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

Vedran Vasic, Steffen Dickopf, Nadine Spranger, Rose-Sophie Rosenberger, Michaela Fischer, Klaus Mayer, Vincent Larraillet, Jack A. Bates, Verena Maier, Tatjana Sela, Bianca Nussbaum, Harald Duerr, Stefan Dengl and Ulrich Brinkmann ()
Additional contact information
Vedran Vasic: Roche Innovation Center Munich
Steffen Dickopf: Roche Innovation Center Munich
Nadine Spranger: Roche Innovation Center Munich
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

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53730-3

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