An efficient route to human bispecific IgG

被引:379
作者
Merchant, AM
Zhu, ZP
Yuan, JQ
Goddard, A
Adams, CW
Presta, LG
Carter, P [1 ]
机构
[1] Genentech Inc, Dept Mol Oncol, San Francisco, CA 94080 USA
[2] Genentech Inc, Dept Biol Mol, San Francisco, CA 94080 USA
[3] Genentech Inc, Dept Antibody Technol, San Francisco, CA 94080 USA
[4] Genentech Inc, Dept Immunol, San Francisco, CA 94080 USA
关键词
applied immunology; antibody engineering; phage display;
D O I
10.1038/nbt0798-677
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Production of bispecific IgG (BsIgG) by coexpressing two different antibodies is inefficient due to unwanted pairings of the component heavy and light chains. To overcome this problem, heavy chains were remodeled for heterodimerization using engineered disulfide bonds in combination with previously identified "knobs-into-holes" mutations. One of the variants, S354C:T366W/Y349'C:T366'S:L368'A:Y407'V, gave near quantitative (similar to 95%) heterodimerization, Light chain mispairing was circumvented by using an identical light chain for each arm of the BsIgG, Antibodies with identical light chains that bind to different antigens were identified from an scFv phage library with a very restricted light chain repertoire for the majority (50/55) of antigen pairs tested, A BsIgG capable of simultaneously binding to the human receptors HER3 and cMpI was prepared by coexpressing the common light chain and corresponding remodeled heavy chains followed by protein A chromatography. The engineered heavy chains retain their ability to support antibody-dependent cell-mediated cytotoxicity as demonstrated with an anti-HER2 antibody.
引用
收藏
页码:677 / 681
页数:5
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