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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.

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Doberstein, S., Lazar, G. & Hayes, R. Rational engineering of Fc/Fc receptor interactions to improve antibody potency. Breast Cancer Res 5 (Suppl 1), 59 (2003).

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  • Effector Function
  • Design Automation
  • Polymorphic Form
  • Gamma Receptor
  • Rational Engineering