{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T20:27:34Z","timestamp":1787084854323,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,15]]},"group-title":"Pharmacology and Toxicology","reference-count":41,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T00:00:00Z","timestamp":1786752000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["R01DK137299"],"award-info":[{"award-number":["R01DK137299"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>CD28 costimulation contributes to pathogenic T cell responses in inflammatory bowel disease (IBD), but current B7-directed blockade also limits CTLA-4 signaling. Using a sensitive NanoBiT split-luciferase screening platform, we identified and optimized CA-23, a small molecule antagonist that directly binds human and mouse CD28 without measurable binding to CD80, CD86, or CTLA-4. CA-23 inhibited CD28-B7 engagement and CD28-dependent T cell activation without agonist activity in human whole blood and peripheral blood mononuclear cells. CA-23 achieved exposure in the colon and mesenteric lymph nodes and reduced disease severity, histologic injury, and pathogenic Th1 and Th17 responses in a T cell transfer model of colitis. In PBMCs from donors with ulcerative colitis or Crohn\u2019s disease, CA-23 suppressed inflammatory cytokine production and T cell activation to a degree matching or exceeding Abatacept. In human intestinal epithelial\u2013PBMC co-cultures, CA-23 preserved Treg suppressive activity and epithelial barrier integrity, whereas Abatacept reduced Treg function. CA-23 did not alter CD80 or CD86 expression on autologous antigen-presenting cells and showed no substantial off-target activity in the tested selectivity panel. These findings support direct CD28 antagonism as a mechanistically differentiated alternative to B7-directed co-stimulation blockade for suppressing pathogenic T cell responses in preclinical models of IBD.<\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary<\/jats:title>\n                  <jats:p>A CD28-selective small molecule blocks pathogenic T cell activation and preserves Treg function unlike Abatacept in IBD models.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.08.10.744081","type":"posted-content","created":{"date-parts":[[2026,8,16]],"date-time":"2026-08-16T05:45:16Z","timestamp":1786859116000},"source":"Crossref","is-referenced-by-count":0,"title":["A small molecule inhibitor of CD28 costimulation restrains pathogenic T-cell responses in inflammatory bowel disease"],"prefix":"10.64898","author":[{"given":"Sungwoo","family":"Cho","sequence":"first","affiliation":[{"name":"Department of Radiology, Columbia University Irving Medical Center, New York, NY, 10032, USA"},{"name":"Department of Radiology, Weill Cornell Medicine, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saurabh","family":"Upadhyay","sequence":"additional","affiliation":[{"name":"Department of Radiology, Columbia University Irving Medical Center, New York, NY, 10032, USA"},{"name":"Department of Radiology, Weill Cornell Medicine, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoren","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Radiology, Weill Cornell Medicine, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moustafa","family":"Gabr","sequence":"additional","affiliation":[{"name":"Department of Radiology, Columbia University Irving Medical Center, New York, NY, 10032, USA"},{"name":"Department of Radiology, Weill Cornell Medicine, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026081812500851000_2026.08.10.744081v1.1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.84.23.8573"},{"issue":"8","key":"2026081812500851000_2026.08.10.744081v1.2","first-page":"3201","article-title":"The murine homologue of the T lymphocyte antigen CD28","volume":"144","year":"1990","journal-title":"Molecular cloning and cell surface expression. 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