGACTCTGTGAA		CCCCTCGGGGGTCTCCA
		AGGCAGATTCACTATCTC		ATCGCTTTTCTGGCAGT
		CAGAGATAACGCCAAAA		AAAAGCGGAAACACAG
		ACAGCTTATACCTGCAGA		CCTCCCTGACTATCAGC
		TGAATTCACTGAGAGCCG		GGCCTCCAAGCTGAAG
		AGGACACAGCCCTGTACT		ACGAGGCTGATTATTAT
		ATTGTGCTAGAGGAAGAT		TGTGGTTCTTACTCTAA
		ATTCGGATGTGTGGGGCC		CTCCAATTTTTACGTTT
		AGGGAACTACAGTTACCG		TCGGAACCGGGACAAA
		TCTCCTCA		GGTGACCGTCTTGGGC
A24-1C09	111	GAAGTGCAGCTGGTCGAG	255	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCA
		AGCGGGTTCACCTTTGAC		CCGGAACAAGTAGCAA
		GCATATGGGATGAACTGG		TGTCGGTAGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATAAT		CCCCCAAACTGATGATT
		GGTGGTAACAAAGCGTAC		TACGACGTTAACGATCG
		GCTGACTCTGTGAGAGGC		CCCCTCAGGGGTCTCCA
		AGATTCACTATCTCCAGA		ATCGCTTTTCTGGCAGT
		GATAACGCCAAAAACAGC		AAAAGCGGAAACACAG
		TTATACCTGCAGATGAAT		CCTCCCTGACTATCAGC
		TCACTGAGAGCCGAGGAC		GGCCTCCAAGCTGAAG
		ACAGCCCTGTACTATTGT		ACGAGGCTGATTATTAT
		GCTAGAGGAAGATATTCG		TGTGGTTCTTACGATAG
		GATGTGTGGGGCCAGGGA		CAACACTTTTTACGTTT
		ACTACAGTTACCGTCTCC		TCGGAACCGGGACAAA
		TCA		GGTGACCGTCTTGGGC
A24-1C04	113	GAAGTGCAGCTGGTCGAG	257	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCA
		AGCGGGTTCACCTTTGAC		CCGGAACAAGTAGCAA
		GGATATGGGATGCACTGG		TATCGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATAATT		CCCCCAAACTGATGATT
		CTGGTAGCACAGCGTACG		TACGACGTTACCAAGC
		CTGACTCTGTGAGAGGCA		GCCCCTCAGGGGTCTCC
		GATTCACTATCTCCAGAG		AATCGCTTTTCTGGCAG
		ATAACGCCAAAAACAGCT		TAAAAGCGGAAACACA
		TATACCTGCAGATGAATT		GCCTCCCTGACTATCAG
		CACTGAGAGCCGAGGACA		CGGCCTCCAAGCTGAA
		CAGCCCTGTACTATTGTG		GACGAGGCTGATTATTA
		CTAGAGGAAGATATTCGG		TTGTGGTTCTTACTCTA
		ATGTGTGGGGCCAGGGAA		ACTCCAATTTTTACGTT
		CTACAGTTACCGTCTCCTCA		TTCGGAACCGGGACAA
				AGGTGACCGTCTTGGGC
A25-1H10	115	GAAGTGCAGCTGGTCGAG	259	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATC		GGAGTCCTGGACAGTC
		CCTTAGACTCTCTTGCGC		GATCACCATTTCCTGCG
		AGCAAGCGGGTTCACCTT		GCGGATCAAGTAGCGA
		TGACGCCTATGGGATGCA		TGTCGGTGGCTATAATT
		CTGGGTGAGACAGGCTCC		ATGTGTCCTGGTACCAG
		AGGGAAGGGTCTGGAGTG		CAGCACCCAGGCAAGG
		GGTGTCTGGCGTTTCATA		CCCCCAAACTGATGATT
		TAATGCTGGTACCACAGC		TACGAAGTTAGCAATC
		GTACGCTGACTCTGTGAG		GCCCCTCAGGGGTCTCC
		AGGCAGATTCACTATCTC		AATCGCTTTTCTGGCAG
		CAGAGATAACGCCAAAA		TAAAAGCGGAAACACA
		ACAGCTTATACCTGCAGA		GCCTCCCTGACTATCAG
		TGAATTCACTGAGAGCCG		CGGCCTCCAAGCTGAA
		AGGACACAGCCCTGTACT		GACGAGGCTGATTATTA
		ATTGTGCTAGAGGAAGAT		TTGTGGTTCTTACTCTA
		ATTCGGATGTGTGGGGCC		ACTCCAATTTTTACGTT
		AGGGAACTACAGTTACCG		TTCGGAACCGGGACAA
		TCTCCTCA		AGGTGACCGTCTTGGGC
A21-4D08	117	GAAGTGCAGCTGGTCGAG	261	CAGGCGGAGGTGGGTC
		AGTGGGGGAGGCTTGGTA		CGGCGGTGGCGGATCG
		CAACCTGGAAGATCCCTT		CAGTCTGCACTTACTCA
		AGACTCTCTTGCGCAGCA		GCCAGCCAGTGTGTCTG
		AGCGGGTTCACCTTTGAC		GGAGTCCTGGACAGTC
		ACATATGGGATGCACTGG		GATCACCATTTCCTGCG
		GTGAGACAGGCTCCAGGG		GCGGAACAAGTAGCGA
		AAGGGTCTGGAGTGGGTG		TGTCGGTGGCTATAATT
		TCTGGCGTTTCATATAATT		ATGTGTCCTGGTACCAG
		CTGGTAACAAAGCGTACG		CAGCACCCAGGCAAGG
		CTGACTCTGTGAAAGGCA		CCCCCAAACTGATGATT
		GATTCACTATCTCCAGAG		TACGACGTTAACGATCG
		ATAACGCCAAAAACAGCT		CCCCTCAGGGGTCTCCA
		TATACCTGCAGATGAATT		ATCGCTTTTCTGGCAGT
		CACTGAGAGCCGAGGACA		AAAAGCGGAAACACAG
		CAGCCCTGTACTATTGTG		CCTCCCTGACTATCAGC
		CTAGAGGAAGATATTCGG		GGCCTCCAAGCTGAAG
		ATGTGTGGGGCCAGGGAA		ACGAGGCTGATTATTAT
		CTACAGTTACCGTCTCCTCA		TGTGGTTCTTACTCTAA
				CAACAATTTTTACGTTT
				TCGGAACCGGGACAAA
				GGTGACCGTCTTGGGC
