Animal models and therapeutic molecules

A transgenic mouse having a germline comprising 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 a mouse CH gene segment, wherein said human IgH gene segments join to mouse J/C intron DNA at a chimeric junction upstream of said enhancer,
• said human IgH V gene segments, D gene segments and J gene segments are operably linked to said C region 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, Vh7-41, Vh-4-4, Vhf-3, Vhf-2 and Vh6-1,
• wherein said human JH gene segments comprise a human 3′JH, said 3′ JH being contiguous with human J/C intronic DNA, wherein said 3′JH is less than 2 kb upstream of said chimeric DNA junction,
• wherein said mouse J/C intron DNA between said chimeric junction and said enhancer comprises said 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 expresses immunoglobulin heavy chains comprising human variable regions.