Animal Models and Therapeutic Molecules

A method of providing an antigen-specific polypeptide comprising a human IgH variable region, an antigen-specific antibody comprising said polypeptide, a cell producing said polypeptide, a nucleic acid encoding said polypeptide or said variable region and/or a biological sample comprising said polypeptide, the method comprising:

• isolating from a transgenic mouse that produces antibody specific for said antigen one or more of said polypeptide, said antigen-specific antibody comprising said polypeptide, said cell producing said polypeptide, said nucleic acid encoding said polypeptide or said variable region and/or said biological sample comprising said polypeptide, wherein said transgenic mouse has a germline comprising a homozygous immunoglobulin heavy chain (IgH) locus comprising a plurality of unrearranged human IgH V gene segments, D gene segments and JH gene segments at an endogenous IgH locus and a constant (C) region comprising an endogenous IgH C gene segment;
• wherein said homozygous IgH locus comprises in 5′ to 3′ transcriptional orientation:
• (i) unrearranged human immunoglobulin heavy chain (IgH) variable region (VH) DNA comprising human IgH V gene segments, human D gene segments and human JH gene segments comprising a human 3′ JH gene segment,
• (ii) a chimeric JC intron comprising (a) human JC intronic DNA downstream of said human 3′ JH gene segment and (b) truncated mouse JC intronic DNA, and
• (iii) a mouse Cμ enhancer and said C region,
• wherein said plurality of unrearranged human V gene segments, D gene segments and J gene segments in said IgH locus are operatively linked to said C region such that said IgH locus of said mouse is capable of undergoing V, D, J joining of said unrearranged human IgH variable region gene segments,
• such that said transgenic mouse is capable, upon stimulation with an antigen, of producing a plurality of antibodies specific for said antigen comprising a chimeric Ig heavy chain comprising a human VH region and a mouse C region;
• wherein said genome comprises all or part of mouse IgH variable region DNA upstream of human VH gene segments, wherein expression of mouse Ig heavy chain comprising a mouse IgH variable region and a mouse IgH constant region is inactive in said mouse.