title: Inhibitory Fcγ 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 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.
authors.affiliation: Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Fubin
authors.initials: F
authors.lastname: Li
authors.forename: Jeffrey V
authors.initials: JV
authors.lastname: Ravetch
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use; D000915:Antibody Affinity; D000920:Antibody-Dependent Cell Cytotoxicity; D000938:Antigen-Presenting Cells / Q000276:immunology; D019013:CD40 Antigens / Q000819:agonists / Q000276:immunology* / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D010047:Ovalbumin / Q000276:immunology; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; C499172:Fcgr2b protein, mouse; D007141:Immunoglobulin Fc Fragments; D017452:Receptors, IgG; D010047:Ovalbumin