title: The anti-lymphoma activities of anti-CD137 monoclonal antibodies are enhanced in FcγRIII(-/-) mice.
abstract: Agonistic monoclonal antibodies (mAbs) directed against the co-signaling molecule CD137 (4-1BB) elicit potent anti-tumor immunity in mice. This anti-tumor immunity has traditionally been thought to result from the ability of the Fab portion of anti-CD137 to function as an analog for CD137L. Although binding of CD137 by anti-CD137 mAbs has the potential to cross-link the Fc fragments, enabling Fc engagement of low to moderate affinity Fc gamma receptors (FcγR), the relative import of such Fc-FcγR interactions in mediating anti-CD137 associated anti-tumor immunity is unknown. We studied the ability of a rat anti-mouse CD137 mAb (2A) to mediate the anti-tumor response against the EL4E7 lymphoma in WT and FcγR(-/-) strains. 2A-treated FcRγ(-/-) mice had improved anti-tumor immunity against EL4E7, which could be completely recapitulated in FcγRIII(-/-) animals. These improved anti-tumor responses were associated with increased splenic CD8β T cell and dendritic cell (DC) populations. Furthermore, there was an increase in the number of DCs expressing high levels of the CD40, CD80, and CD86 molecules that are associated with more effective antigen presentation. Our results demonstrate an unexpected inhibitory role for FcγRIII in the anti-tumor function of anti-CD137 and underscore the need to consider antibody isotype when engineering therapeutic mAbs.
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland School of Medicine, 16 South Eutaw St. Suite 500, Baltimore, MD, 21201-168, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Sallin
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Zhang
authors.forename: Edward C
authors.initials: EC
authors.lastname: So
authors.forename: Erin
authors.initials: E
authors.lastname: Burch
authors.forename: Ling
authors.initials: L
authors.lastname: Cai
authors.forename: Wei
authors.initials: W
authors.lastname: Lin
authors.forename: Andrei I
authors.initials: AI
authors.lastname: Chapoval
authors.forename: Scott E
authors.initials: SE
authors.lastname: Strome
mesh_terms: D000818:Animals; D055910:Antibodies, Immobilized / Q000276:immunology / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008223:Lymphoma / Q000276:immunology / Q000628:therapy*; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D051381:Rats; D017452:Receptors, IgG / Q000172:deficiency* / Q000276:immunology* / Q000378:metabolism; D014162:Transfection; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*
chemical_list: D055910:Antibodies, Immobilized; D000911:Antibodies, Monoclonal; C499172:Fcgr2b protein, mouse; C485700:Fcgr3 protein, mouse; C522404:Fcgr4 protein, mouse; D017452:Receptors, IgG; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9