Glycotherapeutics: Application of Glycans for Therapeutics: Glyco-Engineered Therapeutic Antibodies as a Second-Generation Antibody Therapy

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-generationmousemonoclonal 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.