Animal models and therapeutic molecules

  • US 9,434,782 B2
  • Filed: 12/20/2013
  • Issued: 09/06/2016
  • Est. Priority Date: 07/08/2009
  • Status: Active Grant
First Claim
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1. A method for producing an antibody specific for a selected antigen, the method comprising(a) providing a transgenic mouse whose genome comprises a homozygous chimeric immunoglobulin heavy chain (IgH) locus comprising unrearranged human IgH variable region gene segments at an endogenous mouse heavy chain IgH locus upstream of an enhancer and a constant (C) region comprising an endogenous CH gene segment;

  • wherein said human variable region gene segments in said chimeric IgH locus are operably linked to said C region at a human/mouse chimeric junction within the JC intron of said chimeric IgH locus;

    wherein said homozygous chimeric 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 J/C intron comprising human DNA downstream of and naturally contiguous with said human 3′

    JH gene segment, which is contiguous with mouse JC intronic DNA, and(iii) said enhancer and said C region,wherein said human 3′

    JH is less than 1 kb upstream of said chimeric junction,wherein DNA between said chimeric junction and said enhancer comprises mouse 129 strain JC intronic DNA;

    wherein said enhancer is a mouse 129 strain μ

    enhancer;

    wherein said transgenic mouse is functional to form rearranged human VH, DH and JH gene segments and to express chimeric immunoglobulin heavy chain polypeptide comprising a human VH region and a mouse C region, and wherein said transgenic mouse is capable, upon stimulation with antigen, of producing an antibody comprising a chimeric Ig heavy chain comprising a human IgH variable region and said C region; and

    wherein the genome of said transgenic mouse comprises all or part of the endogenous mouse IgH variable region, and is capable of breeding to produce subsequent generation mice having in their germline an IgH locus comprising unrearranged human IgH variable region gene segments positioned upstream of an IgH constant (C) region comprising an endogenous C gene segment of an IgH locus,(b) contacting said transgenic mouse with said selected antigen for a time and under conditions which permit the contacted mouse to produce antibody specific for said antigen; and

    (c) isolating from said contacted mouse one or more of;

    antibody specific for said antigen, and/or a biological sample comprising antibody specific for said antigen, wherein the antibody comprises a chimeric immunoglobulin heavy chain polypeptide comprising a human VH region and a mouse C region.

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