Advances in Therapeutic Fc Engineering – Modulation of IgG-Associated Effector Functions and Serum Half-life

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.

MicroRNA‐194 reduces inflammatory response and human dermal microvascular endothelial cells permeability through suppression of TGF‐β/SMAD pathway by inhibiting THBS1 in chronic idiopathic urticaria

“…10 The findings in our study demonstrated that miR-194 decreased inflammation and vascular permeability through TGF-β/SMAD pathway by inhibiting THBS1 so as to provide new idea for the treatment of CIU. 30 In a previous research, scientists found that the level of IgG1 and IgE were lower in patients with chronic urticaria caused by raw fish. Besides, patients with CIU had higher concentration of IgA and lower concentration of IgG and IgM, and higher positive expression rate of THBS1.…”

Enhanced CHO Clone Screening: Application of Targeted Locus Amplification and Next‐Generation Sequencing Technologies for Cell Line Development

“…Antibody mAb2 expressing CHO pools were constructed with different effector function silencing mutations, carrying either D265A, P329A (DAPA) or L234A, L235A (LALA) double mutations of the wild‐type human IgG1 in the fragment crystallizable‐part of the antibody heavy chain sequence . Antibodies were purified after 14 days of cell cultivation in shake flasks by protein‐A affinity chromatography.…”

Engineering of a Lectibody Targeting High-Mannose-Type Glycans of the HIV Envelope

“…AvFc's capability to bind to the aforementioned FcgRs was confirmed by flow cytometry using FcgRI-and FcgRIIIa-expressing cells ( Figures 4C and 4D). By contrast, AvFc with an Asn200 / Gln mutation (N200Q-AvFc), which eliminates N-glycosylation in the Fc region corresponding to Asn297 of human IgG 1 and thereby significantly reduces affinity to these FcgRs, 25,26 showed dramatically reduced binding to these receptors ( Figures 4C and 4D; Table 1).…”