Cytotoxic mechanisms of immunotherapy: Harnessing complement in the action of anti-tumor monoclonal antibodies

•Complement is activated in vivo when CD20 mAbs RTX or OFA are infused in CLL patients.•The detailed cellular events that occur in vitro during mAb-mediated CDC have been elucidated for CD20 mAbs.•New and innovative approaches should allow for development of far more effective complement-fixing mAbs for cancer immunotherapy.

Several mAbs that have been approved for the treatment of cancer make use of complement-dependent cytotoxicity (CDC) to eliminate tumor cells. Comprehensive investigations, based on in vitro studies, mouse models and analyses of patient blood samples after mAb treatment have provided key insights into the details of individual steps in the CDC reaction. Based on the lessons learned from these studies, new and innovative approaches are now being developed to increase the clinical efficacy of next generation mAbs with respect to CDC. These improvements include engineering changes in the mAbs to enhance their ability to activate complement. In addition, mAb dosing paradigms are being developed that take into account the capacity as well as the limitations of the complement system to eliminate a substantial burden of mAb-opsonized cells. Over the next few years it is likely these approaches will lead to mAbs that are far more effective in the treatment of cancer.