Abstract 2934: BYON4228, an antagonistic SIRPα mAb with a unique and favorable preclinical profile compared to three comparator SIRPα mAbs

Abstract A growing body of data from early clinical studies supports that targeting the myeloid immune checkpoint CD47-SIRPα represents a successful strategy towards establishing effective new therapies for cancer patients. Initial studies focused on CD47 blockers and more recently also SIRPα antagonistic mAbs entered clinical studies. The latter approach is thought to be more advantageous since SIRPα expression is primarily myeloid restricted whereas CD47 is broadly expressed and -besides SIRPα- binds other ligands as well.We generated BYON4228, an antibody directed against the two existing allelic variants of human SIRPα that does not recognize the closely related T-cell expressed SIRPγ. Functional studies demonstrate that BYON4228 potentiates both macrophage- and neutrophil-mediated elimination of hematologic and solid cancer cells in vitro in the presence of a variety of tumor targeting antibodies, including rituximab, daratumumab, trastuzumab and cetuximab. In vivo, BYON4228 increases the anti-tumor activity of rituximab in a B-cell Raji xenograft model in mice and shows a favorable safety profile in cynomolgus monkeys.To position BYON4228 in the emerging field of myeloid checkpoint inhibitors, head-to-head comparison studies were performed. For these studies, previously described anti-SIRPα mAbs HEFLB, 1H9, and SIRPAB-11 were generated in house that in all probability are representative for three clinical stage SIRPα mAbs. These comparative studies focused on principal characteristics of this class of mAbs that are anticipated to affect their clinical profile, namely 1) recognition of both common allelic forms of SIRPα which determines the broadness of its clinical applicability; 2) binding to SIRPγ on T-lymphocytes which is reported to affect T-cell extravasation and activation and thereby the adaptive immune response; 3) functionality of the Fc-region of the mAb which can mediate depletion of SIRPα-positive host myeloid immune effector cells thereby compromising host defense and undermining the effect of immunotherapy. The comparative studies show that in contrast to HEFLB, BYON4228 recognizes both common allelic forms of SIRPα. Furthermore, lack of binding to T-cell expressed SIRPγ differentiates BYON4228 from 1H9 and SIRPAB-11. Finally, with its impaired Fc-region BYON4228 does not deplete SIRPα+ myeloid cells, in contrast to SIRPAB-11.Thus, BYON4228 differentiates from all three comparator SIRPα mAbs based on at least one fundamental characteristic, thereby underlining its potential to become a best-in-class drug. We therefore endorse its further development for which clinical studies are planned to start in 2023. Citation Format: Mary van Helden, Seline Zwarthoff, Roel Arends, Inge Reinieren-Beeren, Marc Parade, Lilian Driessen-Engels, Karin de Laat-Arts, Desiree Damming, Ellen Santegoeds-Lenssen, Daphne van Kuppeveld, Imke Lodewijks, Ellen Mattaar, Hugo Olsman, Hanke Matlung, Katka Franke, Marloes Stokman, Benny de Wit, Dirk Glaudemans, Danielle van Wijk, Lonnie Joosten Stoffels, Jan Schouten, Paul Boersema, Monique van der Vleuten, Jorien Sanderink, Wendy Kappers, Diels van den Dobbelsteen, Marco Timmers, Ruud Ubink, Gerard Rouwendal, Gijs Verheijden, Miranda M.C. van der Lee, Wim Dokter, Timo van den Berg. BYON4228, an antagonistic SIRPα mAb with a unique and favorable preclinical profile compared to three comparator SIRPα mAbs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2934.