Activation of the immune system to target and eliminate tumor cells is recognized as one of the most promising approaches for cancer therapy. One strategy for immunotherapy is inhibition of negative regulators of immune responsiveness, which is known as checkpoint blockade. The cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) is one of the checkpoint proteins which are targeted by therapeutic monoclonal antibodies for activating immune system against cancer cells. Up to date, however, no small molecular weight inhibitor has been reported for targeting CTLA-4. To address this gap, we applied a high-throughput phage display platform recently established by our group, called ‘MOrPH-PhD’, to discover a new class of macrocyclic peptide inhibitors of CTLA-4. Using this system, large combinatorial libraries of genetically encoded macrocyclic peptides were panned against CTLA-4, resulting in the discovery of a panel of scaffold-diverse macrocyclic peptides capable of targeting CTLA-4 with low micromolar to sub-micromolar affinity. These macrocycle peptides were further characterized for their ability to inhibit CTLA-4 in cell-based assays. These first-in-class macrocyclic peptide modulators of CTLA-4 are expected provide valuable probes for investigating the therapeutic potential of CTLA-4-mediated interactions in cancer as well as starting points for the development of new anticancer agents.

Design and evolution of macrocyclic peptide inhibitors of checkpoint protein CTLA-4

ACS Fall 2021

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