A24-1D08	119	GAAGTGCAGCTGGTCGAG	263	CAGGCGGAGGTGGGTC
		AGTGGGGGAGGCTTGGTA		CGGCGGTGGCGGATCG
		CAACCTGGAAGATCCCTT		CAGTCTGCACTTACTCA
		AGACTCTCTTGCGCAGCA		GCCAGCCAGTGTGTCTG
		AGCGGGTTCACCTTTGAC		GGAGTCCTGGACAGTC
		AACTATGGGATGCACTGG		GATCACCATTTCCTGCG
		GTGAGACAGGCTCCAGGG		CCGGATCAAGTAGCAA
		AAGGGTCTGGAGTGGGTG		TGTCGTGAGCTATAATT
		TCTGGCATTTCATATAATT		ATGTGTCCTGGTACCAG
		CTGGTAACACAGGGTACG		CAGCACCCAGGCAAGG
		CTGACTCTGTGAGAGGCA		CCCCCAAACTGATGATT
		GATTCACTATCTCCAGAG		TACGACGTTAACAAGC
		ATAACGCCAAAAACAGCT		GCCCCTCAGGGGTCTCC
		TATACCTGCAGATGAATT		AATCGCTTTTCTGGCAG
		CACTGAGAGCCGAGGACA		TAAAAGCGGAAACACA
		CAGCCCTGTACTATTGTG		GCCTCCCTGACTATCAG
		CTAGAGGAAGATATTCGG		CGGCCTCCAAGCTGAA
		ATGTGTGGGGCCAGGGAA		GACGAGGCTGATTATTA
		CTACAGTTACCGTCTCCTCA		TTGTGGTTCTTACGATA
				GCAACACTTTTTACGTT
				TTCGGAACCGGGACAA
				AGGTGACCGTCTTGGGC
A24-1A08	121	GAAGTGCAGCTGGTCGAG	265	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCA
		AGCGGGTTCACCTTTGAC		CCGGATCAAGTAGCAA
		GCATATGGGATGCACTGG		TATCGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATGAT		CCCCCAAACTGATGATT
		GCTGGTAACACAGCGTAC		TACGAAGTTAACAATC
		GCTGACTCTGTGAGAGGC		GCCCCTCAGGGGTCTCC
		AGATTCACTATCTCCAGA		AATCGCTTTTCTGGCAG
		GATAACGCCAAAAACAGC		TAAAAGCGGAAACACA
		TTATACCTGCAGATGAAT		GCCTCCCTGACTATCAG
		TCACTGAGAGCCGAGGAC		CGGCCTCCAAGCTGAA
		ACAGCCCTGTACTATTGT		GACGAGGCTGATTATTA
		GCTAGAGGAAGATATTCG		TTGTGCTTCTTACTCTA
		GATGTGTGGGGCCAGGGA		GCAACACTTTTTACGTT
		ACTACAGTTACCGTCTCC		TTCGGAACCGGGACAA
		TCA		AGGTGACCGTCTTGGGC
A21-4A07	123	GAAGTGCAGCTGGTCGAG	267	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCG
		AGCGGGTTCACCTTTGAC		CCGGATCAAGTAGCAA
		ACCTATGGGATGCACTGG		TATCGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCGTTTCATATAATT		CCCCCAAACTGATGATT
		CTGGTAGCAAAGCGTACG		TACGACGTTAACGATCG
		CTGACTCTGTGAAAGGCA		CCCCTCAGGGGTCTCCA
		GATTCACTATCTCCAGAG		ATCGCTTTTCTGGCAGT
		ATAACGCCAAAAACAGCT		AAAAGCGGAAACACAG
		TATACCTGCAGATGAATT		CCTCCCTGACTATCAGC
		CACTGAGAGCCGAGGACA		GGCCTCCAAGCTGAAG
		CAGCCCTGTACTATTGTG		ACGAGGCTGATTATTAT
		CTAGAGGAAGATATTCGG		TGTGGTTCTTACTCTAA
		ATGTGTGGGGCCAGGGAA		CTCCAATTTTTACGTTT
		CTACAGTTACCGTCTCCTCA		TCGGAACCGGGACAAA
				GGTGACCGTCTTGGGC
A24-1B09	125	GAAGTGCAGCTGGTCGAG	269	CAGTCTTCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCA
		AGCGGGTTCACCTTTGAC		CCGGAACAAGTAGCAA
		AGATATGGGATGCACTGG		TATCGGTAGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCGTTTCATATGAT		CCCCCAAACTGATGATT
		GGTGGTACCACAGCGTAC		TACGACGTTAACAAGC
		GCTGACTCTGTGAGAGGC		GCCCCTCAGGGGTCTCC
		AGATTCACTATCTCCAGA		AATCGCTTTTCTGGCAG
		GATAACGCCAAAAACAGC		TAAAAGCGGAAACACA
		TTATACCTGCAGATGAAT		GCCTCCCTGACTATCAG
		TCACTGAGAGCCGAGGAC		CGGCCTCCAAGCTGAA
		ACAGCCCTGTACTATTGT		GACGAGGCTGATTATTA
		GCTAGAGGAAGATATTCG		TTGTGGTTCTTACGATA
		GATGTGTGGGGCCAGGGA		GCAACACTTTTTACGTT
		ACTACAGTTACCGTCTCC		TTCGGAACCGGGACAA
		TCA		AGGTGACCGTCTTGGGC
A24-1E07	127	GAAGTGCAGCTGGTCGAG	271	CAGTCTGCACTTACTCA
		AGTGGGGGAGGCTTGGTA		GCCAGCCAGTGTGTCTG
		CAACCTGGAAGATCCCTT		GGAGTCCTGGACAGTC
		AGACTCTCTTGCGCAGCA		GATCACCATTTCCTGCG
		AGCGGGTTCACCTTTGAC		CCGGATCAAGTAGCAA
		GAATATGGGATGCACTGG		TGTCGGTGGCTATAATT
		GTGAGACAGGCTCCAGGG		ATGTGTCCTGGTACCAG
		AAGGGTCTGGAGTGGGTG		CAGCACCCAGGCAAGG
		TCTGGCATTTCATATGAT		CCCCCAAACTGATGATT
		GCTGGTAGCACAGCGTAC		TACGAAGTTAGCAATC
		GCTGACTCTGTGAGAGGC		GCCCCTCAGGGGTCTCC
		AGATTCACTATCTCCAGA		AATCGCTTTTCTGGCAG
