Chen Jinling, Chi Hongli, Wang Chao, Du Yanlin, Wang Yani, Yang Shijie, Jiang Shiqi, Lv Xinru, He Jiaxuan, Chen Jingyi, Fu Ting, Wang Zeng, Cheng Ming, An Keli, Zhang Penghui, Tan Weihong
School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin 300072, China.
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China.
J Am Chem Soc. 2024 Dec 18;146(50):34311-34323. doi: 10.1021/jacs.4c06189. Epub 2024 Dec 4.
Safely and effectively harnessing innate immunity to boost cancer immunotherapy is promising yet challenging. Hence, we have developed a series of programmable aptamer-based multispecific engagers by encoding various artificial aptamer-drug codons with DNA-templated polymerization, aiming to broadly boost innate and adaptive immunity for antitumor therapy. All circular single-stranded multivalent aptamer-drug conjugates (os-mvApDCs) had a dendritic structure, precise size, and excellent stability, enabling prolonged blood circulation, targeted tumor accumulation, and rapid multireceptor-mediated endocytosis. A trispecific engager (os-mvApDCs), targeting PD-1 on CD8 T cells and PD-L1/c-Met on tumor cells, recruited large amounts of immune cells into the tumor and released cytotoxic MMAE and immunomodulators, inducing severe cell death and broad activation of innate immunity. When combined with the αPD-1 blockade, there was a significant increase in the number of CD8 T cells (10-fold increase versus untreated control) engaged and expanded in the tumor, exhibiting potent function (IFN-γ/GzmB) and low exhaustion (PD-1TIM-3). The orchestrated innate and adaptive immunity effectively eliminated immunosuppressive MDSCs, Tregs, and M2-like macrophages in tumors and promoted the maturation of dendritic cells (DCs) in the draining lymph nodes, resulting in robust and durable systemic antitumor efficacy, with 7 out of 8 mice surviving over 60 days. Our programmable DNA-templated printing technology enables the rational design of multispecific therapeutics with modular composition and function but minimal production issues, providing a versatile tool for the development of multifunctional personalized medicine.
安全有效地利用先天免疫来增强癌症免疫疗法前景广阔但也颇具挑战。因此，我们通过DNA模板聚合编码各种人工适配体-药物密码子，开发了一系列基于可编程适配体的多特异性衔接器，旨在广泛增强先天免疫和适应性免疫以进行抗肿瘤治疗。所有环状单链多价适配体-药物缀合物（os-mvApDCs）均具有树状结构、精确的尺寸和出色的稳定性，能够实现血液循环延长、肿瘤靶向积累以及快速多受体介导的内吞作用。一种三特异性衔接器（os-mvApDCs）靶向CD8 T细胞上的PD-1以及肿瘤细胞上的PD-L1/c-Met，将大量免疫细胞募集到肿瘤中，并释放细胞毒性MMAE和免疫调节剂，诱导严重的细胞死亡和先天免疫的广泛激活。当与αPD-1阻断联合使用时，肿瘤中被招募和扩增的CD8 T细胞数量显著增加（与未治疗的对照组相比增加了10倍），表现出强大的功能（IFN-γ/GzmB）和低耗竭（PD-1/TIM-3）。精心编排的先天免疫和适应性免疫有效消除了肿瘤中免疫抑制性的MDSC、Treg和M2样巨噬细胞，并促进了引流淋巴结中树突状细胞（DC）的成熟，从而产生强大且持久的全身抗肿瘤疗效，8只小鼠中有7只存活超过60天。我们的可编程DNA模板印刷技术能够合理设计具有模块化组成和功能但生产问题最少的多特异性疗法，为开发多功能个性化药物提供了一种通用工具。
