Osori et al. addressed contributions of the Fc domain to the antitumor activity of anti-CD47 Abs. Using immune-competent mouse models, optimal in vivo activity required both Fab-mediated blockade of CD47/SIRPα binding and Fc-mediated binding to activating but not inhibitory FcγRs. Activating Fcs augmented anti-CD47 antitumor efficacy, which correlated with increased numbers of tumor-infiltrating macrophages, enhanced phagocytosis, decreased Tregs, and increased CD8+ T cell responses with long-term tumor-specific immunity. A novel humanized knock-in model demonstrated intratumoral Fc-optimized anti-hCD47 Ab (magrolimab) boosted systemic antitumor immunity with minimal toxicity.
Contributed by Katherine Turner
ABSTRACT: While anti-CD47 antibodies hold promise for cancer immunotherapy, early-phase clinical trials have shown limited clinical benefit, suggesting that CD47 blockade alone might be insufficient 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 insights into the mechanisms behind the efficacy of this emerging class of therapeutic antibodies. Using a mouse model humanized for CD47, SIRPα, and FcγRs, we demonstrate that local administration of Fc-engineered anti-CD47 antibodies with enhanced binding to activating FcγRs promotes tumor infiltration of macrophages and antigen-specific T cells, while depleting regulatory T cells. These effects result 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 an attractive strategy to enhance the activity of this promising immunotherapy.
Author Info: (1) Laboratory of Molecular Genetics and Immunology, Rockefeller University, New York, NY, 10065, USA. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY,
Author Info: (1) Laboratory of Molecular Genetics and Immunology, Rockefeller University, New York, NY, 10065, USA. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. (2) Laboratory of Molecular Genetics and Immunology, Rockefeller University, New York, NY, 10065, USA. (3) Laboratory of Molecular Genetics and Immunology, Rockefeller University, New York, NY, 10065, USA. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. (4) Laboratory of Molecular Genetics and Immunology, Rockefeller University, New York, NY, 10065, USA.