		GATAACGCCAAAAACAGC		TAAAAGCGGAAACACA
		TTATACCTGCAGATGAAT		GCCTCCCTGACTATCAG
		TCACTGAGAGCCGAGGAC		CGGCCTCCAAGCTGAA
		ACAGCCCTGTACTATTGT		GACGAGGCTGATTATTA
		GCTAGAGGAAGATATTCG		TTGTGGTTCTTACGATA
		GATGTGTGGGGCCAGGGA		GCAACACTTTTTACGTT
		ACTACAGTTACCGTCTCC		TTCGGAACCGGGACAA
		TCA		AGGTGACCGTCTTGGGC
H21-3A07	129	CAAGTGCAGCTGGTGGAG	273	GACATCCAGATGACCC
		TCTGGCGGAGGTGTGGTC		AGTCTCCTTCCACCCTG
		CAACCCGGTAAGTCTCTG		TCTGCATCTGTAGGAGA
		AGACTCTCCTGCGCAGCC		CAGAGTCACCATCACTT
		TCTGGCTTTACATTCAGTA		GTCGAGCTAGTCAGAG
		ACTACTACATGAATTGGG		TATTAGTAACCGGTTGG
		TCAGACAGGCTCCAGGAA		CTTGGTATCAGCAGAA
		AAGGCTTGGAGTGGGTGG		ACCAGGGAAAGCCCCT
		CCACTGTTTCTTACGATA		AAGCTCCTGATCTATAA
		GCGGCAACAAATACTATG		GGCATCTAACTTAGAA
		CAGATTCTGTGAAAGGGC		AGTGGGGTCCCATCAA
		GATTCACCATTTCCAGAG		GGTTCAGCGGCAGTGG
		ACAACTCTAAGAACACTC		ATCTGGGACAGAATTC
		TTTATCTGCAGATGAATA		ACTCTCACCATCAGCAG
		GCCTGAGAGCTGAAGACA		CCTGCAGCCTGATGATT
		CTGCCGTTTACTATTGTGC		TTGCAACTTACTATTGT
		GAGGGGGAGTTGAAGAC		CAACAGACGAACAGTT
		GGGATGCTTTTGACGTGT		TCCCTCTCACTTTCGGC
		GGGGCCAGGGCACAATG		GGAGGGACCAAGGTGG
		GTCACCGTATCATCA		AGATCAAA
H21-4D11	131	CAAGTGCAGCTGGTGGAG	275	GACATCCAGATGACCC
		TCTGGCGGAGGTGTGGTC		AGTCTCCTTCCACCCTG
		CAACCTGGAAGGTCTCTG		TCTGCATCTGTAGGAGA
		AGACTCTCCTGCGCAGCC		CAGAGTCACCATCACTT
		TCTGGATTTACATTCAGT		GTCAAGCTAGTCAGGG
		AACTACGCCATGAATTGG		TATTAGTAACCGGTTGG
		GTCAGACAGGCTCCAGGA		CTTGGTATCAGCAGAA
		AAAGGCTTGGAGTGGGTG		ACCAGGGAAAGCCCCT
		GCCATTATTTCTTACGATA		AAGCTCCTGATCTATAA
		GCAGCAGCAAATACTATG		GGCATCTAACTTACAAA
		CAGATTCTGTGAAAGGGC		GTAGGGTCCCATCAAG
		GATTCACCATTTCCAGAG		GTTCAGCGGCAGTGGA
		ACAACTCTAAGAACACTC		TCTGGGACAGAATTCAC
		TTTATCTGCAGATGAATA		TCTCACCATCAGCAGCC
		GCCTGAGAGCTGAAGACA		TGCAGCCTGATGATTTT
		CTGCCGTTTACTATTGTGC		GCAACTTACTATTGTCA
		GAGGGGGAGTGGGAAGC		ACAGACGAACAGTTTC
		GGGATGCTTTTGACGTGT		CCTCTCACTTTCGGCGG
		GGGGCCAGGGCACAATG		AGGGACCAAGGTGGAG
		GTCACCGTATCATCA		ATCAAA
H21-3C11	133	CAAGTGCAGCTGGTGGAG	277	GACATCCAGATGACCC
		TCTGGCGGAGGTGTGGTC		AGTCTCCTTCCACCCTG
		CAACCTGGAAGGTCTCTG		TCTGCATCTGTAGGAGA
		AGACTCTCCTGCGCAGCC		CAGAGTCACCATCACTT
		TCTGGCTTTACATTCAGTA		GTCGAGCTAGTCAGAG
		ACTACGCCATGCATTGGG		TATTAGTAACCGGTTGG
		TCAGACAGGCTCCAGGAA		CTTGGTATCAGCAGAA
		AAGGCTTGGAGTGGGTGG		ACCAGGGAAAGCCCCT
		CCGTTGTTTCTTACGATGG		AAGCTCCTGATCTATAA
		CGGCAACATATACTATGC		GGCATCTAGCTTACAAA
		AGATTCTGTGAAAGGGCG		GTGGGGTCCCATCAAG
		ATTCACCATTTCCAGAGA		GTTCAGCGGCAGTGGA
		CAACTCTAAGAACACTCT		TCTGGGACAGAATTCAC
		TTATCTGCAGATGAATAG		TCTCACCATCAGCAGCC
		CCTGAGAGCTGAAGACAC		TGCAGCCTGATGATTTT
		TGCCGTTTACTATTGTGCG		GCAACTTACTATTGTCA
		AGGGGGAGTGGGCGGCG		ACAGACGAACAGTTTC
		GGATGCTTTTGACGTGTG		CCTCTCACTTTCGGCGG
		GGGCCAGGGCACAATGGT		AGGGACCAAGGTGGAG
		CACCGTATCATCA		ATCAAA
H21-3A09	135	CAAGTGCAGCTGGTGGAG	279	GACATCCAGATGACCC
		TCTGGCGGAGGTGTGGTC		AGTCTCCTTCCACCCTG
		CAACCTGGAAGGTCTCTG		TCTGCATCTGTAGGAGA
		AGACTCTCCTGCGCAGCC		CAGAGTCACCATCACTT
		TCTGGCTTTACATTCAGTA		GTCGAGCTAGTCAGAG
		ACTACGACATTCATTGGG		TATTAGTAACCGGTTGG
		TCAGACAGGCTCCAGGAA		CTTGGTATCAGCAGAA
		AAAGCTTGGAGTGGGTGG		ACCAGGGAAAGCCCCT
		CCGTTGTTTCTTACGATGG		AAGCTCCTGATCTATAA
		CAGCAACACATACTATGC		GGCATCTAACTTACAAA
		AGATTCTGTGAAAGGGCG		GTGGGGTCCCATCAAG
		ATTCACCATTTCCAGAGA		GTTCAGCGGCAGTGGA
		CAACTCTAAGAACACTCT		TCTGGGAAAGAATTCA
		TTATCTGCAGATGAATAG		CTCTCACCATCAGCAGC
		CCTGAGAGCTGAAGACAC		CTGCAGCCTGATGATTT
		TGCCGTTTACTATTGTGCG		TGCAACTTACTATTGTC
