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Inhibitory Fc? receptor engagement drives adjuvant and anti-tumor activities of agonistic CD40 antibodies.

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

SUBMITTER: Li F

PROVIDER: S-EPMC3164589 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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

Li Fubin F Ravetch Jeffrey V JV

Science (New York, N.Y.) 20110801 6045

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 acti ...[more]

PMID: 21852502

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Project description:Background: OX40 (CD134) is a co-stimulatory molecule of the tumor necrosis factor receptor (TNFR) superfamily, that is currently investigated as a target for cancer immunotherapy. However, despite promising results in murine tumor models, the clinical efficacy of agonistic αOX40 antibodies in treatment of cancer patients has fallen short of the high expectation in earlier stage trials. Methods: Using lymphocytes from resected tumor, tumor-free tissue and PBMC of 4 hepatocellular and colorectal cancer patients, we performed RNA-Seq to evaluate OX40-mediated transcriptional changes in CD4+ and CD8+ human tumor-infiltrating lymphocytes (TILs). Results: The transcriptional landscape of CD4+ and CD8+ TILs shifted towards a pro-survival, inflammatory and chemotactic profile upon treatment with αOX40_v12.

2020-06-22 | GSE152904 | GEO

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