Mice that make VL binding proteins

摘要

Genetically modified mice and methods for making an using them are provided, wherein the mice comprise a replacement of all or substantially all immunoglobulin heavy chain V gene segments, D gene segments, and J gene segments with at least one light chain V gene segment and at least one light chain J gene segment. Mice that make binding proteins that comprise a light chain variable domain operably linked to a heavy chain constant region are provided. Binding proteins that contain an immunoglobulin light chain variable domain, including a somatically hypermutated light chain variable domain, fused with a heavy chain constant region, are provided. Modified cells, embryos, and mice that encode sequences for making the binding proteins are provided.

主权项

1. A mouse whose germline genome comprises a modified endogenous mouse immunoglobulin heavy chain locus comprising a replacement of all functional endogenous mouse immunoglobulin heavy chain variable (VH) gene segments, all functional endogenous mouse immunoglobulin heavy chain diversity (DH) gene segments and all functional endogenous mouse immunoglobulin heavy chain joining (JH) gene segments at the endogenous mouse immunoglobulin heavy chain locus with a nucleotide sequence that comprises a plurality of contiguous unrearranged functional human immunoglobulin light chain variable Vκ (hVκ) gene segments and all five unrearranged functional human immunoglobulin light chain joining gene segments (hJκ1-hJκ5),
wherein the plurality of unrearranged functional hVκ gene segments and the five unrearranged functional human immunoglobulin light chain joining gene segments (hJκ1-hJκ5) are operably linked to an intact endogenous mouse immunoglobulin heavy chain constant region at the endogenous mouse immunoglobulin heavy chain locus, wherein the plurality of unrearranged functional hVκ gene segments and the five unrearranged functional human immunoglobulin light chain joining gene segments (hJκ1-hJκ5) rearrange in a B cell during B cell development to form a rearranged human immunoglobulin light chain variable region Vκ/Jκ nucleotide sequence operably linked to the endogenous mouse immunoglobulin heavy chain constant region at the endogenous mouse immunoglobulin heavy chain locus, and wherein the mouse comprises a CD19+ B cell comprising the rearranged human immunoglobulin light chain variable region Vκ/Jκ nucleotide sequence operably linked to the endogenous mouse immunoglobulin heavy chain constant region at the endogenous mouse immunoglobulin heavy chain locus.