Inhibitory Fcγ receptor engagement drives adjuvant and anti-tumor activities of agonistic CD40 antibodies

F Li, JV Ravetch - Science, 2011 - science.org
Science, 2011science.org
CD40, a member of the tumor necrosis factor receptor (TNFR) superfamily, is expressed on
antigen-presenting cells (APCs) and is essential for immune activation. Although agonistic
CD40 antibodies have been developed for immunotherapy, their clinical efficacy has been
limited. We have found that coengagement of the Fc domain of agonistic CD40 monoclonal
antibodies (mAbs) with the inhibitory Fcγ receptor FcγRIIB is required for immune activation.
Direct comparison of mAbs to CD40 enhanced for activating FcγR binding, hence capable of …
CD40, a member of the tumor necrosis factor receptor (TNFR) superfamily, is expressed on antigen-presenting cells (APCs) and is essential for immune activation. Although agonistic CD40 antibodies have been developed for immunotherapy, their clinical efficacy has been limited. We have found that coengagement of the Fc domain of agonistic CD40 monoclonal antibodies (mAbs) with the inhibitory Fcγ receptor FcγRIIB is required for immune activation. Direct comparison of mAbs to CD40 enhanced for activating FcγR binding, hence capable of cytotoxicity, or for inhibitory FcγRIIB binding, revealed that enhancing FcγRIIB binding conferred immunostimulatory activity and considerably greater anti-tumor responses. This unexpected requirement for FcγRIIB in enhancing CD40-mediated immune activation has direct implications for the design of agonistic antibodies to TNFR as therapeutics.
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