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Generation of binder-format-payload conjugate-matrices by antibody chain-exchange

Author

Listed:
  • Vedran Vasic

    (Roche Innovation Center Munich)

  • Steffen Dickopf

    (Roche Innovation Center Munich
    Veraxa Biotech)

  • Nadine Spranger

    (Roche Innovation Center Munich
    Technical University Munich (TUM))

  • Rose-Sophie Rosenberger

    (Roche Innovation Center Munich)

  • Michaela Fischer

    (Roche Innovation Center Munich)

  • Klaus Mayer

    (Roche Innovation Center Munich)

  • Vincent Larraillet

    (Roche Innovation Center Munich)

  • Jack A. Bates

    (Roche Innovation Center Munich)

  • Verena Maier

    (Roche Innovation Center Munich)

  • Tatjana Sela

    (Roche Innovation Center Munich)

  • Bianca Nussbaum

    (Roche Innovation Center Munich)

  • Harald Duerr

    (Roche Innovation Center Munich)

  • Stefan Dengl

    (Roche Innovation Center Munich)

  • Ulrich Brinkmann

    (Roche Innovation Center Munich)

Abstract

The generation of antibody-drug conjugates with optimal functionality depends on many parameters. These include binder epitope, antibody format, linker composition, conjugation site(s), drug-to-antibody ratio, and conjugation method. The production of matrices that cover all possible parameters is a major challenge in identifying optimal antibody-drug conjugates. To address this bottleneck, we adapted our Format Chain Exchange technology (FORCE), originally established for bispecific antibodies, toward the generation of binder-format-payload matrices (pair-FORCE). Antibody derivatives with exchange-enabled Fc-heterodimers are combined with payload-conjugated Fc donors, and subsequent chain-exchange transfers payloads to antibody derivatives in different formats. The resulting binder-format-conjugate matrices can be generated with cytotoxic payloads, dyes, haptens, and large molecules, resulting in versatile tools for ADC screening campaigns. We show the relevance of pair-FORCE for identifying optimal HER2-targeting antibody-drug conjugates. Analysis of this matrix reveals that the notion of format-defines-function applies not only to bispecific antibodies, but also to antibody-drug conjugates.

Suggested Citation

  • Vedran Vasic & Steffen Dickopf & Nadine Spranger & Rose-Sophie Rosenberger & Michaela Fischer & Klaus Mayer & Vincent Larraillet & Jack A. Bates & Verena Maier & Tatjana Sela & Bianca Nussbaum & Haral, 2024. "Generation of binder-format-payload conjugate-matrices by antibody chain-exchange," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53730-3
    DOI: 10.1038/s41467-024-53730-3
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    References listed on IDEAS

    as
    1. Stefan Dengl & Klaus Mayer & Felix Bormann & Harald Duerr & Eike Hoffmann & Bianca Nussbaum & Michael Tischler & Martina Wagner & Andreas Kuglstatter & Lea Leibrock & Can Buldun & Guy Georges & Ulrich, 2020. "Format chain exchange (FORCE) for high-throughput generation of bispecific antibodies in combinatorial binder-format matrices," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    2. Chisato M. Yamazaki & Aiko Yamaguchi & Yasuaki Anami & Wei Xiong & Yoshihiro Otani & Jangsoon Lee & Naoto T. Ueno & Ningyan Zhang & Zhiqiang An & Kyoji Tsuchikama, 2021. "Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
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