Reversible CD28 checkpoint modulation by cyclic peptides outperforms biologic blockade under exposure-limited conditions

CD28 co-stimulatory blockade is an established therapeutic strategy in autoimmune disease, yet every clinical-stage agent shares a structural limitation: high-affinity, long-lived receptor occupancy that precludes dynamic control of immune suppression. In chronic inflammatory conditions, where prolonged immunosuppression carries infection risk and necessitates treatment interruptions, no existing agent permits rapid restoration of immune function. We report CP8, a disulfide-constrained cyclic peptide antagonist that matches the inhibitory potency of clinical-stage CD28 biologics (FR104, Acazicolcept, and Lulizumab) across primary human immune cells from healthy and ulcerative colitis donors, suppressing IL-2 and IFN-{gamma} production without agonist activity. Unlike these biologics, CP8 enables rapid and near-complete restoration of T-cell function upon compound removal, a property mechanistically inaccessible to antibody-based therapeutics and demonstrated here for the first time for any CD28-targeting agent. In a T-cell transfer colitis model, CP8 maintains efficacy under intermittent dosing and outperforms Acazicolcept, a dual CD28/ICOS inhibitor, under exposure-limited conditions, achieving superior disease suppression, tissue preservation, and cytokine reduction. These results demonstrate that potency and pharmacological persistence are decoupled properties, and reframe cyclic peptides as a superior modality for immune checkpoints where temporal control of signaling is essential to balance efficacy with the risks of chronic immune suppression.