A general requirement for FcγRIIB co-engagement of agonistic anti-TNFR antibodies (P4449)

Abstract

Abstract The tumor necrosis factor receptor (TNFR) superfamily members are type I transmembrane proteins widely expressed on both normal and malignant tissues and control essential biological processes including cell apoptosis, activation, and proliferation1. A number of TNFR signaling pathways have been reported to be beneficial in immune and antitumor responses. For example, CD40 mediated immunostimulatory effects and DR5 mediated direct apoptotic effects display potent antitumor activity through distinct mechanisms. Agonistic antibodies targeting TNFRs have therefore been extensively investigated as a therapeutic approach to trigger TNFR signaling pathways in antitumor responses. Despite their impressive performance in animal models, clinical results of these agonistic anti-TNFR antibodies appear to be disappointing. Our studies on the role of the Fc for agonistic anti-CD40 and anti-DR5 antibodies, and the FcγR binding properties of other agonistic anti-TNFR antibodies suggest an explanation for this discrepancy between the pre-clinical animal studies and clinical application of these agonistic antibodies. It is now apparent that agonistic anti-TNFR antibodies display a general requirement for FcγRIIB co-engagement for their in vivo activity and the selection of the appropriate Fc was not taken into consideration in the advancement of therapeutic versions of these antibodies into the clinic.