Macrocyclic Peptide Inhibitor of PD‐1/PD‐L1 Immune Checkpoint
Katarzyna Magiera‐Mularz, Katarzyna Kuśka, Łukasz Skalniak, P. Grudnik, Bogdan Musielak, Jacek Plewka, Justyna Kocik-Krol, Małgorzata Stec, Kazimierz Węglarczyk, Dominik Sala, Benedykt Władyka, Maciej Siedlar, Tad A. Holak, Grzegorz Dubin
Abstract
Abstract Immune checkpoint‐targeting antibodies brought a recent breakthrough in cancer immunotherapy, but the development of small molecule checkpoint inhibitors is lagging behind. Here, the characterization of a macrocyclic peptide (p101) capable of blocking the PD‐L1/PD‐1 immune checkpoint is reported at the interface of cancer and immune cells. NMR and other physicochemical data demonstrate that the macrocycle binds to PD‐L1 to sterically hinder its interaction with PD‐1. The crystal structure of the complex highlights the detailed features of the binding site and demonstrates that the interaction is primarily guided by hydrophobic forces. A reporter PD‐L1/PD‐1 blockade bioassay demonstrates that p101 is able to inhibit the interaction in the cellular environment. Finally, it is shown that p101 releases the immune response of primary human T‐cells from PD‐L1 mediated inhibition.