Abstract
Monoclonal antibodies (mAbs) are one of the most widely used drug platforms for infectious diseases or cancer therapeutics because they selectively target pathogens, infectious cells, cancerous cells, and even immune cells. In this way, they mediate the elimination of target molecules and cells with fewer side effects than other therapeutic modalities. In particular, cancer therapeutic mAbs can recognize cell-surface proteins on target cells and then kill the targeted cells by multiple mechanisms that are dependent upon a fragment crystallizable (Fc) domain interacting with effector Fc gamma receptors, including antibody-dependent cell-mediated cytotoxicity and antibody-dependent cell-mediated phagocytosis. Extensive engineering efforts have been made toward tuning Fc functions by either reinforcing (e.g. for targeted therapy) or disabling (e.g. for immune checkpoint blockade therapy) effector functions and prolonging the serum half-lives of antibodies, as necessary. In this report, we review Fc engineering efforts to improve therapeutic potency, and propose future antibody engineering directions that can fulfill unmet medical needs.
Highlights
Thirty-one new monoclonal antibodies have been approved by the Food and Drug Administration (FDA) in the USA and the European Medicines Agency in the EU since 2013, to constitute a total of 57 mAbs used in clinics by the end of 20171
fragment crystallizable (Fc) variants displaying high affinity for the FcγRIIa-R131 isoform and high selectivity for FcγRIIa over FcγRIIb have been shown to mediate improved antibodydependent cellular phagocytosis (ADCP) activity[30]. These results suggest that antibodies with increased binding affinity for activating Fcγ receptors (FcγRs), but not for inhibitory FcγRIIb, elicit stronger ADCP and potentially represent more effective therapeutics for cancer treatment
Xtend has been adapted to ravulizumab (ALXN1210), which has been approved by US FDA on December 2018 for treatment of paroxysmal nocturnal hemoglobinuria/hemolyticuremic syndrome[112], or VRC01LS, which is under clinical evaluation for the prevention of human immunodeficiency virus[113]
Summary
Antibody Fc domains are responsible for function in antibodies and Fab domains are responsible for targeting. Humans express two FcγRIIIa allotypes that differ in a single amino acid at position 158; the residue can be either valine (V) or phenylalanine (F), whereby the isoform with V at position 158 has high affinity for the Fc domain of IgG1, and the one with F at position 158 has low affinity This FcγRIIIa polymorphism has been shown to contribute to clinical responses of IgG1 therapeutic antibodies[7–10]. Fc variants displaying high affinity for the FcγRIIa-R131 isoform and high selectivity for FcγRIIa over FcγRIIb have been shown to mediate improved ADCP activity[30] These results suggest that antibodies with increased binding affinity for activating FcγRs, but not for inhibitory FcγRIIb, elicit stronger ADCP and potentially represent more effective therapeutics for cancer treatment. The strict pH-dependent ligand-binding property of FcRn seems to have evolved in the endo-lysosomal system to function as a mediator of IgG trafficking and pharmacological parameters, including stability, biodistribution, and immunogenicity, in humans
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