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

Abstract

While 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, SIRP and Fc{gamma}Rs, we demonstrate that local administration of an Fc-engineered anti-CD47 antibody with enhanced binding to activating Fc{gamma}Rs 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 Fc{gamma}Rs augments the in vivo antitumor activity of CD47 blocking antibodies - Humanized mice for CD47, SIRP and Fc{gamma}Rs allow assessment of hFc{gamma}Rs contribution to the activity of anti-hCD47 Abs - Fc-optimized anti-hCD47 ab promotes systemic antitumor immunity with abscopal effect and minimal on-target toxicity Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=158 SRC="FIGDIR/small/547082v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1c25202org.highwire.dtl.DTLVardef@960e84org.highwire.dtl.DTLVardef@1930edforg.highwire.dtl.DTLVardef@1b58fcd_HPS_FORMAT_FIGEXP M_FIG C_FIG