Inhibitory receptors (IRs) such as CTLA-4, PD-1, LAG3, TIM-3, and TIGIT are critical regulators of immune homeostasis, functioning to restrain excessive immune activation and prevent autoimmunity. While the blockade of IRs has transformed cancer immunotherapy by reinvigorating antitumor T cell responses, emerging strategies aim to harness the immunosuppressive potential of these receptors for treating autoimmune and inflammatory diseases. Agonistic antibodies that activate IR signaling have demonstrated promising results in preclinical models by promoting immune tolerance and suppressing pathological effector T cell functions. This review highlights recent progress in the development of agonistic IR-targeted therapies, examining their mechanisms of action, therapeutic efficacy, and the translational challenges that must be addressed to bring these innovative approaches into clinical practice for the management of autoimmunity and inflammatory disorders.
Inhibitory receptor agonists: Emerging strategies in immune modulation
https://orcid.org/0000-0003-0787-6868
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https://orcid.org/0000-0001-8742-249X
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https://orcid.org/0000-0001-7177-2110
https://orcid.org/0000-0002-2771-5992
K.R. Adam and A. Suhail contributed equally to this paper.
Disclosures: V.K. Kuchroo reported financial interests in Bicara Therapeutics, Biocon Biologic, Catalio Capital, Compass, Elpiscience Biopharmaceutical Ltd., Equillium Inc., Larkspur Therapeutics, PerkinElmer/Revvity, Syngene Intl, Tizona Therapeutics, Trishula, Werewolf Therapeutics, and Zumutor; and is a member of scientific advisory boards for AltruBio, Cell Signaling Technology, Elpiscience Biopharmaceutical Ltd., Larkspur, Noetik, Tr1X, and Werewolf Therapeutics. His interests were reviewed and managed by Mass General Brigham in accordance with their conflict of interest policies. D.A. Vignali is a cofounder and stockholder of Novasenta and Trishula, a stockholder of Werewolf, has patents licensed and royalties from BMS and Novasenta; is a scientific advisory board member of Werewolf, Apeximmune, T7/Imreg Bio, and Secarna; is a consultant of Third Arc Bio, Curie Bio, Ablytx, Radionetics Oncology, and Ellipses; and received funding from BMS and Novasenta. No other disclosures were reported.
