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Improving Antibody-Based Cancer Therapeutics Through Glycan Engineering

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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.

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Authors and Affiliations

  1. The Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton, Faculty of Medicine, General Hospital, Southampton, SO16 6YD, UK

    Xiaojie Yu, Michael J. E. Marshall & Mark S. Cragg

  2. Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK

    Max Crispin

  3. Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, 92037, USA

    Max Crispin

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MC is supported by a research grant from Against Breast Cancer (http://www.againstbreastcancer.org; UK charity number 1121258) and is the Against Breast Cancer Fellow at Oriel College, Oxford, UK. MC was founder and director of Immago Biosystems which was acquired by Hansa Medical. MM is supported by a BBSRC iCASE studentship in partnership with Roche. MSC acts as a consultant for Bioinvent International and has previously received research grant support from Roche, UCB and Promega, and has received honorarium from Baxalta. XY declares no conflicts of interest. No additional funding was received for the preparation of this review.

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Yu, X., Marshall, M.J.E., Cragg, M.S. et al. Improving Antibody-Based Cancer Therapeutics Through Glycan Engineering. BioDrugs 31, 151–166 (2017). https://doi.org/10.1007/s40259-017-0223-8

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