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Proc Natl Acad Sci U S A. 2013 Nov 26;110(48):19501-6. doi: 10.1073/pnas.1319502110. Epub 2013 Nov 11.

Antitumor activities of agonistic anti-TNFR antibodies require differential FcγRIIB coengagement in vivo.

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Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065.


Agonistic anti-TNF receptor (TNFR) superfamily member antibodies are a class of promising antitumor therapies in active clinical investigation. An unexpected requirement for inhibitory Fcγ receptor FcγRIIB coengagement has recently been described for their in vivo antitumor activities. Although these findings have informed the design of more potent antitumor agonistic, anti-TNFR therapies, the underlying mechanism has remained obscure. Through detailed genetic analysis of strains conditionally deleted for FcγRIIB on defined cellular populations or mutated in specific signaling components, we now demonstrate that different agonistic anti-TNFR antibodies have specific requirements for FcγRIIB expression on defined cellular populations and function in trans in the absence of FcγRIIB signaling components, thus supporting a general mechanism of FcγRIIB cross-linking in vivo for the activities of these antibodies.


Fc engineering; ITAM; ITIM; anti-CD40; anti-DR5

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