Abstract
Today, monoclonal immunoglobulin gamma (IgG) antibodies have become a major option in cancer therapy especially for the patients with advanced or metastatic cancers. Efficacy of monoclonal antibodies (mAbs) is achieved through both its antigen-binding fragment (Fab) and crystallizable fragment (Fc). Fab can specifically recognize tumor-associated antigen (TAA) and thus modulate TAA-linked downstream signaling pathways that may lead to the inhibition of tumor growth, induction of tumor apoptosis, and differentiation. The Fc region can further improve mAbs’ efficacy by mediating effector functions such as antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cell-mediated phagocytosis. Moreover, Fc is the region interacting with the neonatal Fc receptor in a pH-dependent manner that can slow down IgG’s degradation and extend its serum half-life. Loss of the antibody Fc region dramatically shortens its serum half-life and weakens its anticancer effects. Given the essential roles that the Fc region plays in the modulation of the efficacy of mAb in cancer treatment, Fc engineering has been extensively studied in the past years. This review focuses on the recent advances in therapeutic Fc engineering that modulates its related effector functions and serum half-life. We also discuss the progress made in aglycosylated mAb development that may substantially reduce the cost of manufacture but maintain similar efficacies as conventional glycosylated mAb. Finally, we highlight several Fc engineering-based mAbs under clinical trials.
Highlights
Monoclonal antibodies can target tumors through specific recognition of tumor-associated antigens and subsequent recruitment of effector elements including macrophages, dendritic cells, natural killer (NK) cells, T-cells, and the complement pathway components [1]. Such recruitments are achieved by interactions among the immunoglobulin gamma (IgG)-crystallizable fragment (Fc) and the immune cell receptors like Fcγ receptors (FcγRs) and the complement protein C1q of the complement system [2,3,4]. These interactions lead to the activation of immune cells for enhanced antibody-dependent cellular cytotoxicity (ADCC)/antibody-dependent cell-mediated phagocytosis (ADCP), formation of the membrane attack complex, and more efficient presentation of antigen
We focus on the recent progress in therapeutic Fc engineering-associated effector functions (ADCC, ADCP, and complement dependent cytotoxicity (CDC)) and pharmacokinetics
The inability of FcγRIIIb to activate immune signaling in such a scenario can be overcome by imparting high-affinity binding to FcγRIIa, which can enhance both NK cell- and polymorphonuclear cell (PMN) mediated ADCC [55]
Summary
Laboratory of Antibody Engineering, Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China. Efficacy of monoclonal antibodies (mAbs) is achieved through both its antigen-binding fragment (Fab) and crystallizable fragment (Fc). The Fc region can further improve mAbs’ efficacy by mediating effector functions such as antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cell-mediated phagocytosis. Loss of the antibody Fc region dramatically shortens its serum half-life and weakens its anticancer effects. Given the essential roles that the Fc region plays in the modulation of the efficacy of mAb in cancer treatment, Fc engineering has been extensively studied in the past years. This review focuses on the recent advances in therapeutic Fc engineering that modulates its related effector functions and serum half-life.
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