FcγR requirements and costimulatory capacity of Urelumab, Utomilumab, and Varlilumab

Frontiers in Immunology

Immunology

Peter Steinberger¹  Judith Leitner¹  Ricarda Egerer¹  Petra Waidhofer-Söllner²  Katharina Grabmeier-Pfistershammer² 

[1] Division of Immune Receptors and T Cell Activation, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria;Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria;

关键词: human T cell costimulation;    41BB;    CD137;    CD27;    agonistic antibodies;    Urelumab;    Utomilumab;    Varlilumab;   

DOI  :  10.3389/fimmu.2023.1208631

 received in 2023-04-19, accepted in 2023-06-28,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionTargeting costimulatory receptors of the tumor necrosis factor receptor (TNFR) superfamily with agonistic antibodies is a promising approach in cancer immuno therapy. It is known that their efficacy strongly depends on FcγR cross-linking.MethodsIn this study, we made use of a Jurkat-based reporter platform to analyze the influence of individual FcγRs on the costimulatory activity of the 41BB agonists, Urelumab and Utomilumab, and the CD27 agonist, Varlilumab.ResultsWe found that Urelumab (IgG4) can activate 41BB-NFκB signaling without FcγR cross-linking, but the presence of the FcγRs (CD32A, CD32B, CD64) augments the agonistic activity of Urelumab. The human IgG2 antibody Utomilumab exerts agonistic function only when crosslinked via CD32A and CD32B. The human IgG1 antibody Varlilumab showed strong agonistic activity with all FcγRs tested. In addition, we analyzed the costimulatory effects of Urelumab, Utomilumab, and Varlilumab in primary human peripheral blood mononuclear cells (PBMCs). Interestingly, we observed a very weak capacity of Varlilumab to enhance cytokine production and proliferation of CD4 and CD8 T cells. In the presence of Varlilumab the percentage of annexin V positive T cells was increased, indicating that this antibody mediated FcγR-dependent cytotoxic effects.ConclusionCollectively, our data underscore the importance to perform studies in reductionist systems as well as in primary PBMC samples to get a comprehensive understanding of the activity of costimulation agonists.

【 授权许可】

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Copyright © 2023 Leitner, Egerer, Waidhofer-Söllner, Grabmeier-Pfistershammer and Steinberger