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

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Modularly Designed Peptide Nanoprodrug Augments Antitumor Immunity of PD-L1 Checkpoint Blockade by Targeting Indoleamine 2,3-Dioxygenase
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2020-01-16 , DOI: 10.1021/jacs.9b12232
Xuexiang Han _{1,

2} , Keman Cheng _{1,

3} , Ying Xu ₁ , Yazhou Wang ₁ , Huan Min ₁ , Yinlong Zhang _{1,

2} , Xiao Zhao _{1,

2} , Ruifang Zhao _{1,

2} , Gregory J Anderson ₄ , Lei Ren ₃ , Guangjun Nie _{1,

2} , Yiye Li _{1,

2}

Affiliation

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 histi-dines 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 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 anti-tumor immunity of checkpoint inhibitors.

中文翻译：

模块化设计的肽纳米前药通过靶向吲哚胺 2,3-双加氧酶增强 PD-L1 检查点阻断的抗肿瘤免疫

单药免疫检查点抑制剂在治疗肿瘤方面的有限疗效促使对其组合伙伴进行研究。在这里，据报道，肿瘤归巢吲哚胺 2, 3-双加氧酶 (IDO) 纳米抑制剂可选择性抑制肿瘤微环境中的免疫抑制 IDO 通路。它由模块化设计的肽-药物偶联物自组装而成，该偶联物包含亲水性靶向基序（精氨酰-甘氨酰-天冬氨酸；RGD）、两个可质子化的组氨酸和一个酯键连接的疏水性 IDO 抑制剂，具有 pH 响应性分解和酯酶催化的药物释放。值得注意的是，它实现了对瘤内 IDO 活性的有效和持久抑制，同时降低了全身毒性，这大大增强了体内程序性细胞死亡 - 配体 1 阻断的治疗效果。全面的，

更新日期：2020-01-16

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