FcγR-Binding Is an Important Functional Attribute for Immune Checkpoint Antibodies in Cancer Immunotherapy

Abstract

T cells play critical roles in anti-tumor immunity. Up-regulation of immune checkpoint molecules (PD-1, PD-L1, CTLA-4, TIM-3, Lag-3, TIGIT, CD73, VISTA, B7-H3) in the tumor microenvironment is an important mechanism that restrains effector T cells from the anti-tumor activity. To date, immune checkpoint antibodies have demonstrated significant clinical benefits for cancer patients treated with mono- or combination immunotherapies. However, many tumors do not respond to the treatment well, and merely blocking the immune suppression pathways by checkpoint-regulatory antibodies may not render optimal tumor growth inhibition. Binding of the antibody Fc-hinge region to Fc gamma receptors (FcγRs) has been shown to exert a profound impact on antibody function and in vivo efficacy. Investigation of immune checkpoint antibodies regarding their effector functions and impact on therapeutic efficacy has gained more attention in recent years. In this review, we discuss Fc variants of antibodies against immune checkpoint targets and the potential mechanisms of how FcγR-binding could influence the anti-tumor activity of these antibodies.

Plasticity in Pro- and Anti-tumor Activity of Neutrophils: Shifting the Balance

“…The relevance of the IgG backbone used for such antibodies has to do with the different binding affinities to the several Fcγ receptors that are in turn differentially expressed on a number of immune cells ( 137 , 138 ). This results in the induction of extremely diverse and highly regulated antibody responses, as the distinct affinities can also convey stronger or weaker effector functions by the different Fcγ receptor-expressing cells ( 139 ).…”

Mechanisms of hyperprogressive disease after immune checkpoint inhibitor therapy: what we (don’t) know

“…The interaction between the Fc domain of an antibody and its cognate FcR triggers a cascade of immune events stimulating phagocytic or cytotoxic cells to eradicate pathogens or infected/tumor cells through different mechanisms, such as antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and antibody-mediated phagocytosis (ADCP) [ 87 , 89 ]. To avoid the killing of T cells that express ICs, most ICIs were developed by choosing antibody isotypes with low or significantly reduced binding to FcRs [ 90 – 92 ]. Indeed, nivolumab and pembrolizumab, anti-PD-1 antibodies, are IgG4, an isotype considered immunologically inert but that still retains the ability to bind FcγRI and FcγRIIb, activating and inhibitory FcRs, respectively [ 90 – 92 ].…”

“…To avoid the killing of T cells that express ICs, most ICIs were developed by choosing antibody isotypes with low or significantly reduced binding to FcRs [ 90 – 92 ]. Indeed, nivolumab and pembrolizumab, anti-PD-1 antibodies, are IgG4, an isotype considered immunologically inert but that still retains the ability to bind FcγRI and FcγRIIb, activating and inhibitory FcRs, respectively [ 90 – 92 ]. In this regard, it has been reported that tumor-associated macrophages (TAMs) are able to capture anti-PD-1 antibodies from the T cell membrane through FcγRIIb [ 93 ].…”

A role for the immune system in advanced laryngeal cancer

“…Moreover, FCGR1 protein activates the phagocytic activity of myeloid-cells, inducing antitumoral activity 44 , 45 . Interestingly, the binding receptor, the Fc fragment of γ immunoglobulin, could also influence the anti-tumor activity of antibodies against immune checkpoint targets 46 .…”