Non-human animals expressing pH-sensitive immunoglobulin sequences

A genetically modified non-human animal, comprising

• at an endogenous immunoglobulin heavy chain locus at least a portion of an unrearranged human immunoglobulin heavy chain variable region nucleic acid sequence comprising unrearranged human VH, unrearranged human DH, and unrearranged human JH gene segments operably linked to an immunoglobulin heavy chain constant region gene sequence, wherein one or more of the unrearranged human VH, DH, and JH gene segments comprise in a CDR3 encoding sequence at least one substitution of a non-histidine codon with a histidine codon, or at least one histidine codon insertion;
• and
• at an endogenous immunoglobulin light chain locus at least a portion of an unrearranged human immunoglobulin light chain variable region nucleic acid sequence comprising unrearranged human VL and unrearranged human JL gene segments operably linked to an immunoglobulin light chain constant region gene sequence, wherein one or more of the unrearranged human VL and JL gene segments comprise in a CDR3 encoding sequence at least one substitution of a non-histidine codon with a histidine codon, or at least one histidine codon insertion;
• wherein the non-human animal comprises 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 an immunoglobulin heavy chain variable domain and/or in a CDR3 of an immunoglobulin light chain variable domain.

A genetically modified non-human animal, comprising

• at an endogenous heavy chain locus at least a portion of a human unrearranged immunoglobulin heavy chain variable region nucleic acid sequence comprising unrearranged human VH, unrearranged human DH, and unrearranged human JH gene segments operably linked to an immunoglobulin heavy chain constant region gene sequence, wherein one or more of the unrearranged VH, DH, and JH gene segments comprise in a CDR3 encoding sequence at least one substitution of a non-histidine codon with a histidine codon, or at least one histidine codon insertion;
• and
• at an endogenous light chain locus a rearranged human immunoglobulin light chain variable region nucleic acid sequence comprising a human VL gene segment rearranged with a human JL gene segment operably linked to an immunoglobulin light chain constant region gene sequence, wherein the rearranged human immunoglobulin light chain variable region nucleic acid sequence comprises in a CDR3 encoding sequence at least one substitution of a non-histidine codon with a histidine codon, or at least one histidine codon insertion;
• wherein the non-human animal comprises in vivo a diverse repertoire of antibodies, each of which are 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 an immunoglobulin heavy chain variable domain and/or in a CDR3 of an immunoglobulin light chain variable domain.