A DXd/TLR7-Agonist Dual-Conjugate Anti-HER2 ADC Exerts Robust Antitumor Activity Through Tumor Cell Killing and Immune Activation

doi:10.1158/1535-7163.MCT-24-0078

	A DXd/TLR7-Agonist Dual-Conjugate Anti-HER2 ADC Exerts Robust Antitumor Activity Through Tumor Cell Killing and Immune Activation
	Yue, Hangtian1,3,4 ; Xu, Hui 1; Ma, Lanping 2; Li, Xiyuan1,3,4 ; Yang, Biyu 1; Wang, Xiyuan 1; Zeng, Qingzhong1,3,4 ; Li, Han1,3 ; Zhang, Deqiang 1,4; Geng, Meiyu1,3,4,5 ; Meng, Tao 2; Xie, Zuoquan 1,4
	2024-11-04
发表期刊	MOLECULAR CANCER THERAPEUTICS (IF:5.3[JCR-2023],5.4[5-Year])
ISSN	1535-7163
EISSN	1538-8514
卷号	23 期号:11
发表状态	已发表
DOI	10.1158/1535-7163.MCT-24-0078
摘要	The emergence of trastuzumab deruxtecan (T-DXd), a new-generation antibody-drug conjugate (ADC), has profoundly altered the therapeutic paradigm for HER2-positive solid tumors, demonstrating remarkable clinical benefits. However, the combined outcomes of T-DXd with immunotherapy agents remain ambiguous. In this study, we introduce Tras-DXd-MTL1, an innovative HER2 targeting ADC that integrates the topoisomerase inhibitor DXd and a toll like receptor 7 (TLR7) agonist MTT5, linked to trastuzumab via a GGFG tetrapeptide linker. Mechanistically, Tras-DXd-MTL1 retains the DNA-damaging and cell-killing properties of topoisomerase inhibitors while simultaneously enhancing the immune response within the tumor microenvironment. This is achieved by promoting immune cell infiltration and activating dendritic cells and CD8+T cells via MTT5. In vivo evaluation of Tras-DXd-MTL1's antitumor potency revealed a notably superior performance compared with the T-DXd (Tras-DXd) or Tras-MTL1 in immunocompetent mice with trastuzumab-resistant EMT6-HER2 tumor and immunodeficient mice with JIMT-1 tumor. This improved efficacy is primarily attributed to its dual functions of immune stimulation and cytotoxicity. Our findings highlight the potential of incorporating immunostimulatory agents into ADC design to potentiate antitumor effects and establish durable immune memory, thereby reducing tumor recurrence risks. Therefore, our study offers a novel strategy for the design of immune-activating ADCs and provides a potential approach for targeting solid tumors with different levels of HER2 expression.
URL	查看原文
收录类别	SCI
语种	英语
资助项目	National Natural Science Foundation of China (NSFC)[81821005] ; Natural Science Foundation of China for Innovation Research Group[SIMM0120231001] ; Shanghai Municipal Science and Technology Major Project[2020CXJQ02]
WOS研究方向	Oncology
WOS类目	Oncology
WOS记录号	WOS:001348480800008
出版者	AMER ASSOC CANCER RESEARCH
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/421483
专题	生命科学与技术学院生命科学与技术学院_特聘教授组_耿美玉组生命科学与技术学院_博士生
通讯作者	Meng, Tao; Xie, Zuoquan
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Med Chem, 555 Zuchongzhi Rd, Shanghai 202203, Peoples R China 3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 4.Univ Chinese Acad Sci, Beijing, Peoples R China 5.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai, Peoples R China
第一作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Yue, Hangtian,Xu, Hui,Ma, Lanping,et al. A DXd/TLR7-Agonist Dual-Conjugate Anti-HER2 ADC Exerts Robust Antitumor Activity Through Tumor Cell Killing and Immune Activation[J]. MOLECULAR CANCER THERAPEUTICS,2024,23(11).
APA	Yue, Hangtian.,Xu, Hui.,Ma, Lanping.,Li, Xiyuan.,Yang, Biyu.,...&Xie, Zuoquan.(2024).A DXd/TLR7-Agonist Dual-Conjugate Anti-HER2 ADC Exerts Robust Antitumor Activity Through Tumor Cell Killing and Immune Activation.MOLECULAR CANCER THERAPEUTICS,23(11).
MLA	Yue, Hangtian,et al."A DXd/TLR7-Agonist Dual-Conjugate Anti-HER2 ADC Exerts Robust Antitumor Activity Through Tumor Cell Killing and Immune Activation".MOLECULAR CANCER THERAPEUTICS 23.11(2024).