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Published on: January 26, 2016
AI-Designed Cyclic Peptides Enable Controllable Modulation of the CD28 Immune Checkpoint
Katarzyna Kuncewicz1,2, Saurabh Upadhyay1, Renjie Zhu3
1Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, New York, New York, USA.
Summary
AI-designed cyclic peptides offer controllable immune modulation by targeting CD28 checkpoints. This synthetic approach shows therapeutic potential for inflammatory diseases, unlike traditional biologics.
Area of Science:
- Immunology
- Synthetic Biology
- Computational Drug Discovery
Background:
- Immune checkpoint therapies, primarily biologics, face limitations in controllability and prolonged receptor occupancy.
- Synthetic modalities targeting protein-protein interactions for immune modulation are underexplored.
- The costimulatory receptor CD28 plays a crucial role in T-cell activation and immune responses.
Purpose of the Study:
- To develop a novel, AI-guided strategy for discovering synthetic peptide antagonists of immune checkpoints.
- To investigate the potential of cyclic peptides as controllable immunomodulatory agents.
- To evaluate a lead cyclic peptide antagonist of CD28 for its therapeutic efficacy in preclinical models.
Main Methods:
- Utilized an AI-guided strategy to identify cyclic peptide antagonists targeting the CD28 receptor.
- Characterized the lead peptide (CIP-3) for binding affinity to CD28 and its ability to disrupt CD28-ligand interactions.
- Assessed CIP-3's effects on CD28-dependent T-cell activation in human immune systems and its pharmacologic reversibility.
- Evaluated CIP-3's therapeutic efficacy in a T-cell transfer model of chronic colitis and its impact on cytokine production in patient-derived cells.
Main Results:
- Discovered CIP-3, a cyclic peptide antagonist of CD28 with nanomolar binding affinity.
- Demonstrated that CIP-3 suppresses CD28-dependent T-cell activation without agonist activity and exhibits rapid, exposure-dependent reversibility.
- Showed dose-dependent therapeutic efficacy of CIP-3 in a chronic colitis model, reducing inflammatory cytokines.
- Confirmed CIP-3's ability to suppress cytokine production in healthy donors and ulcerative colitis patient PBMCs, comparable to anti-CD28 biologics.
Conclusions:
- AI-designed cyclic peptides represent a promising controllable synthetic modality for immune checkpoint modulation.
- CIP-3 offers a potential therapeutic strategy for immune-related diseases with enhanced pharmacologic control.
- This approach advances the development of synthetic immunomodulatory agents beyond traditional biologics.
