Boosting therapeutic potency of antibodies by taming Fc domain functions

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.

Fig. 1. The effector functions of immunoglobulin G antibodies.

Human natural killer cells, which only express FcγRIIIa, activate antibody-dependent cellular cytotoxicity via FcγRIIIa (a). Macrophages are one of the main contributing lymphocytes for antibody-dependent cellular phagocytosis activity, which is known to be triggered by FcγRIIa intracellular signaling (b).

Fig. 2. Recycling or transcytosis through endothelium of immunoglobulin G (IgG) antibodies.

When IgGs are internalized by an endothelial cell or a circulating monocyte, they initially encounter FcRn within the early acidified endosome. This binding protects IgG from being sorted into a lysosome, in which serum proteins without FcRn binding are degraded; instead, IgGs are recycled back into the extracellular space. At neutral pH on the cell surface, IgGs immediately dissociate from FcRn and return to the circulation.