		AGGGGGAGTGGGAAGCG		AACAGACGAACAGTTT
		GGATGCTTTTGACGTGTG		CCCTCTCACTTTCGGCG
		GGGCCAGGGCACAATGGT		GAGGGACCAAGGTGGA
		CACCGTATCATCA		GATCAAA
H21-4H04	137	CAAGTGCAGCTGGTGGAG	281	GACATCCAGATGACCC
		TCTGGCGGAGGTGTGGTC		AGTCTCCTTCCACCCTG
		CAACCCGTTTAAGTCTCT		TCTGCATCTGTAGGAGA
		GAGACTCTCCTGCGCAGC		CAGAGTCACCATCACTT
		CTCTGGCTTTACACTTAGT		GTCAAGCTAGTCAGAG
		AGCTACGCCATTCATTGG		TATTAGTAGCCGGTTGG
		GTCAGACAGGCTCCAGGA		CTTGGTATCAGCAGAA
		AAAGGCTTGGAGTGGGTG		ACCAGGGAAAGCCCCT
		GCCGTTGTTTCTTACGATG		AAGCTCCTGATCTATAA
		GCGGCAGCAAATACTATG		GGCATCTAGCTTACAAA
		CAGATTCTGTGAAAGGGC		GTGGGGTCCCATCAAG
		GATTCACCATTTCCAGAG		GTTCAGCGGCGGTGGA
		ACAACTCTAAGAACACTC		TCTGGGACAGAATTCAC
		TTTATCTGCAGATGAATA		TCTCACCATCAGCAGCC
		GCCTGAGAGCTGAAGACA		TGCAGCCTGATGATTTT
		CTGCCGTTTACTATTGTGC		GCAACTTACTATTGTCA
		GAGGGGGAGTGGGAGGC		ACAGACGAACAGTTTC
		GGGATGCTTTTGACGTGT		CCTCTCACTTTCGGCGG
		GGGGCCAGGGCACAATG		AGGGACCAAGGTGGAG
		GTCACCGTATCATCA		ATCAAA
H23-3D08	139	CAAGTGCAGCTGGTGGAG	283	GACATCCAGATGACCC
		TCTGGCGGAGGTGTGGTC		AGTCTCCTTCCACCCTG
		CAACCTGGAAGGTCTCTG		TCTGCATCTGTAGGAGA
		AGACTCTCCTGCGCAGAC		CAGAGTCACCATCACTT
		TCTGGCTTTACATTCAGTG		GTCAAGCTAGTCAGGG
		ACTACGACATGCATTGGG		TATTAGTAACCGGTTGG
		TCAGACAGGCTCCAGGAA		CTTGGTATCAGCAGAA
		AAGGCTTGGAGTGGGTGG		ACCAGGGAAAGCCCCT
		CCGTTATTTCTTACGATGG		AAGCTCCTGATCTATAA
		CGGCAGCAAATACTATGC		GGCATCTAACTTAGAA
		AGATTCTGTGAAAGGGCG		ACTGGGGTCCCATCAA
		ATTCACCATTTCCAGAGA		GGTTCAGCGGCAGTGG
		CAACTCTAAGAACACTCT		ATCTGGGACAGAATTC
		TTATCTGCAGATGAATAG		ACTCTCACCATCAGCAG
		CCTGAGAGCTGAAGACAC		CCTGCAGCCTGATGATT
		TGCCGTTTACTATTGTGCG		TTGCAACTTACTATTGT
		AGGGGGAGTGGGCAGCG		CAACAGACGAACAGTT
		GGATGCTTTTGACGTGTG		TCCCTCTCACTTTCGGC
		GGGCCAGGGCACAATGGT		GGAGGGACCAAGGTGG
		CACCGTATCATCA		AGATCAAA
H21-4D09	141	CAAGTGCAGCTGGTGGAG	285	GACATCCAGATGACCC
		TCTGGCGGAGGTGTGGTC		AGTCTCCTTCCACCCTG
		CAACCTGGAAGGTCTCTG		TCTGCATCTGTAGGAGA
		AGACTCTCCTGCGCAGCC		CAGAGTCACCATCACTT
		TCTGGCTTTACATTCAGTA		GTCAAGCTAGTCAGGG
		ACTACTACATTAATTGGG		TATTCGTAACCGGTTGG
		TCAGACAGGCTCCAGGAA		CTTGGTATCAGCAGAA
		AAGGCTTGGAGTGGGTGG		ACCAGGGAAAGCCCCT
		CCAGTGTTTCTTACGATG		AAGCTCCTGATCTATAA
		GCGGCAGCATATACTATG		GGCATCTAACTTACAAA
		CAGATTCTGTGAAAGGGC		GTGGGGTCCCATCAAG
		GATTCACCATTTCCAGAG		GTTCAGCGGCAGTGGA
		ACAACTCTAAGAACACTC		TCTGGGACAGAATTCAC
		TTTATCTGCAGATGAATA		TCTCACCATCAGCAGCC
		GCCTGAGAGCTGAAGACA		TGCAGCCTGATGATTTT
		CTGCCGTTTACTATTGTGC		GCAACTTACTATTGTCA
		GAGGGGGAGTGGGAGGC		ACAGACGAACAGTTTC
		GGGATGCTTTTGACGTGT		CCTCTCACTTTCGGCGG
		GGGGCCAGGGCACAATG		AGGGACCAAGGTGGAG
		GTCACCGTATCATCA		ATCAAA
H24-1D11	143	CAAGTGCAGCTGGTGGAG	287	GACATCCAGATGACCC
		TCTGGCGGAGGTGTGGTC		AGTCTCCTTCCACCCTG
		CAACCTGGAAGGTCTCTG		TCTGCATCTGTAGGAGA
		AGACTCTCCTGCGCAGCC		CAGAGTCACCATCACTT
		TCTGGCTTTACATTCAGTA		GCCGGGCCAGTCAGAG
		GCTACGCCATGCACTGGG		TATTAGTAGCCGGTTGG
		TCAGACAGGCTCCAGGAA		CCTGGTATCAGCAGAA
		AAGGCTTGGAGTGGGTGG		ACCAGGGAAAGCCCCT
		CCGTTATCTCTTACGATG		AAGCTCCTGATCTATAA
		GTAGCAATAAGTACTATG		GGCATCTAGCTTAGAA
		CAGATTCTGTGAAAGGGC		ACTGGGGTCCCATCAA
		GATTCACCATTTCCAGAG		GGTTCAGCGGCAGTGG
		ACAACTCTAAGAACACTC		ATCTGGGACAGAATTC
		TTTATCTGCAGATGAATA		ACTCTCACCATCAGCAG
		GCCTGAGAGCTGAAGACA		CCTGCAGCCTGATGATT
		CTGCCGTTTACTATTGTGC		TTGCAACTTACTATTGT
		GAGGGGGAGTGGGGGAC		CAACAGACGAACAGTT
		GGGATGCTTTTGACGTGT		TCCCTCTCACTTTCGGC
		GGGGCCAGGGCACAATG		GGAGGGACCAAGGTGG
		GTCACCGTATCATCA		AGATCAAA

