Animal models and therapeutic molecules

A transgenic mouse comprising in its germline a chimeric homozygous immunoglobulin heavy chain (IgH) locus comprising unrearranged human IgH chain variable region gene segments at an endogenous IgH locus upstream of and operatively linked to a heavy chain constant region comprising an endogenous C gene segment of a mouse IgH locus comprising a mouse Cμ gene segment;

• wherein said chimeric IgH chain locus comprises, in 5′ to 3′ orientation, said IgH chain variable region gene segments comprising human IgH V gene segments, human D gene segments and human J segments comprising a 3′ JH gene segment, a truncated human IgH JC intron, a mouse IgH JC intron truncated at its 5′ end, an enhancer, and said heavy chain constant region;
• wherein said human 3′ JH gene segment is less than 2 kb upstream of said truncated mouse IgH JC intron;
• wherein genome of said transgenic mouse comprises all or part of mouse IgH variable region DNA and wherein expression of the mouse IgH chain locus comprising the mouse IgH variable region and the mouse IgH constant region is inactive in said transgenic mouse;
• wherein said mouse comprises in its germline a chimeric homozygous Ig light chain kappa (Igκ) locus comprising unrearranged human immunoglobulin kappa (Igκ) chain variable region gene segments at an endogenous Igκ locus upstream of and operatively linked to a light chain constant region comprising an endogenous IgκC gene segment;
• wherein said chimeric Ig light chain kappa locus comprises, in 5′ to 3′ orientation, said unrearranged human Igκ chain variable region gene segments comprising human Vκ gene segments and human Jκ segments comprising a 3′ Jκ gene segment, a truncated human Igκ JC intronic DNA, a mouse Igκ JC intronic DNA truncated at its 5′ end, a kappa chain locus enhancer, and said light chain constant region,
• wherein said transgenic mouse is capable of producing chimeric antibodies comprising a chimeric heavy chain comprising a human IgH variable region and a mouse Cμ region and a chimeric kappa chain comprising a human Igκ variable region and a mouse Cκ region upon stimulation with antigen;
• wherein said transgenic mouse is capable of breeding with another said transgenic mouse to provide subsequent generation mice comprising in their genomes homozygous IgH loci comprising unrearranged human IgH variable region gene segments at an endogenous IgH locus upstream of a constant (C) region comprising an endogenous C segment of an IgH locus and operably linked to the C region.