A Totipotent "All‐In‐One" Peptide Sequentially Blocks Immune Checkpoint and Reverses the Immunosuppressive Tumor Microenvironment. Issue 2 (4th December 2022)

• Record Type: Journal Article
• Authors: Zhang, Limin; Jiang, Zhenqi; Yang, Xi; Qian, Yixia; Wang, Minxuan; Wu, Shang; Li, Lingyun; Jia, Fei; Wang, Zihua; Hu, Zhiyuan; Zhao, Minzhi; Tang, Xiaoying; Li, Gang; Shang, Hanbing; Chen, Xiaoyuan; Wang, Weizhi
• Is Part Of: Advanced materials. Volume 35:Issue 2(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-04
• Subjects: combination therapy -- immune checkpoints -- peptide self‐assembly -- screening; Materials -- Periodicals; Chemical vapor deposition -- Periodicals; 620.11
• DOI: 10.1002/adma.202207330
• Languages: English
• ISSNs: 0935-9648

Abstract

Abstract: Immune checkpoint blockade combined with reversal of the immunosuppressive tumor microenvironment (TME) can dramatically enhance anti‐tumor immunity, which can be achieved by using multiple‐agent therapy. However, the optimal dose and order of administration of different agents remain elusive. To address this dilemma, multiple agents are often grafted together to construct "all‐in‐one" totipotent drugs, but this usually comes at the cost of a lack of synergy between the agents. Herein, by comprehensively analyzing the conserved sites of the immune checkpoint and TME drug targets, peptide secondary structures, assembly properties, and other physicochemical properties, a high‐content peptide library is designed. By using the "3D‐molecular‐evolution" screening strategy, an efficient and totipotent "all‐in‐one" peptide (TAP) is obtained, which possesses the abilities of self‐assembling, blocking the PD‐1/PD‐L1 axis, inhibiting Rbm38‐eIF4E complex formation, and activating p53. It is shown that in mice treated with TAP, with either subcutaneous tumors or patient‐derived xenografts, PD‐L1 is blocked, with increased activation of both T and NK cells whilst reversing the immunosuppressive TME. Moreover, TAP can mitigate tumor activity and suppress tumor growth, showing superior therapeutic effect over antibody‐based drugs. Abstract : A totipotent "all‐in‐one" peptide can transform into α‐helix in response to the tumor microenvironment. It possesses the abilities of self‐assembling, blocking the PD‐1/PD‐L1 axis, inhibiting Rbm38‐eIF4E complex formation, and activating p53.