TABLE 16 — CDR3 sequences of heavy-chain and light-chain variable regions of selected antibodies

	Heavy-chain	Light-chain
	variable regions	variable regions
Clone	SEQ ID				SEQ ID
name	NO:	CDR1	CDR2	CDR3	NO:	CDR1	CDR2	CDR3
A11-C07	18	EYGMH	GVSWNSGS	GRYSDV	162	TGSSSDVG	DVTKRPS	ASYSSNT
		SEQ ID	IAYADSVRG	SEQ ID		GYNYVS	SEQ ID	FYV
		NO:	SEQ ID	NO:		SEQ ID	NO:	SEQ ID
		293	NO: 313	362		NO: 374	406	NO: 426
A11-G06	20	EYGMH	GVSWNSGS	GRMLDV	164	TGSSSDVG	DVTKRPS	GSYNNNT
		SEQ ID	IAYADSVRG	SEQ ID		GYNYVS	SEQ ID	FYV
		NO:	SEQ ID	NO:		SEQ ID	NO:	SEQ ID
		293	NO: 313	363		NO: 374	406	NO: 427
A12-C09	22	EYGMH	GVSWNSGS	GRTMDV	166	TGSSSDVG	DVTKRPS	GSYSSNT
		SEQ ID	IAYADSVRG	SEQ ID		GYNYVS	SEQ ID	FYV
		NO:	SEQ ID	NO:		SEQ ID	NO:	SEQ ID
		293	NO: 313	364		NO: 374	406	NO: 428
A12-E05	24	EYGMH	GVSWNSGS	GRSLDV	168	TGSSSDVG	DVTKRPS	ASYSSNT
		SEQ ID	IAYADSVRG	SEQ ID		GYNYVS	SEQ ID	FYV
		NO:	SEQ ID	NO:		SEQ ID	NO:	SEQ ID
		293	NO: 313	365		NO: 374	406	NO: 426
A12-E01	26	EYGMH	GVSWNSGS	GRLLDV	170	TGSSSDVG	DVTKRPS	GSYSNNN
		SEQ ID	IAYADSVRG	SEQ ID		GYNYVS	SEQ ID	FYV
		NO:	SEQ ID	NO:		SEQ ID	NO:	SEQ ID
		293	NO: 313	366		NO: 374	406	NO: 429
A12-E04	28	EYGMH	GVSWNSGS	GRLFDV	172	TGSSSDVG	DVTKRPS	GSYSNSN
		SEQ ID	IAYADSVRG	SEQ ID		GYNYVS	SEQ ID	FYV
		NO:	SEQ ID	NO:		SEQ ID	NO:	SEQ ID
		293	NO: 313	367		NO: 374	406	NO: 430
A12-F02	30	EYGMH	GVSWNSGS	GRYLDV	174	TGSSSDVG	DVTKRPS	GSYDSNT
		SEQ ID	IAYADSVRG	SEQ ID		GYNYVS	SEQ ID	FYV
		NO:	SEQ ID	NO:		SEQ ID	NO:	SEQ ID
		293	NO: 313	368		NO: 374	406	NO: 431
A12-H04	32	EYGMH	GVSWNSGS	GRLLDV	176	TGSSSDVG	DVTKRPS	GAYSNTN
		SEQ ID	IAYADSVRG	SEQ ID		GYNYVS	SEQ ID	FYV
		NO:	SEQ ID	NO:		SEQ ID	NO:	SEQ ID
		293	NO: 313	366		NO: 374	406	NO: 432

