TY - JOUR T1 - BYON4228 is a pan-allelic antagonistic SIRPα antibody that potentiates destruction of antibody-opsonized tumor cells and lacks binding to SIRPγ on T cells JF - Journal for ImmunoTherapy of Cancer JO - J Immunother Cancer DO - 10.1136/jitc-2022-006567 VL - 11 IS - 4 SP - e006567 AU - Mary J van Helden AU - Seline A Zwarthoff AU - Roel J Arends AU - Inge M J Reinieren-Beeren AU - Marc C B C Paradé AU - Lilian Driessen-Engels AU - Karin de Laat-Arts AU - Désirée Damming AU - Ellen W H Santegoeds-Lenssen AU - Daphne W J van Kuppeveld AU - Imke Lodewijks AU - Hugo Olsman AU - Hanke L Matlung AU - Katka Franke AU - Ellen Mattaar-Hepp AU - Marloes E M Stokman AU - Benny de Wit AU - Dirk H R F Glaudemans AU - Daniëlle E J W van Wijk AU - Lonnie Joosten-Stoffels AU - Jan Schouten AU - Paul J Boersema AU - Monique van der Vleuten AU - Jorien W H Sanderink AU - Wendela A Kappers AU - Diels van den Dobbelsteen AU - Marco Timmers AU - Ruud Ubink AU - Gerard J A Rouwendal AU - Gijs Verheijden AU - Miranda M C van der Lee AU - Wim H A Dokter AU - Timo K van den Berg Y1 - 2023/04/01 UR - http://jitc.bmj.com/content/11/4/e006567.abstract N2 - Background Preclinical studies have firmly established the CD47-signal-regulatory protein (SIRP)α axis as a myeloid immune checkpoint in cancer, and this is corroborated by available evidence from the first clinical studies with CD47 blockers. However, CD47 is ubiquitously expressed and mediates functional interactions with other ligands as well, and therefore targeting of the primarily myeloid cell-restricted inhibitory immunoreceptor SIRPα may represent a better strategy.Method We generated BYON4228, a novel SIRPα-directed antibody. An extensive preclinical characterization was performed, including direct comparisons to previously reported anti-SIRPα antibodies.Results BYON4228 is an antibody directed against SIRPα that recognizes both allelic variants of SIRPα in the human population, thereby maximizing its potential clinical applicability. Notably, BYON4228 does not recognize the closely related T-cell expressed SIRPγ that mediates interactions with CD47 as well, which are known to be instrumental in T-cell extravasation and activation. BYON4228 binds to the N-terminal Ig-like domain of SIRPα and its epitope largely overlaps with the CD47-binding site. BYON4228 blocks binding of CD47 to SIRPα and inhibits signaling through the CD47-SIRPα axis. Functional studies show that BYON4228 potentiates macrophage-mediated and neutrophil-mediated killing of hematologic and solid cancer cells in vitro in the presence of a variety of tumor-targeting antibodies, including trastuzumab, rituximab, daratumumab and cetuximab. The silenced Fc region of BYON4228 precludes immune cell-mediated elimination of SIRPα-positive myeloid cells, implying anticipated preservation of myeloid immune effector cells in patients. The unique profile of BYON4228 clearly distinguishes it from previously reported antibodies representative of agents in clinical development, which either lack recognition of one of the two SIRPα polymorphic variants (HEFLB), or cross-react with SIRPγ and inhibit CD47-SIRPγ interactions (SIRPAB-11-K322A, 1H9), and/or have functional Fc regions thereby displaying myeloid cell depletion activity (SIRPAB-11-K322A). In vivo, BYON4228 increases the antitumor activity of rituximab in a B-cell Raji xenograft model in human SIRPαBIT transgenic mice. Finally, BYON4228 shows a favorable safety profile in cynomolgus monkeys.Conclusions Collectively, this defines BYON4228 as a preclinically highly differentiating pan-allelic SIRPα antibody without T-cell SIRPγ recognition that promotes the destruction of antibody-opsonized cancer cells. Clinical studies are planned to start in 2023.Data are available upon reasonable request. ER -