Genetically modified mice that produce hybrid antibodies

A genetically modified mouse comprising in its germline human unrearranged heavy chain variable region gene segments operably linked to a mouse heavy chain constant region gene at an endogenous mouse heavy chain immunoglobulin locus, wherein rearrangement of the human heavy chain variable region gene segments in the mouse results in a rearranged human heavy chain variable region gene linked to the mouse heavy chain constant region gene, wherein the mouse in response to an antigen produces a hybrid antibody that comprises a human heavy chain variable region encoded by the rearranged human heavy chain variable region gene and a mouse heavy chain constant region encoded by the mouse heavy chain constant region gene, and wherein the mouse does not produce fully human antibodies.

A genetically modified mouse comprising in its germline:n(i) a hybrid heavy chain immunoglobulin locus comprising human unrearranged heavy chain variable region gene segments operably linked to a mouse heavy chain constant region gene at an endogenous heavy chain immunoglobulin locus, wherein rearrangement of the human heavy chain variable region gene segments in the mouse results in a rearranged human heavy chain variable region gene linked to the mouse heavy chain constant region gene; and(ii) a hybrid light chain immunoglobulin locus comprising human unrearranged light chain variable region gene segments linked to a mouse light chain constant region gene at an endogenous light chain immunoglobulin locus wherein rearrangement of the human light chain variable region gene segments in the mouse results in a rearranged human light chain variable region gene linked to the mouse light chain constant region gene;wherein the mouse in response to an antigen produces a hybrid antibody, the hybrid antibody comprising a heavy chain comprising a human heavy chain variable region encoded by the rearranged human heavy chain variable region gene and a mouse heavy chain constant region encoded by the mouse heavy chain constant region gene and a light chain comprising a human light chain variable region encoded by the rearranged human light chain variable region gene and a mouse light chain constant region encoded by the mouse light chain constant region gene;wherein the mouse does not produce fully human antibodies.