Animal models and therapeutic molecules

  • US 10,064,398 B2
  • Filed: 10/16/2014
  • Issued: 09/04/2018
  • Est. Priority Date: 07/08/2009
  • Status: Active Grant
First Claim
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1. A transgenic mouse having a genome 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, said human gene segments join mouse DNA at a human/mouse chimeric DNA junction within the JC intron of said IgH locus downstream of said human JH gene segments and upstream of an enhancer 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 J/C intron comprising human JC intronic DNA downstream of and naturally contiguous with said human 3′

    JH gene segment, which is contiguous with mouse JC intronic DNA, wherein said mouse JC intronic DNA comprises DNA of an IgH locus of a 129 strain mouse which, in its native position in a non-transgenic mouse, is naturally contiguous with and upstream of a mouse Cμ

    enhancer, and(iii) said enhancer and said C region,wherein said human 3′

    JH is less than 2 kb upstream of said human/mouse chimeric DNA junction, wherein said enhancer of (iii) is a mouse μ

    enhancer;

    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 the mouse IgH variable region DNA in a position that is upstream of its native chromosomal position, wherein expression of mouse Ig heavy chain comprising a mouse IgH variable region and a mouse IgH constant region is inactive in said mouse,and wherein said transgenic mouse is capable of breeding with a second transgenic mouse, said second transgenic mouse having a genome comprising a homozygous IgH locus comprising unrearranged human IgH variable region gene segments at an endogenous IgH locus upstream of and operably linked to a constant (C) region comprising an endogenous C segment of an IgH locus, to provide subsequent generation mice comprising in their genome a homozygous IgH locus comprising unrearranged human IgH variable region gene segments at an endogenous IgH locus upstream of a constant (C) region comprising an endogenous C segment of an IgH locus and operably linked to the C region.

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