Induction of Antigen-Specific T Cell Tolerance by CNP-104 Positively Affects Clinical Response in Primary Biliary Cholangitis (PBC) 9237
Abstract Description PBC is an archetypal autoimmune disease where the dominant autoantigen is mitochondrial PDC-E2. Hitherto, PBC treatment has been neither specific nor directed toward restoration of tolerance. CNP-104, a tolerogenic nanoparticle encapsulating PDC-E2, is hypothesized to restore tolerance to pathogenic T cells. We conducted a Phase 2a First-in-Human randomized controlled trial of CNP-104 in PBC patients unresponsive/intolerant to ursodeoxycholic acid. The 42 enrolled subjects were randomized 2:1 to receive two doses of CNP-104 or placebo (PBO) one week apart and were followed for 120 days to assess safety and treatment durability. CNP-104 was safe and well-tolerated. Compared to PBO, the CNP-104 group had a reduced percentage of antigen-specific Th17 T cells and increased antigen-specific tolerogenic CD8+ T cell counts (TIGIT, GARP). ALP, ALT, and total bilirubin were similar between groups. Clinically relevant effects on albumin levels, liver stiffness, and the rate of change in 5-year UK-PBC risk for liver outcomes were improved in the CNP-104 group compared to PBO. This trial is limited by small size and data variability. Induction of antigen-specific T cell tolerance, shown by reduced Th17 cells and increased TIGIT and GARP cells correlates with improved liver stiffness, albumin, and UK-PBC. These findings suggest the CNP-104 tolerogenic mechanism of action translates to clinical benefits. These data support future studies with this unique therapeutic platform to treat PBC. Topic Categories Therapeutic Approaches to Autoimmunity (THER)
Authors
- Stuart Gordon (ORCID: https://orcid.org/0000-0003-0878-0585)
- Adam Elhofy
- Roberto Firpi-Morell
- Brett E. Fortune (ORCID: https://orcid.org/0000-0002-0646-467X)
- Raymond E. Phillips (ORCID: https://orcid.org/0000-0001-6197-4333)
- Stephen H. Caldwell (ORCID: https://orcid.org/0000-0003-1323-4191)
- Bobby Zervos
- Christopher L. Bowlus (ORCID: https://orcid.org/0000-0002-3906-6811)
- Jatinder Pruthi
- Marina Silveira (ORCID: https://orcid.org/0000-0002-3775-5154)
- Tarek Hassanein (ORCID: https://orcid.org/0000-0002-9157-0329)
- Molly Frey (ORCID: https://orcid.org/0000-0002-4578-8183)
- Erik Wambre (ORCID: https://orcid.org/0000-0002-3628-0011)
- Matthew Robert Kappus (ORCID: https://orcid.org/0000-0003-3365-5903)
- Scott McHenry (ORCID: https://orcid.org/0000-0001-6786-0345)
- Daniel S. Pratt (ORCID: https://orcid.org/0000-0002-7426-969X)
- Derrick McCarthy
- Govarthanan Rajendiran (ORCID: https://orcid.org/0000-0002-4054-2774)
- E. Läwitz
- Paul M. Peloso (ORCID: https://orcid.org/0000-0001-6979-306X)
- Bhaktasharan Patel
- Denise M. Harnois (ORCID: https://orcid.org/0000-0001-7307-2900)
- Gautham Reddy
- Michael Galambos
- M. Eric Gershwin
- Manuel Rodrı́guez
Institutions
- Sanford Health (US)
- Cleveland Clinic (US)
- Montefiore Medical Center (US)
- Harvard University (US)
- Henry Ford Health System (US)
- Duke University (US)
- Washington University in St. Louis (US)
- WinnMed (US)
- Yale University (US)
- University of Florida (US)
- University of Chicago (US)
- Massachusetts General Hospital (US)
- Genoscience Pharma (France) (FR)
- Southern California Reproductive Center (US)
- Oxford Medical Diagnostics (United Kingdom) (GB)
- Prostate Cancer Research (GB)
- Research Institute of South Florida (US)
- Peak Associates (United Kingdom) (GB)
- Texas Liver Institute (US)
- Mayo Clinic in Florida (US)
- Digestive Care (United States) (US)
- University of Virginia (US)
- University of California, Davis (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- The Journal of Immunology
- Published
- 2025-11-01
- DOI
- https://doi.org/10.1093/jimmun/vkaf283.2663
- Primary Topic
- Liver Diseases and Immunity
- Type
- article
- Field-Weighted Citation Impact
- 0.00