BYON4228 is a pan-allelic antagonistic SIRPα antibody that potentiates destruction of antibody-opsonized tumor cells and lacks binding to SIRPγ on T cells

BackgroundPreclinical studies have firmly established the CD47-signal-regulatory protein (SIRP)alpha 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 SIRP alpha may represent a better strategy.MethodWe generated BYON4228, a novel SIRP alpha-directed antibody. An extensive preclinical characterization was performed, including direct comparisons to previously reported anti-SIRP alpha antibodies.ResultsBYON4228 is an antibody directed against SIRP alpha that recognizes both allelic variants of SIRP alpha in the human population, thereby maximizing its potential clinical applicability. Notably, BYON4228 does not recognize the closely related T-cell expressed SIRP gamma 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 SIRP alpha and its epitope largely overlaps with the CD47-binding site. BYON4228 blocks binding of CD47 to SIRP alpha and inhibits signaling through the CD47-SIRP alpha 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 SIRP alpha-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 SIRP alpha polymorphic variants (HEFLB), or cross-react with SIRP gamma and inhibit CD47-SIRP gamma 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 SIRP alpha(BIT) transgenic mice. Finally, BYON4228 shows a favorable safety profile in cynomolgus monkeys.ConclusionsCollectively, this defines BYON4228 as a preclinically highly differentiating pan-allelic SIRP alpha antibody without T-cell SIRP gamma recognition that promotes the destruction of antibody-opsonized cancer cells. Clinical studies are planned to start in 2023.

Automated summary

This study describes a novel antibody called BYON4228, which recognizes both allelic variants of SIRP alpha and shows potential clinical applicability. BYON4228 blocks the binding of CD47 to SIRP alpha, enhancing the ability of macrophages and neutrophils to kill tumor cells. It has a unique profile compared to other SIRP alpha antibodies, making it a promising candidate for further preclinical and clinical studies.