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An efficient route to human bispecific IgG

Nature Biotechnology volume 16, pages 677–681 (1998)Cite this article

Abstract

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 (∼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.

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Author information

Author notes

  1. Zhenping Zhu

    Present address: Department of Molecular and Cell Biology, ImClone Systems, Inc., New York, NY, 10014

  2. Paul Carter: Corresponding author (e-mail: pjc@gene.com).

Authors and Affiliations

  1. Department of Molecular Oncology, Genentech Inc., South San Francisco, CA, 94080

    A. Margaret Merchant, Zhenping Zhu & Paul Carter

  2. Department of Molecular Biology, Genentech Inc., South San Francisco, CA, 94080

    Jean Q. Yuan & Audrey Goddard

  3. Department of Antibody Technologies, Genentech Inc., South San Francisco, CA, 94080

    Camellia W. Adams

  4. Department of Immunology, Genentech Inc., South San Francisco, CA, 94080

    Leonard G. Presta

Authors
  1. A. Margaret Merchant
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  2. Zhenping Zhu
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  3. Jean Q. Yuan
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  4. Audrey Goddard
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  5. Camellia W. Adams
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  6. Leonard G. Presta
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  7. Paul Carter
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Merchant, A., Zhu, Z., Yuan, J. et al. An efficient route to human bispecific IgG. Nat Biotechnol 16, 677–681 (1998). https://doi.org/10.1038/nbt0798-677

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  • DOI: https://doi.org/10.1038/nbt0798-677

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