biostudies-literatureUnknown210(2)Yang JAlector, IncAntagonizing the CD47-signal regulatory protein (SIRP)α pathway, a critical myeloid checkpoint, promotes antitumor immunity. In this study, we describe the development of AL008, a pan-allelic, SIRPα-specific Ab that triggers the degradation of SIRPα and, concurrently, stimulates FcγR activation of myeloid cells through an engineered Fc domain. AL008 showed superior enhancement of phagocytosis of tumor cells opsonized with antitumor Ag Abs compared with another SIRPα Ab tested. Unlike ligand-blocking SIRPα Abs, AL008 demonstrated single-agent activity by increasing tumor cell engulfment by human monocyte-derived macrophages even in the absence of opsonizing agents. This effect was due to enhanced Fc function, as blocking FcγR2A abrogated AL008-mediated phagocytic activity. AL008 also promotJournal of immunology (Baltimore, Md. : 1950)204-215https://www.ebi.ac.uk/biostudies/studies/S-EPMC9772397biostudies-literatureAL008 Enhances Myeloid Antitumor Function by Inhibiting SIRPα Signaling and Activating Fc Receptors.PMC9772397Yang JHo WHLong HPincetic AMaslyar DLiang SCDeresa IRosenthal AfalseAL008 Enhances Myeloid Antitumor Function by Inhibiting SIRPα Signaling and Activating Fc Receptors.Antagonizing the CD47-signal regulatory protein (SIRP)α pathway, a critical myeloid checkpoint, promotes antitumor immunity. In this study, we describe the development of AL008, a pan-allelic, SIRPα-specific Ab that triggers the degradation of SIRPα and, concurrently, stimulates FcγR activation of myeloid cells through an engineered Fc domain. AL008 showed superior enhancement of phagocytosis of tumor cells opsonized with antitumor Ag Abs compared with another SIRPα Ab tested. Unlike ligand-blocking SIRPα Abs, AL008 demonstrated single-agent activity by increasing tumor cell engulfment by human monocyte-derived macrophages even in the absence of opsonizing agents. This effect was due to enhanced Fc function, as blocking FcγR2A abrogated AL008-mediated phagocytic activity. AL008 also promot2023-01-01T00:00:00Z2023 Jan2026-06-23T03:26:01.037Z2025-02-19T04:45:36.505ZS-EPMC97723973648026110.4049/jimmunol.2200157