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Science 333 (6045): 1030-1034

Copyright © 2011 by the American Association for the Advancement of Science

Inhibitory Fc{gamma} Receptor Engagement Drives Adjuvant and Anti-Tumor Activities of Agonistic CD40 Antibodies

Fubin Li, and Jeffrey V. Ravetch*

Abstract: 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 Fc{gamma} receptor Fc{gamma}RIIB is required for immune activation. Direct comparison of mAbs to CD40 enhanced for activating Fc{gamma}R binding, hence capable of cytotoxicity, or for inhibitory Fc{gamma}RIIB binding, revealed that enhancing Fc{gamma}RIIB binding conferred immunostimulatory activity and considerably greater anti-tumor responses. This unexpected requirement for Fc{gamma}RIIB in enhancing CD40-mediated immune activation has direct implications for the design of agonistic antibodies to TNFR as therapeutics.

Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065, USA.
* To whom correspondence should be addressed. E-mail: ravetch{at}rockefeller.edu

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