Fc-Engineered Therapeutic Antibodies: Recent Advances and Future Directions

Abstract

Monoclonal therapeutic antibodies have revolutionized the treatment of cancer and other diseases. Fc engineering aims to enhance the effector functions or half-life of therapeutic antibodies by modifying their Fc regions. Recent advances in the Fc engineering of modern therapeutic antibodies can be considered the next generation of antibody therapy. Various strategies are employed, including altering glycosylation patterns via glycoengineering and introducing mutations to the Fc region, thereby enhancing Fc receptor or complement interactions. Further, Fc engineering strategies enable the generation of bispecific IgG-based heterodimeric antibodies. As Fc engineering techniques continue to evolve, an expanding portfolio of Fc-engineered antibodies is advancing through clinical development, with several already approved for medical use. Despite the plethora of Fc-based mutations that have been analyzed in in vitro and in vivo models, we focus here in this review on the relevant Fc engineering strategies of approved therapeutic antibodies to finetune effector functions, to modify half-life and to stabilize asymmetric bispecific IgGs.

Next generation single-domain antibodies against respiratory zoonotic RNA viruses

“…Adding the Fc region can result in the initiation of Fc-mediated effector functions due to interaction with either Fcγ receptor (FcγR) on the surface of immune cells or the complement component 1q (C1q) protein. FcγR interaction can initiate antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cell-mediated phagocytosis (ADCP), whilst interaction with C1q leads to complement-dependent cytotoxicity (CDC) ( Nimmerjahn and Ravetch, 2008 ; Abdeldaim and Schindowski, 2023 ). It has been shown that sdAb Fc-domain addition can significantly improve in vivo protection against IAV and IBV, explained by the initiation of ADCC mediated protection due to the strong activation of FcγRIIIa ( Laursen et al, 2018 ).…”

Reversible Chemical Modification of Antibody Effector Function Mitigates Unwanted Systemic Immune Activation

“…These interactions can also initiate cell–cell processes, such as ADCC and ADCP. , Modulation of these properties are of particular interest to the development of immune-oncology therapeutics, which include immune agonists and checkpoint inhibitors . While therapeutic antibodies often demonstrate impressive clinical activity, clinical benefit can be limited by toxicities, and the appropriate tuning of effector function is an area of opportunity to optimize activity and tolerability …”

Regulatory considerations in the design, development and quality of monoclonal antibodies and related products for the diagnosis and treatment of cancer

“…Amino acid residues in IgG1 that bind to complement, FcγR or the neonatal Fc receptor, FcRn, have been identified and mutated in mAbs to achieve the desired outcome. Some mutations enhance binding to FcγRIIIA for improved antibody-dependent cellular cytotoxicity (ADCC) and/or to FcγRIIA to improve antibody-dependent cellular phagocytosis (ADCP) activities, while other mutations that reduce binding to FcγRs are used when effector functions are not wanted ( 22 – 25 ). Cell line engineering is also used to produce afucosylated glycan structures to enhance ADCC ( 26 ).…”

“…Increasing binding to FcγRIIB has been shown to improve the performance of agonist immunostimulatory mAbs, likely due to cross-linking agonist mAb bound to its target on the cell surface ( 29 , 30 ). Many reviews provide a more in-depth discussion of isotype selection, Fc engineering approaches for FcγR, FcRn, or complement binding and the mechanisms by which these modifications achieve the desired outcome to promote efficacy and safety of the mAb ( 22 – 25 , 31 , 32 ).…”