Rational engineering of Fc/Fc receptor interactions to improve antibody potency

Despite the growing clinical application of monoclonal antibodies as anti-cancer therapeutics, their ability to destroy targeted tumor cells is suboptimal. We have leveraged our Protein Design Automation^® technology to engineer antibodies with greater tumor killing power by augmenting the capacity of the Fc region to interact with the Fc gamma receptors (FcγRs) that mediate cytotoxic effector functions. A panel of Fc variants has been generated that display substantial enhancements over existing variants in both in vitro Fc/FcγR binding assays and cell-based ADCC assays. Our most promising candidates have been validated in the context of three approved anti-cancer antibodies, and characterized with regard to their specificity for activation versus inhibitory receptors, and their affinity for clinically relevant polymorphic forms of FcγRIIIa.