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Non-human animals expressing pH-sensitive immunoglobulin sequences

  • US 9,648,856 B2
  • Filed: 11/20/2013
  • Issued: 05/16/2017
  • Est. Priority Date: 03/16/2012
  • Status: Active Grant
First Claim
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1. A method for making a non-human animal that makes antibody variable domains with a histidine amino acid encoded by a histidine codon substituted or inserted in the germline genome, comprising:

  • modifying the non-human animal in its germline to comprise either or both(i) at an endogenous non-human immunoglobulin heavy chain locus an unrearranged immunoglobulin heavy chain variable region gene sequence comprising in a complementary determining region 3 (CDR3) encoding sequence a substitution of at least one non-histidine codon with a histidine codon or an insertion of at least one histidine codon, and(ii) at an endogenous non-human immunoglobulin light chain locus an unrearranged immunoglobulin light chain variable region gene sequence comprising in a CDR3 encoding sequence a substitution of at least one non-histidine codon with a histidine codon or an insertion of at least one histidine codon;

    such that the non-human animal generates in vivo a diverse repertoire of antibodies, each of which is specific for an antigen of interest and retains at least one histidine amino acid encoded by the substituted or inserted histidine codon, wherein the at least one histidine amino acid is present in a CDR3 of a heavy chain variable domain and/or a CDR3 of a light chain variable domain.

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