Improving effector functions of antibodies for cancer treatment: Enhancing ADCC and CDC
Drug Design, Development and Therapy
As platforms for therapeutic agents, monoclonal antibodies (MAbs) have already been approved, and several MAbs have demonstrated clinical effectiveness in a variety of malignancies. However, several issues have also been emerging in antibody therapy, such as high cost and insuffi cient drug action. Recently, to improve MAb activity in humans, effector functions have been subjects of focus, especially antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity
... t cytotoxicity (CDC). Extensive efforts have been made to enhance these effector functions of MAbs, and successful approaches have been reported by us and others, wherein the binding activity of MAbs to FcγRIIIa or C1q is increased by introducing amino acid mutations into heavy chain constant regions or through glyco-modifi cation of Fc-linked oligosaccharides. In addition, one of the next approaches to optimizing therapeutic antibodies would be to combine multiple enhancing modifi cations into a single antibody platform to overcome the diverse mechanisms of clinical resistance of tumor cells. For this aim, we have recently developed a successful combination composed of ADCC-enhancing modifi cation by the fucose depletion from Fc-linked oligosaccharides and CDC-enhancing modifi cation by IgG1 and IgG3 isotype shuffl ing in heavy chains, which could be of great value for the development of third-generation antibody therapeutics.