Role of Fc–FcγR interactions in the antitumor activity of therapeutic antibodies

The use of antibody therapy for cancer has steadily increased in recent years and has become standard treatment for numerous tumor types. It is now appreciated that the clinical activity of these antibodies relies upon their specific interactions with Fc receptors in addition to the well-studied target-binding region. The interactions mediated by antibody Fc domains can strongly affect the functional outcome of antibody therapy. The Fc portion of an antibody defines its interaction with numerous immune cells and has become an intense area of research as selecting the optimal Fc can greatly enhance the activity as well as mechanism of action of therapeutic antibodies. Recent advances in antibody engineering have enabled the development of antibodies that have altered Fc receptor interactions to take advantage of these findings. Engineering the Fc can fulfill diverse functions such as enhancing effector function for killing of tumor cells or depletion of unwanted immune subsets, enhancing agonist receptor signaling on particular immune cells or eliminating interaction with Fc receptors to avoid cellular depletion or toxicity in normal tissues. This review highlights important data and studies examining the role of Fc-Fc receptor interactions in therapeutic antibodies with a considerations for the future of engineered antibody therapy.