TABLE 17 — CDR sequences of heavy-chain and light-chain variable regions of selected antibodies

	heavy-chain	light-chain
	variable regions	variable regions
Clone	SEQ ID				SEQ ID
name	NO:	CDR1	CDR2	CDR3	NO:	CDR1	CDR2	CDR3
A23-	34	TYGMN	GISYNGGTT	GRYSDV	178	GGSSSDVG	DVNKRPS	GSYDSNT
3H04		SEQ	AYADSVRG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 407	SEQ ID
		294	NO: 314	362		NO: 375		NO: 431
A24-	38	AYGMH	GISYNSGTK	GRYSDV	182	GGSSSNIG	DVNKRPS	ASYSNSN
1G10		SEQ	AYADSVKG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 407	SEQ ID
		295	NO: 315	362		NO: 376		NO: 430
A24-	40	AYGMH	GVSYNSGTT	GRYSDV	184	SGSSSNVG	DVTKRPS	GSYSNSN
1F07		SEQ	AYADSVRG	SEQ		SYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 406	SEQ ID
		295	NO: 316	362		NO: 377		NO: 369
A21-	42	EYGMH	GISYNSGNK	GRYSDV	186	SGSSSNIG	DVSKRPS	GSYDSNT
4B10		SEQ	AYADSVRG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 408	SEQ ID
		293	NO: 317	362		NO: 378		NO: 431
A21-	44	SYGMH	GISYNGGNT	GRYSDV	188	SGSSSNIG	DVNERPS	GSYSNNN
4G04		SEQ	AYADSVRG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 409	SEQ ID
		296	NO: 318	362		NO: 378		NO: 429
A23-	46	AYGMN	GISYNSGTI	GRYSDV	190	GGSSSNVG	DVSNRPS	GSYSNSN
3H05		SEQ	AYADSVKG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 410	SEQ ID
		297	NO: 319	362		NO: 379		NO: 430
A21-	48	NYGMN	GISYNSGTK	GRYSDV	192	SGSSSDIG	DVNKRPS	ASYSSNT
3A09		SEQ	AYADSVKG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 407	SEQ ID
		298	NO: 315	362		NO: 380		NO: 426
A21-	50	SYGMH	GISYNGGSK	GRYSDV	194	SGSSSNIG	DVTDRPS	GSYSSNT
4B06		SEQ	AYADSVRG	SEQ		SYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 411	SEQ ID
		296	NO: 320	362		NO: 381		NO: 428
A24-	52	KYGMN	GISYNSGNT	GRYSDV	196	AGSSSDIG	DVSKRPS	GSYDSNT
1B05		SEQ	AYADSVRG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 408	SEQ ID
		299	NO: 321	362		NO: 382		NO: 431
A23-	54	AYGMH	GISYNSGTT	GRYSDV	198	AGSSSNIG	DVSKRPS	GSYSNSN
3A08		SEQ	AYADSVKG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 408	SEQ ID
		295	NO: 322	362		NO: 383		NO: 430
A21-	56	TYGMH	GISYNAGNK	GRYSDV	200	SGSSSNVG	DVNNRPS	GSYSSNT
4C08		SEQ	AYADSVRG	SEQ		SYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 412	SEQ ID
		300	NO: 323	362		NO: 377		NO: 428
A23-	58	AYGMH	GVSYDAGNT	GRYSDV	202	SGSSSNIG	DVTDRPS	GSYSSNT
4D09		SEQ	AYADSVRG	SEQ		SYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 411	SEQ ID
		295	NO: 324	362		NO: 381		NO: 428
A23-	60	AYGMN	GISYNAGST	GRYSDV	204	TGSSSDVG	DVTNRPS	GSYDSNT
3D03		SEQ	AYADSVRG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 413	SEQ ID
		297	NO: 325	362		NO: 374		NO: 431
A21-	62	AYGMN	GISYNAGNK	GRYSDV	206	SGSSSNIG	DVNKRPS	ASYSSNT
4B03		SEQ	AYADSVRG	SEQ		SYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 407	SEQ ID
		297	NO: 323	362		NO: 381		NO: 426
A21-	64	NYGMH	GISYDAGTT	GRYSDV	208	GGTSSNIG	DVTNRPS	GSYSNTN
3D10		SEQ	AYADSVKG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 413	SEQ ID
		301	NO: 326	362		NO: 384		NO: 434
A21-	66	AYGMH	GISYNAGNK	GRYSDV	210	AGSSSNIG	DVSKRPS	GSYSNSN
3A10		SEQ	AYADSVRG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 408	SEQ ID
		295	NO: 323	362		NO: 383		NO: 430
A21-	68	SYGMH	GISYNSGNK	GRYSDV	212	SGTSSDIG	DVSKRPS	GSYSNNN
4H04		SEQ	AYADSVKG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 408	SEQ ID
		296	NO: 327	362		NO: 386		NO: 429
A21-	70	AYGMN	GISYNGGTK	GRYSDV	214	GGTSSNIG	DVNDRPS	ASYSSNT
4F11		SEQ	AYADSVRG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 414	SEQ ID
		297	NO: 328	362		NO: 384		NO: 426
A23-	72	TYGMH	GISYNSGTI	GRYSDV	216	AGSSSNIG	DVSNRPS	GSYDSNT
3G05		SEQ	AYADSVRG	SEQ		SYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 410	SEQ ID
		300	NO: 329	362		NO: 385		NO: 431
A23-	74	KYGMH	GISYNAGSK	GRYSDV	218	AGSSSNIG	DVSDRPS	GSYDSNT
3A10		SEQ	AYADSVKG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 415	SEQ ID
		302	NO: 330	362		NO: 383		NO: 431
A25-	76	AYGMN	GISYNSGNT	GRYSDV	220	AGSSSDIG	DVSERPS	GSYDSNT
