Abstract
Antibodies targeting T-cell inhibitory pathways, such as CTLA-4 and PD-1/PD-L1, are emerging as an important class of cancer therapeutics, and a next generation of immunomodulatory therapies targeting alternative inhibitory (e.g. TIM-3, LAG-3, B7-H4, B7-H3, VISTA, A2aR), as well as co-stimulatory (e.g. CD27, OX40, GITR, CD137), pathways are poised to join them. Most of these immunomodulatory antibodies are of IgG isotypes that have low, or no, binding to the Fc gamma receptors (FcγRs) that trigger cell-mediated cytotoxic effector functions such as antibody dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). These isotypes were selected to minimise the risk of depleting the T cells upon which such antibodies depend for their mechanism of action. However, recent preclinical data highlight a potential role for FcγR engagement in the activity of such antibodies. Here we review the biology of the FcγRs and IgG isotypes in both humans and mice, detail the potential roles that FcγR interactions can play in the activity of monoclonal antibodies in general, and of immunomodulatory antibodies in particular, and discuss how preclinical studies on these interactions might be best interpreted and translated to a human setting.
Highlights
Antibodies of the IgG sub-class are bi-functional molecules, possessing a F(ab) domain, variable in sequence and responsible for the binding of antigen, and an Fragment crystallisable (Fc) domain, constant in sequence and responsible for mediating a range of antibody effector functions [1]
Effector functions mediated by the Fc gamma receptor (FcγR), such as antibody dependent cellular cytotoxicity (ADCC) and Antibody dependent cellular phagocytosis (ADCP), are believed to play an important role in the activity of several therapeutic antibodies; including a number used in Oncology, for example rituximab and trastuzumab
In addition it has been shown that for CD137 antibody mediated internalisation of receptor can play a role in driving signalling [29], and it is unclear how changes in Fc isotype might affect this property. For those antibodies that target inhibitory receptors like Programmed death 1 (PD-1) and Cytotoxic T lymphocyte antigen 4 (CTLA-4) there has been little reason to believe, based on their antagonistic mechanism of action, that FcγR engagement plays an important role in their activity, and no significant evidence to contradict this belief exists in the clinical setting
Summary
Antibodies of the IgG sub-class are bi-functional molecules, possessing a F(ab) domain, variable in sequence and responsible for the binding of antigen, and an Fc domain, constant in sequence and responsible for mediating a range of antibody effector functions [1]. Recent studies in mice have, highlighted a potential role for FcγR binding, and FcγR mediated effector functions in the activity of antibodies targeting a number of these pathways.
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