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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Inflammation Pharmacology
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1397995
This article is part of the Research Topic Rheumatoid Arthritis: Discovery of Potential Therapeutic Targets View all 6 articles

Duvelisib is a novel NFAT inhibitor that mitigates adalimumab-induced immunogenicity

Provisionally accepted
Aboli Bhingarkar Aboli Bhingarkar 1Yuyin Wang Yuyin Wang 1Keito Hoshitsuki Keito Hoshitsuki 1Katherine Marie Eichinger Katherine Marie Eichinger 1,2Sanjay Rathod Sanjay Rathod 1Yin Zhu Yin Zhu 1He Lyu He Lyu 1Andrew T Mcnutt Andrew T Mcnutt 3Larry W Moreland Larry W Moreland 4Lee Mcdermott Lee Mcdermott 5David Ryan Koes David Ryan Koes 3Christian Fernandez Christian Fernandez 1,6*
  • 1 Center for Pharmacogenetics, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • 2 Duo Oncology, Pittsburgh, United States
  • 3 Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • 4 Division of Rheumatology, School of Medicine, University of Colorado, Aurora, United States
  • 5 Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • 6 University of Pittsburgh, Pittsburgh, United States

The final, formatted version of the article will be published soon.

    TNFα inhibitor (TNFi) immunogenicity in rheumatoid arthritis (RA) is a major obstacle to its therapeutic effectiveness. Methotrexate (MTX) can mitigate TNFi immunogenicity, but its adverse effects necessitate alternative strategies. Targeting nuclear factor of activated T cells (NFAT) transcription factors may protect against biologic immunogenicity. Therefore, developing a potent NFAT inhibitor to suppress this immunogenicity may offer an alternative to MTX. We performed a structure based virtual screen of the NFATC2 crystal structure to identify potential small molecules that could interact with NFATC2. We identified duvelisib (DV) as a novel NFATC2 and NFATC1 inhibitor that attenuates NFAT transcriptional activity without inhibiting calcineurin or NFAT nuclear localization. Our results suggest that DV inhibits NFAT independently of PI3K by interfering with nuclear NFAT binding to the NFAT consensus promoter sequence. DV significantly protected mice from adalimumab immunogenicity and attenuated ex vivo CD4 + T cell proliferation and B cell antibody secretion. We conclude that DV is a promising NFAT inhibitor that can protect from TNFi immunogenicity without inhibiting calcineurin phosphatase activity. Our results suggest that the future development of DV analogs may be of interest to pursue as agents to attenuate unwanted immune responses.

    Keywords: rheumatoid arthritis, Antidrug antibodies (ADA), NFAT (nuclear factor expression of activated T cell), Methotrexate, Adalimumab, duvelisib

    Received: 08 Mar 2024; Accepted: 12 Dec 2024.

    Copyright: © 2024 Bhingarkar, Wang, Hoshitsuki, Eichinger, Rathod, Zhu, Lyu, Mcnutt, Moreland, Mcdermott, Koes and Fernandez. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Christian Fernandez, University of Pittsburgh, Pittsburgh, United States

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