Improving Antibody-Based Cancer Therapeutics Through Glycan Engineering

Abstract

Antibody-based therapeutics has emerged as a major tool in cancer treatment. Guided by the superb specificity of the antibody variable domain, it allows the precise targeting of tumour markers. Recently, eliciting cellular effector functions, mediated by the Fc domain, has gained traction as a means by which to generate more potent antibody therapeutics. Extensive mutagenesis studies of the Fc protein backbone has enabled the generation of Fc variants that more optimally engage the Fcγ receptors known to mediate cellular effector functions such as antibody-dependent cellular cytotoxicity (ADCC) and cellular phagocytosis. In addition to the protein backbone, the homodimeric Fc domain contains two opposing N-linked glycans, which represent a further point of potential immunomodulation, independent of the Fc protein backbone. For example, a lack of core fucose usually attached to the IgG Fc glycan leads to enhanced ADCC activity, whereas a high level of terminal sialylation is associated with reduced inflammation. Significant growth in knowledge of Fc glycosylation over the last decade, combined with advancement in genetic engineering, has empowered glyco-engineering to fine-tune antibody therapeutics. This has culminated in the approval of two glyco-engineered antibodies for cancer therapy: the anti-CCR4 mogamulizumab approved in 2012 and the anti-CD20 obinutuzumab in 2013. We discuss here the technological platforms for antibody glyco-engineering and review the current clinical landscape of glyco-engineered antibodies.

Boosting therapeutic potency of antibodies by taming Fc domain functions

“…For example, margetuximab, developed by Mac-roGenics, had adapted the same Fab target (Her2) as transtuzumab but had been Fc-engineered to maximize immune effector function by elevating relative affinity to activating Fcγ receptor, FcγRIIIa over inhibitory Fcγ receptor, FcγRIIb, and it recently showed a 24% risk reduction in patients relative to that of trastuzumab in a phase 3 clinical trial in 536 breast cancer patients 69 . Other significant efforts have been directed to the engineering of antibodies with improved affinity for FcγRIIIa and enhanced effector function by amino acid mutations 36,[70][71][72][73][74] or glycan modifications [75][76][77][78][79][80][81] . Hatori and coworkers also engineered an antibody Fc variant (P238D/L328E) that showed selectively enhanced FcγRIIb binding over both FcγRIIa-R131 and FcγRIIa-H131 82 .…”

Microheterogeneity of Recombinant Antibodies: Analytics and Functional Impact

“…[40] Absence of core fucose leads to increased binding to FcyRIII, which increases the ADCC response in vitro [41] and increases activity in vivo, which leads to a lower required dose in the clinic. [42] Terminal Galactose Galactose depleted IgG exhibits a significantly reduced binding affinity to C1q [43][44][45] but increased binding to the mannosebinding lectin, which can also activate the complement pathway. [44] New findings by Subedi and Barb [41] showed that increased galactosylation leads to increased binding to FcγRIII Figure 2.…”

Protein Engineering on Human Recombinant Follistatin: Enhancing Pharmacokinetic Characteristics for Therapeutic Application

“…Glycoengineering technology is becoming an attractive strategy to improve the pharmaceutical properties of therapeutic agents. There are many approaches for glycoengineering, including the introduction of new glycosylation sites to increase carbohydrate content or to block specific binding (Yu et al, 2017;Mimura et al, 2018). In this study, we generated 10 variants with six new consensus N-linked glycosylation sites within the HBS region.…”