1H04		SEQ	AYADSVRG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 416	SEQ ID
		297	NO: 321	362		NO: 382		NO: 431
A23-	78	AYGMH	GISYNSGSK	GRYSDV	222	SGSSSDVG	DVSERPS	GSYDSNT
3B06		SEQ	AYADSVKG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 416	SEQ ID
		295	NO: 331	362		NO: 387		NO: 431
A23-	80	NYGMN	GISYDSGNK	GRYSDV	224	GGSSSNIG	DVTKRPS	ASYSSNT
4A09		SEQ	AYADSVKG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 406	SEQ ID
		298	NO: 332	362		NO: 376		NO: 426
A25-	82	AYGMH	GISYNGGTI	GRYSDV	226	GGTSSDVG	DVNKRPS	GSYSNSN
1D09		SEQ	AYADSVKG	SEQ		SYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 407	SEQ ID
		295	NO: 333	362		NO: 388		NO: 430
A21-	84	AYGMN	GVSYNAGNK	GRYSDV	228	TGSSSNVG	DVSKRPS	GSYSSNT
4E10		SEQ	AYADSVRG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 408	SEQ ID
		297	NO: 334	362		NO: 389		NO: 428
A23-	86	TYGMH	GISYDSGTT	GRYSDV	230	SGTSSDIG	DVTEPPS	ASYSSNT
3C04		SEQ	AYADSVKG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 417	SEQ ID
		300	NO: 335	362		NO: 386		NO: 426
A23-	88	AYGMN	GISYNSGNI	GRYSDV	232	AGTSSNIG	DVNDRPS	GSYDSNT
3G06		SEQ	AYADSVRG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 414	SEQ ID
		297	NO: 336	362		NO: 390		NO: 431
A24-	90	KYGMH	GVSYNAGTT	GRYSDV	234	TGSSSNIG	DVTNRPS	GSYSNSN
1E09		SEQ	AYADSVRG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 413	SEQ ID
		302	NO: 337	362		NO: 391		NO: 430
A23-	92	TYGMH	GISYNSGNI	GRYSDV	236	GGSSSNIG	DVTKRPS	GSYDSNT
3F03		SEQ	AYADSVKG	SEQ		SYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 406	SEQ ID
		300	NO: 338	362		NO: 392		NO: 431
A21-	94	AYGMN	GISYNAGNK	GRYSDV	238	SGTSSNVG	DVSDRPS	GSYSNSN
4F07		SEQ	AYADSVKG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 415	SEQ ID
		297	NO: 339	362		NO: 393		NO: 430
A24-	96	AYGMN	GISYNAGNT	GRYSDV	240	GGSSSNVG	DVSKRPS	GSYSNSN
1A03		SEQ	AYADSVKG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 408	SEQ ID
		297	NO: 340	362		NO: 379		NO: 430
A24-	98	AYGMH	GISYNSGTT	GRYSDV	242	TGSSSDVG	EVNKRPS	ASYSSNT
1H11		SEQ	AYADSVRG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 418	SEQ ID
		295	NO: 341	362		NO: 374		NO: 426
A21-	100	NYGMN	GISYNSGTK	GRYSDV	244	SGTSSNVG	DVNKRPS	GSYSNSN
3D09		SEQ	AYADSVKG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 407	SEQ ID
		298	NO: 315	362		NO: 393		NO: 430
A24-	102	NYGMH	GISYNSGNK	GRYSDV	246	SGSSSDIG	DVTDRPS	GSYSNNN
1D10		SEQ	AYADSVKG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 411	SEQ ID
		301	NO: 327	362		NO: 380		NO: 429
A21-	104	AYGMH	GISYDAGNI	GRYSDV	248	AGTSSNIG	DVSNRPS	ASYSSNT
4B04		SEQ	AYADSVRG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 410	SEQ ID
		295	NO: 342	362		NO: 390		NO: 426
A23-	106	AYGMN	GVSYNSGNK	GRYSDV	250	SGTSSDVG	DVTKRPS	GSYSSNT
4C12		SEQ	AYADSVRG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 406	SEQ ID
		297	NO: 343	362		NO: 394		NO: 428
A21-	108	TYGMN	GISYNAGTK	GRYSDV	252	AGSSSNVG	DVTKRPS	GSYSNSN
4G06		SEQ	AYADSVRG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 406	SEQ ID
		294	NO: 344	362		NO: 395		NO: 430
A23-	110	KYGMH	GISYNAGTT	GRYSDV	254	TGSSSDVG	DVTDRPS	GSYSNSN
3E04		SEQ	AYADSVKG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 411	SEQ ID
		302	NO: 345	362		NO: 374		NO: 430
A24-	112	AYGMN	GISYNGGNK	GRYSDV	256	TGTSSNVG	DVNDRPS	GSYDSNT
1C09		SEQ	AYADSVRG	SEQ		SYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 414	SEQ ID
		297	NO: 346	362		NO: 396		NO: 431
A24-	114	GYGMH	GISYNSGST	GRYSDV	258	TGTSSNIG	DVTKRPS	GSYSNSN
1C04		SEQ	AYADSVRG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 406	SEQ ID
		303	NO: 347	362		NO: 397		NO: 430
A25-	116	AYGMH	GVSYNAGTT	GRYSDV	260	GGSSSDVG	EVSNRPS	GSYSNSN
1H10		SEQ	AYADSVRG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 419	SEQ ID
		295	NO: 337	362		NO: 375		NO: 430
A21-	118	TYGMH	GVSYNSGNK	GRYSDV	262	GGTSSDVG	DVNDRPS	GSYSNNN
4D08		SEQ	AYADSVKG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 414	SEQ ID
