i-shaped antibody engineering enables conformational tuning of biotherapeutic receptor agonists

Matthew G. Romei, Brandon Leonard, Zachary B. Katz, Daniel Le, Yanli Yang, Eric S. Day, Christopher W. Koo, Preeti Sharma, Jack Bevers, Ingrid Kim, Huiguang Dai, Farzam Farahi, May Lin, Andrey S. Shaw, Gerald Nakamura, Jonathan T. Sockolosky () and Greg A. Lazar ()
Additional contact information
Matthew G. Romei: Genentech Inc.
Brandon Leonard: Genentech Inc.
Zachary B. Katz: Genentech Inc.
Daniel Le: Proteomic, Lipidomics, and Next Generation Sequencing, Genentech Inc.
Yanli Yang: Genentech Inc.
Eric S. Day: Genentech Inc.
Christopher W. Koo: Genentech Inc.
Preeti Sharma: Genentech Inc.
Jack Bevers: Genentech Inc.
Ingrid Kim: Genentech Inc.
Huiguang Dai: Genentech Inc.
Farzam Farahi: Genentech Inc.
May Lin: Genentech Inc.
Andrey S. Shaw: Genentech Inc.
Gerald Nakamura: Genentech Inc.
Jonathan T. Sockolosky: Genentech Inc.
Greg A. Lazar: Genentech Inc.

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract The ability to leverage antibodies to agonize disease relevant biological pathways has tremendous potential for clinical investigation. Yet while antibodies have been successful as antagonists, immune mediators, and targeting agents, they are not readily effective at recapitulating the biology of natural ligands. Among the important determinants of antibody agonist activity is the geometry of target receptor engagement. Here, we describe an engineering approach inspired by a naturally occurring Fab-Fab homotypic interaction that constrains IgG in a unique i-shaped conformation. i-shaped antibody (iAb) engineering enables potent intrinsic agonism of five tumor necrosis factor receptor superfamily (TNFRSF) targets. When applied to bispecific antibodies against the heterodimeric IL-2 receptor pair, constrained bispecific IgG formats recapitulate IL-2 agonist activity. iAb engineering provides a tool to tune agonist antibody function and this work provides a framework for the development of intrinsic antibody agonists with the potential for generalization across broad receptor classes.

Date: 2024
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DOI: 10.1038/s41467-024-44985-x

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