The Antitumor Activities of Anti-CD47 Antibodies Require Fc-FcγR interactions

Abstract

SummaryWhile anti-CD47 antibodies hold promise for cancer immunotherapy, early phase clinical trials have shown limited signs of clinical benefit, suggesting that blockade of CD47 alone may not be sufficient for effective tumor control. Here, we investigate the contributions of the Fc domain of anti-CD47 antibodies required for optimal in vivo antitumor activity across multiple species-matched models, providing new insights into the mechanisms underlying the efficacy of this emerging class of therapeutic antibodies. Using a novel mouse model humanized for CD47, SIRPα and FcγRs, we demonstrate that local administration of an Fc-engineered anti-CD47 antibody with enhanced binding to activating FcγRs modulates myeloid and T-cell subsets in the tumor microenvironment, resulting in improved long-term systemic antitumor immunity and minimal on-target off-tumor toxicity. Our results highlight the importance of Fc optimization in the development of effective anti-CD47 therapies and provide a novel approach for enhancing the antitumor activity of this promising immunotherapy.Highlights-Engagement of activating FcγRs augments the in vivo antitumor activity of CD47 blocking antibodies-Humanized mice for CD47, SIRPα and FcγRs allow assessment of hFcγRs contribution to the activity of anti-hCD47 Abs-Fc-optimized anti-hCD47 ab promotes systemic antitumor immunity with abscopal effect and minimal on-target toxicityGraphical Abstract