Abstract
Since the establishment of monoclonal antibody production using mouse hybridoma technology in the 1980s, there has been expanding progress and continuous technological improvement in the development of therapeutic antibodies. The chimeric, humanized, and fully human technologies broke through the immunogenicity issues of the first-generation mouse monoclonal antibodies and have led to the great success of therapeutic antibodies, such as rituximab, trastuzumab, cetuximab, and bevacizumab. As of 2013, more than 30 therapeutic antibodies had been approved for clinical use, and these antibodies represent a major new class of drugs. However, there still remain unmet needs for the improvement of the efficacy of these therapeutic antibodies. Based on the current understanding of the clinical mechanisms of several therapeutic antibodies, it has been demonstrated that the antibody constant region (Fc)-mediated effector function, especially antibody-dependent cellular cytotoxicity (ADCC), is important for improving the clinical outcome of therapeutic antibodies and that the Fc-linked oligosaccharide structure of the antibody dramatically influences ADCC. The present review focuses on the recent progress in the development of “glyco-engineered therapeutic antibodies,” which have an improved Fc-mediated effector function of ADCC. This is achieved by reducing the fucosylation level of the Fc-linked oligosaccharides. In 2012, the first non-fucosylated therapeutic antibody, mogamulizumab, was approved for the treatment of adult T-cell leukemia/lymphoma, and a new type anti-CD20, obinutuzumab, with a low level of the Fc fucosylation, was later approved in 2013. The glyco-engineered therapeutic antibodies have just started to be used in the clinical setting, and their use will continue to expand in various clinical areas.
Similar content being viewed by others
Abbreviations
- ADCC:
-
Antibody-dependent cellular cytotoxicity
- CDC:
-
Complement-dependent cytotoxicity
- CHO:
-
Chinese hamster ovary
- Fc:
-
Antibody constant region
- FcγRIIIa:
-
Human Fcγ-receptor IIIa
- IgG:
-
Immunoglobulin G
- NK cell:
-
Natural killer cell
References
Bibeau F, Lopez-Crapez E, Di Fiore F et al (2009) Impact of FcγRIIa-FcγRIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with cetuximab plus irinotecan. J Clin Oncol 27:1122–1129
Cartron G, Dacheux L, Salles G et al (2002) Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcγRIIIa gene. Blood 99:754–758
Delord JP, Tabernero J, García-Carbonero R et al (2014) Open-label, multicentre expansion cohort to evaluate imgatuzumab in pre-treated patients with KRAS-mutant advanced colorectal carcinoma. Eur J Cancer 50:496–505
Ferrara C, Brünker P, Suter T et al (2006) Modulation of therapeutic antibody effector functions by glycosylation engineering: influence of Golgi enzyme localization domain and co-expression of heterologous beta1, 4-N-acetylglucosaminyltransferase III and Golgi alpha-mannosidase II. Biotechnol Bioeng 93:851–861
Ferrara C, Grau S, Jäger C et al (2011) Unique carbohydrate-carbohydrate interactions are required for high affinity binding between FcγRIII and antibodies lacking core fucose. Proc Natl Acad Sci U S A 108:12669–12674
Goede V, Fischer K, Busch R et al (2014) Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 370:1101–1110
Iida S, Kuni-Kamochi R, Mori K et al (2009) Two mechanisms of the enhanced antibody-dependent cellular cytotoxicity (ADCC) efficacy of non-fucosylated therapeutic antibodies in human blood. BMC Cancer 9:58
Ishida T, Joh T, Uike N et al (2012) Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a multicenter phase II study. J Clin Oncol 30:837–842
Laviolette M, Gossage DL, Gauvreau G et al (2013) Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. J Allergy Clin Immunol 132:1086–1096
Mizushima T, Yagi H, Takemoto E (2011) Structural basis for improved efficacy of therapeutic antibodies on defucosylation of their Fc glycans. Genes Cells 16:1071–1080
Musolino A, Naldi N, Bortesi B et al (2008) Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J Clin Oncol 26:1789–1796
Shields RL, Lai J, Keck R et al (2002) Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human FcγRIII and antibody-dependent cellular toxicity. J Biol Chem 277:26733–26740
Shinkawa T, Nakamura K, Yamane N et al (2003) The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity. J Biol Chem 278:3466–3473
Ward E, Mittereder N, Kuta E et al (2011) A glycoengineered anti-CD19 antibody with potent antibody-dependent cellular cytotoxicity activity in vitro and lymphoma growth inhibition in vivo. Br J Haematol 155:426–437
Yamane-Ohnuki N, Kinoshita S, Inoue-Urakubo M et al (2004) Establishment of FUT8 knockout Chinese hamster ovary cells: an ideal host cell line for producing completely defucosylated antibodies with enhanced antibody-dependent cellular cytotoxicity. Biotechnol Bioeng 87:614–622
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Japan
About this entry
Cite this entry
Niwa, R., Shitara, K., Satoh, M. (2014). Glyco-engineered Therapeutic Antibodies as a Second-Generation Antibody Therapy. In: Endo, T., Seeberger, P., Hart, G., Wong, CH., Taniguchi, N. (eds) Glycoscience: Biology and Medicine. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54836-2_196-1
Download citation
DOI: https://doi.org/10.1007/978-4-431-54836-2_196-1
Received:
Accepted:
Published:
Publisher Name: Springer, Tokyo
Online ISBN: 978-4-431-54836-2
eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences