FYI--> AACR Abstract from Xencor. Xencor also has another abstract at AACR using an ADCC-enhanced anti-CD19.
Abstract Number: 4791
John O. Richards. Xencor, Monrovia, CA
It is now well-established that Fc gamma receptor (F?R) -mediated effector functions play an important role in the anti-tumor capacity of some monoclonal antibodies. These receptors are present on a wide variety of effector cell populations, including natural killer (NK) cells, dendritic cells (DC), neutrophils, and macrophages. We have previously engineered the Fc domains of antibodies to enhance their affinity for Fc?R, leading to dramatic enhancements in NK cell-mediated ADCC. NK cell-mediated lysis occurs predominantly through a single activating receptor Fc?RIIIa. Activation of antigen presenting cells such as DC and macrophage, which has potential to induce adaptive immunity against the tumor target, can also be influenced by the activating receptor Fc?RIIa and inhibitory receptor Fc?RIIb. We have engineered a panel of anti-EpCAM antibody variants with a variety of unique Fc?R affinities and specificities, including selective engagement of Fc?RIIIa and Fc?RIIa over Fc?RIIb. Results indicate that NK cell-mediated killing of LS180 target cells is correlated strongly with Fc?RIIIa affinity, with enhancements in antibody-dependent cytotoxic potency ranging from 3-fold to 10-fold and up to a 20% increase in maximal ADCC against LS180 target cells. Phagocytosis by macrophages is dependent on binding to both Fc?RIIa and Fc?RIIIa, with enhancements in phagocytic potency ranging from 3-fold to 30-fold. Surprisingly, our data show that absolute Fc?RIIb affinity does not negatively impact phagocytosis. Overall these variants have the potential to improve anti-cancer therapy by increasing not only innate effector functions, but also by enhancing adaptive anti-tumor responses, a novel feature of engineered therapeutic antibodies.
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