Animal models and therapeutic molecules

A method of providing one or more of an antigen-specific antibody or a fragment thereof, comprising a human IgH variable region,

• a cell producing said antibody or said fragment thereof,
• a nucleic acid encoding said antibody or said fragment thereof, and
• a biological sample comprising said antibody or said fragment thereof, the method comprising:
• (a) contacting a transgenic mouse with an antigen and expressing said antibody or said fragment thereof, and
• (b) isolating from said transgenic mouse of step (a) one or more of said antigen-specific antibody or said fragment thereof, said cell producing said antibody or said fragment thereof, said nucleic acid encoding said antibody or said fragment thereof, and said biological sample comprising said antibody or said fragment thereof,
• wherein said transgenic mouse of step (a) comprises in its germline a homozygous immunoglobulin heavy chain (IgH) locus,
• wherein said homozygous IgH locus comprises unrearranged human IgH V gene segments, D gene segments and J gene segments at an endogenous IgH locus upstream of an enhancer and a constant (C) region comprising an endogenous CH gene segment,
• said human IgH V gene segments, D gene segments and J gene segments are operably linked to said C region via a chimeric JC intron to permit expression of an Ig heavy chain polypeptide comprising a human variable region and a mouse constant region,
• said unrearranged human IgH V gene segments, D gene segments and J gene segments comprise all the functional human D and JH gene segments and human V gene segments Vh2-5, Vh7-4-1, Vh4-4, Vh1-3, Vh1-2 and Vh6-1,
• wherein said chimeric JC intron comprises human JC intronic DNA and mouse JC intronic DNA, wherein said human JH gene segments comprise a human 3′JH gene segment, said 3′ JH gene segment being contiguous with said human JC intronic DNA, wherein said 3′JH gene segment is less than 2 kb upstream of said mouse JC intronic DNA,
• wherein said mouse J/C intronic DNA between said human JC intronic DNA and said enhancer comprises mouse 129 strain or C57BL/6 strain DNA,
• wherein bone marrow B cells of said mouse comprise more pro-B cells than pre-B cells, wherein said pro B cells express CD43Med B220Med and said pre B cells express CD43low B220high,
• wherein said transgenic mouse of step (b) comprises rearranged human VH, D and JH gene segments, and expresses said antigen-specific antibody or said fragment thereof.