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

• Published in: Nature communications Vol. 15; no. 1; p. 642
• Main Authors: Romei, Matthew G., Leonard, Brandon, Katz, Zachary B., Le, Daniel, Yang, Yanli, Day, Eric S., Koo, Christopher W., Sharma, Preeti, Bevers III, Jack, Kim, Ingrid, Dai, Huiguang, Farahi, Farzam, Lin, May, Shaw, Andrey S., Nakamura, Gerald, Sockolosky, Jonathan T., Lazar, Greg A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20-01-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 101/47; 13/1; 13/106; 13/31; 13/95; 14/28; 14/63; 38/91; 631/250/2152/2153/1291; 631/553/1886; 631/61/338/469; 631/61/51/1568; 82/103; 82/16; 82/80; 82/83; 9/10; Agonists; Antagonists; Antibodies; Antibodies, Bispecific; Bispecific antibodies; Conformation; Engineering; Fab; Humanities and Social Sciences; Immunoglobulin G; Immunoglobulin G - genetics; Interleukin 2; Interleukin 2 receptors; multidisciplinary; Protein Engineering; Receptors; Receptors, Tumor Necrosis Factor; Science; Science (multidisciplinary); Therapeutic targets
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-44985-x

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.
In contrast to their clinical success as inhibitors and targeting agents, antibodies have generally been ineffective as receptor agonists. Here, Romei et al. leverage a natural homotypic interface to tune antibody geometry, enabling optimization of agonist activity for multiple therapeutic targets.