Animal models and therapeutic molecules

  • US 10,165,763 B2
  • Filed: 11/14/2013
  • Issued: 01/01/2019
  • Est. Priority Date: 07/08/2009
  • Status: Active Grant
First Claim
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1. A transgenic mouse whose genome comprises a homozygous immunoglobulin heavy chain (IgH) locus comprising a human heavy chain variable region at an endogenous IgH locus, upstream of a constant (C) region, said constant region comprising an endogenous C gene segment,said human heavy chain variable region comprising a plurality of unrearranged human immunoglobulin heavy chain variable (VH) gene segments, a plurality of unrearranged human immunoglobulin heavy chain diversity (DH) gene segments and a plurality of unrearranged human immunoglobulin heavy chain joining (JH) gene segments comprising a 3′

  • JH gene segment, wherein the human variable region gene segments in said IgH locus are operably linked to said endogenous IgH C gene segment,said IgH locus in a 5′

    to 3′

    transcriptional orientation comprising said 3′

    JH gene segment, human DNA, a human/mouse DNA junction, mouse DNA, an enhancer, and said constant region;

    wherein said human DNA comprises human intronic DNA downstream of and contiguous with said human JH region,wherein said mouse DNA comprises mouse intronic DNA downstream of and contiguous with said human/mouse DNA junction and upstream of said constant region,wherein DNA between said human/mouse DNA junction and said enhancer comprises mouse 129 strain JC intronic DNAwherein said 3′

    JH gene segment is less than 2 Kb upstream of said human/mouse DNA junction,said mouse being functional to breed to another said mouse to produce progeny having in its germline said homozygous recombinant immunoglobulin heavy chain locus,said mouse being functional to form rearranged human VH, DH, and JH gene segments and to produce mRNA transcripts encoding immunoglobulin heavy chain polypeptide comprising a human VH region and a mouse Cμ

    region,wherein said mouse comprises IgH mRNA transcripts comprising IgH-VDJCμ

    transcripts encoding polypeptide comprising a human VH region and mouse Cμ

    ,wherein said IgH-VDJCμ

    transcripts comprise transcripts encoding a human variable region comprising a CDR-H3 length of 17 amino acids and transcripts encoding a human variable region comprising a CDR-H3 length of 18 amino acids according to the Kabat numbering system,wherein the mean frequency of the group consisting of said transcripts encoding CDR-H3 lengths of 17 and 18 amino acids present in said IgH-VDJCμ

    transcripts of said mouse is between 5% and 10%.

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