		300	NO: 348	362		NO: 398		NO: 429
A24-	120	NYGMH	GISYNSGNT	GRYSDV	264	AGSSSNVV	DVNKRPS	GSYDSNT
1D08		SEQ	GYADSVRG	SEQ		SYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 407	SEQ ID
		301	NO: 349	362		NO: 399		NO: 431
A24-	122	AYGMH	GISYDAGNT	GRYSDV	266	TGSSSNIG	EVNNRPS	ASYSSNT
1A08		SEQ	AYADSVRG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 420	SEQ ID
		295	NO: 350	362		NO: 391		NO: 426
A21-	124	TYGMH	GVSYNSGSK	GRYSDV	268	AGSSSNIG	DVNDRPS	GSYSNSN
4A07		SEQ	AYADSVKG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 414	SEQ ID
		300	NO: 351	362		NO: 383		NO: 430
A24-	126	RYGMH	GVSYDGGTT	GRYSDV	270	TGTSSNIG	DVNKRPS	GSYDSNT
1B09		SEQ	AYADSVRG	SEQ		SYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 407	SEQ ID
		304	NO: 352	362		NO: 400		NO: 431
A24-	128	EYGMH	GISYDAGST	GRYSDV	272	AGSSSNVG	EVSNRPS	GSYDSNT
1E07		SEQ	AYADSVRG	SEQ		GYNYVS	SEQ ID	FYV
		ID NO:	SEQ ID	ID NO:		SEQ ID	NO: 419	SEQ ID
		293	NO: 353	362		NO: 395		NO: 431
A21-				GRYSDV	180
4C03	36			SEQ ID
				NO: 362
H21-	130	NYYMN	TVSYDSGNK	GSRR	274	RASQSISN	KASNLES	QQTNSFP
3A07		SEQ	YYADSVKG	DAFDV		RLA	SEQ ID	LT
		ID NO:	SEQ ID	SEQ ID		SEQ ID	NO: 421	SEQ ID
		305	NO: 354	NO: 369		NO: 401		NO: 435
H21-	132	NYAMN	IISYDSSSK	GSGKRD	276	QASQGISN	KASNLQS	QQTNSFP
4D11		SEQ	YYADSVKG	AFDV		RLA	SEQ ID	LT
		ID NO:	SEQ ID	SEQ ID		SEQ ID	NO: 422	SEQ ID
		306	NO: 355	NO: 370		NO: 402		NO: 435
H21-	134	NYAMH	VVSYDGGNI	GSGRRD	278	RASQSISN	KASSLQS	QQTNSFP
3C11		SEQ	YYADSVKG	AFDV		RLA	SEQ ID	LT
		ID NO:	SEQ ID	SEQ ID		SEQ ID	NO: 423	SEQ ID
		307	NO: 356	NO: 371		NO: 401		NO: 435
H21-	136	NYDIH	VVSYDGSNT	GSGKRD	280	RASQSISN	KASNLQS	QQTNSFP
3A09		SEQ	YYADSVKG	AFDV		RLA	SEQ ID	LT
		ID NO:	SEQ ID	SEQ ID		SEQ ID	NO: 422	SEQ ID
		308	NO: 357	NO: 370		NO: 401		NO: 435
H21-	138	SYAIH	VVSYDGGSK	GSGRRD	282	QASQSISS	KASSLQS	QQTNSFP
4H04		SEQ	YYADSVKG	AFDV		RLA	SEQ ID	LT
		ID NO:	SEQ ID	SEQ ID		SEQ ID	NO: 423	SEQ ID
		309	NO: 358	NO: 371		NO: 403		NO: 435
H23-	140	DYDMH	VISYDGGSK	GSGQRD	284	QASQGISN	KASNLET	QQTNSFP
3D08		SEQ	YYADSVKG	AFDV		RLA	SEQ ID	LT
		ID NO:	SEQ ID	SEQ ID		SEQ ID	NO: 424	SEQ ID
		310	NO: 359	NO: 372		NO: 402		NO: 435
H21-	142	NYYIN	SVSYDGGSI	GSGRRD	286	QASQGIRN	KASNLQS	QQTNSFP
4D09		SEQ	YYADSVKG	AFDV		RLA	SEQ ID	LT
		ID NO:	SEQ ID	SEQ ID		SEQ ID	NO: 422	SEQ ID
		311	NO: 360	NO: 371		NO: 404		NO: 435
H24-	144	SYAMH	VISYDGSNK	GSGGRD	288	RASQSISS	KASSLET	QQTNSFP
1D11		SEQ	YYADSVKG	AFDV		RLA	SEQ ID	LT
		ID NO:	SEQ ID	SEQ ID		SEQ ID	NO: 425	SEQ ID
		312	NO: 361	NO: 373		NO: 405		NO: 435

Claims as granted

5 claims

Classifications

8 codes

IPC · International Patent Classification

Section A — Human necessities

A61K49/00
A61K39/395
A61K39/40

Section C — Chemistry; metallurgy

C12P21/08
C07K16/00
C07K16/28
C07K14/705

Section G — Physics

G01N33/566

Claim changes

Soon

Coming soonHow the claims changed between publication and grant

See which claims were amended, added or cancelled during examination, with every added and removed word marked.

AmendedAddedCancelledUnchanged

The published claims of this application are not paired with the granted ones in what we hold.

File wrapper

⤢ drag to zoom

USPTOApplicanthover for detail · click to open

Pendency

4.9 y

1,782 days filing → grant

Office actions

after a restriction

Responses

no RCE

Interviews

examiner interview summaries

Examiner

Chun W Dahle

art unit 1644 · TC 1600

Law firm

Law firm · Log in to unlock

Citations: 22 back · 0 forward

See the full prosecution history — every USPTO and applicant action on this file, in order.

Documents

Log in to open the documents of this file: the application as filed, every office action and response, the notice of allowance.

Chain of title

⤢ drag to zoom

Titlehover for detail · click to open

See the full assignment history — every owner this patent has passed through, with recordation dates and reel/frame numbers.