Modularly Designed Peptide Nanoprodrug Augments Antitumor Immunity of PD-L1 Checkpoint Blockade by Targeting Indoleamine 2,3-Dioxygenase

The limited efficacy of single-agent immune checkpoint inhibitors in treating tumors has prompted investigations on their combination partners. Here, a tumor-homing indoleamine 2,3-dioxygenase (IDO) nanoinhibitor is reported to selectively inhibit immunosuppressive IDO pathway in the tumor microenvi...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2020-02, Vol.142 (5), p.2490-2496
Main Authors: Han, Xuexiang, Cheng, Keman, Xu, Ying, Wang, Yazhou, Min, Huan, Zhang, Yinlong, Zhao, Xiao, Zhao, Ruifang, Anderson, Gregory J, Ren, Lei, Nie, Guangjun, Li, Yiye
Format: Article
Language:English
Subjects:
B7-H1 Antigen - antagonists & inhibitors
Drug Design
Humans
Immunotherapy
Indoleamine-Pyrrole 2,3,-Dioxygenase - antagonists & inhibitors
Nanoparticles
Oligopeptides - chemistry
Prodrugs - pharmacokinetics
Prodrugs - pharmacology
Tumor Microenvironment
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Summary:The limited efficacy of single-agent immune checkpoint inhibitors in treating tumors has prompted investigations on their combination partners. Here, a tumor-homing indoleamine 2,3-dioxygenase (IDO) nanoinhibitor is reported to selectively inhibit immunosuppressive IDO pathway in the tumor microenvironment. It is self-assembled from a modularly designed peptide–drug conjugate containing a hydrophilic targeting motif (arginyl-glycyl-aspartic acid; RGD), two protonatable histidines, and an ester bond-linked hydrophobic IDO inhibitor, which exhibits pH-responsive disassembly and esterase-catalyzed drug release. Markedly, it achieved potent and persistent inhibition of intratumoral IDO activity with a reduced systemic toxicity, which greatly enhanced the therapeutic efficacy of programmed cell death-ligand 1 blockade in vivo. Overall, this study provides a promising paradigm of combinatorial normalization immunotherapy by exploiting a targeted IDO nanoinhibitor to augment the antitumor immunity of checkpoint inhibitors.
ISSN:0002-7863
1520-5126
DOI:10.1021/jacs.9b12232