A DXd/TLR7-Agonist Dual-Conjugate Anti-HER2 ADC Exerts Robust Antitumor Activity Through Tumor Cell Killing and Immune Activation
文献类型：期刊论文
| 作者 | Yue, Hangtian2,3,5; Xu, Hui5; Ma, Lanping4 ; Li, Xiyuan2,3,5; Yang, Biyu5; Wang, Xiyuan5; Zeng, Qingzhong2,3,5; Li, Han3,5; Zhang, Deqiang2,5; Geng, Meiyu1,2,3,5
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| 刊名 | MOLECULAR CANCER THERAPEUTICS
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| 出版日期 | 2024-11-04 |
| 卷号 | 23期号:11页码:1639-1651 |
| ISSN号 | 1535-7163 |
| DOI | 10.1158/1535-7163.MCT-24-0078 |
| 英文摘要 | 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. |
| WOS关键词 | ANTIBODY-DRUG CONJUGATE ; DENDRITIC CELLS ; EFFICACY ; DS-8201A ; ROLES |
| 资助项目 | National Natural Science Foundation of China (NSFC)[81821005] ; Natural Science Foundation of China for Innovation Research Group[SIMM0120231001] ; Project of Shanghai Institute of Materia Medica, Chinese Academy of Sciences ; Shanghai Municipal Science and Technology Major Project[2020CXJQ02] ; Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning |
| WOS研究方向 | Oncology |
| WOS记录号 | WOS:001351585800014 |
| 出版者 | AMER ASSOC CANCER RESEARCH |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/314354]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Meng, Tao; Xie, Zuoquan |
| 作者单位 | 1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai, Peoples R China 2.Univ Chinese Acad Sci, Beijing, Peoples R China 3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, Div Med Chem, Shanghai, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China |
| 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):1639-1651. |
| 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),1639-1651. |
| 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):1639-1651. |
入库方式： OAI收割
来源：上海药物研究所
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