Tailored FcγR blockade enhances immune checkpoint therapy and overcomes resistance

Abstract Background Fc-gamma receptors (FcγRs) regulate IgG antibody activity, and Fc-engineering is a proven method to improve the efficacy of tumor-targeting antibodies. Here, we explore tailored FcγR blockade to enhance the therapeutic efficacy and tolerability of immune checkpoint-blocking (ICB) antibodies. Methods Mechanistically matched murine surrogate and human lead FcγR-blocking and immune checkpoint-blocking antibodies were used to study whether tailored FcγR-blockade, targeting FcγRIIB selectively or all FcγRs, can enhance the efficacy and overcome resistance to immune checkpoint therapy in vivo and in vitro. Mechanistic studies were performed with clinical reagents, including ipilimumab, nivolumab, pembrolizumab, and human FcγRIIB-selective (BI-1607) and pan-FcγR-blocking (BI-1206) antibodies, using human cells and transgenic animals with clinically relevant expression of immune checkpoint receptors. Results We demonstrate that FcγRIIB-selective and pan-FcγR-blocking antibodies increase the in vivo efficacy of αCTLA-4 and αPD-1 antibodies, respectively. FcγRIIB-selective antibody enhancement of αCTLA-4 was associated with increased intratumoral Treg depletion, myeloid reprogramming, interferon-γ and CXCL10-induction, and increased activated effector CD8 + T cells, correlating with higher activating-to-inhibitory (A:I) FcγR engagement ratios. Conversely, pan-FcγR blockade protected αPD-1-coated T cells from macrophage phagocytosis, increasing intratumoral activated CD8 + T cells by decreasing activating and inhibitory FcγRs. Conclusions Our studies provide in vivo proof of concept that tailored FcγR blockade enhances immune checkpoint therapy and overcomes resistance through mechanistically distinct pathways. Clinical trials with tailored human FcγRIIB-blocking antibodies are ongoing. Graphical Abstract FcγRIIB-selective blockade enhances αCTLA-4-mediated Treg depletion, myeloid reprogramming, and effector CD8 + T cell activation by increasing the activating-to-inhibitory (A:I) FcγR engagement ratio. Conversely, pan-FcγR blockade protects αPD-1-coated T cells from macrophage phagocytosis and from αPD-1 removal via trogocytosis, thereby increasing intratumoral activated CD8 + T cells by decreasing activating and inhibitory FcγRs.