A small molecule inhibitor of CD28 costimulation restrains pathogenic T-cell responses in inflammatory bowel disease
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…
A small molecule inhibitor, CA-23, shows promise in curbing inflammatory responses in inflammatory bowel disease (IBD). Researchers discovered CA-23 using a sensitive screening platform, which revealed that the molecule binds directly to human and mouse CD28 without affecting CTLA-4 signaling. CA-23 effectively inhibits CD28-B7 engagement and T cell activation, even in human whole blood and peripheral blood mononuclear cells.
In a colitis model, CA-23 reduced disease severity, histologic injury, and pathogenic Th1 and Th17 responses. When tested on PBMCs from patients with ulcerative colitis or Crohn's disease, CA-23 suppressed inflammatory cytokine production and T cell activation, matching or surpassing the effects of Abatacept. Importantly, CA-23 preserves Treg suppressive activity and epithelial barrier integrity, unlike Abatacept which reduces Treg function.
Notably, CA-23 does not alter CD80 or CD86 expression on antigen-presenting cells and exhibits no significant off-target activity. These findings suggest that direct CD28 antagonism could offer a unique approach to suppressing pathogenic T cell responses in IBD preclinical models.
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