ANIMAL MODELS AND THERAPEUTIC MOLECULES

摘要

The invention discloses methods for the generation of chimaeric human—non-human antibodies and chimaeric antibody chains, antibodies and antibody chains so produced, and derivatives thereof including fully humanised antibodies; compositions comprising said antibodies, antibody chains and derivatives, as well as cells, non-human mammals and vectors, suitable for use in said methods.

主权项

1. A transgenic mouse having a genome with homozygous immunoglobulin heavy chain (IgH) locus,
wherein said homozygous IgH locus comprises unrearranged human immunoglobulin heavy chain (IgH) variable region (VH) DNA comprising one or more human IgH V gene segments, one or more human D gene segments, one or more human JH gene segments and human intronic DNA contiguous with mouse intronic DNA and located at an endogenous IgH locus upstream of an enhancer and a constant (C) region comprising an endogenous CH gene segment, wherein said C region comprises mouse Cμ and said human variable region gene segments are operably linked to said C region to permit rearrangement and expression of IgM heavy chain polypeptide comprising a human variable region and a mouse μ constant region, wherein in said transgenic mouse expression of IgH heavy chains comprising endogenous mouse variable regions is reduced or prevented; wherein said mouse comprises IgH-VDJCμ transcripts encoding said chimeric IgM polypeptide and wherein said IgM comprises human CDR-H3, and said IgH-VDJCμ transcripts comprise transcripts encoding human variable region CDR-H3 lengths of 19 to 22 amino acids, wherein the mean frequency of said transcripts encoding CDR-H3 lengths selected from the group consisting of 18 and 19 amino acids present in said IgH-VDJCμ transcripts of said mouse is between 5% and 10%.