Rational engineering of degradation tail-driven CELMoD-antibody conjugates for precision malignancy therapy
文献类型：期刊论文
| 作者 | Guo, Yu1; Song, Yi1; Wang, Hanlin6,7; Lu, Yang1; Zhang, Jingyu1; Shen, Zheyuan1; Kan, Weijuan7; Wang, Yuxian7; Duan, Haiting1; Geng, Shuangshuang1 |
| 刊名 | ACTA PHARMACEUTICA SINICA B
 |
| 出版日期 | 2025-12-01 |
| 卷号 | 15期号:12页码:6510-6528 |
| 关键词 | Degrader-antibody conjugate Antibody-drug conjugate Cereblon E3 ligase modulator Immunomodulatory drug Molecular glue Targeted protein degradation Multiple myeloma Hematologic malignancy |
| ISSN号 | 2211-3835 |
| DOI | 10.1016/j.apsb.2025.09.009 |
| 通讯作者 | Wang, Hanlin(wanghanlin@simm.ac.cn) ; Zhou, Yubo(ybzhou@simm.ac.cn) ; Che, Jinxin(chejx@zju.edu.cn) ; Dong, Xiaowu(dongxw@zju.edu.cn) |
| 英文摘要 | Degrader-antibody conjugates (DACs) represent a promising drug modality for targeting hematological malignancy, but still lack rational design frameworks. Here, we show the strategies of reasonable antibody-degrader compatibility and degradation tail-derived conjugatability through a systematic exploration. Inspired by the success of IKZF1/3 degraders, we sought to explore the potential of cereblon E3 ligase modulators (CELMoDs) in constructing novel conjugates. By combining a modular library with neo-substrate screening and further conjugatable derivation, I034 was identified, a potent CELMoD payload with picomolar degradation activity and antiproliferative effects. Through linker chemistry, I034-based DACs were constructed and demonstrated superior efficacy and safety compared to auristatin-based conjugates both in vitro and in vivo, with the CD38-targeting Dara-VA-I034 achieving complete tumor eradication at low doses. Mechanistic insights revealed distinct positive feedback regulation of CD38 conjugates, highlighting the need for compatibility between payloads and antigens. These results demonstrate that the approach could provide a framework for discovering CELMoD payloads and advancing DACs for treating multiple myeloma and other malignancies. (c) 2025 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
| WOS关键词 | MULTIPLE-MYELOMA ; MEDIATED DELIVERY ; LENALIDOMIDE ; CEREBLON ; TARGET ; DRUGS |
| 资助项目 | National Natural Science Foun-dation of China[82173660] ; National Natural Science Foun-dation of China[82273951] ; National Natural Science Foun-dation of China[82404655] ; National Natural Science Foun-dation of China[92253306] ; China Postdoctoral Science Foundation[2024M750708] ; Shanghai Science and Technology Development Foundation[24YF275530] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001642092500001 |
| 出版者 | INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/322414]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Wang, Hanlin; Zhou, Yubo; Che, Jinxin; Dong, Xiaowu |
| 作者单位 | 1.Zhejiang Univ, Inst Drug Discovery & Design, Coll Pharmaceut Sci, Hangzhou 310058, Peoples R China 2.Zhejiang Univ, Coll Pharmaceut Sci, State Key Lab Adv Drug Delivery & Release Syst, Hangzhou 310058, Peoples R China 3.Chinese Acad Sci, Zhejiang Canc Hosp, Hangzhou Inst Med, Dept Pharm, Hangzhou 310022, Peoples R China 4.Zhejiang Univ, Sch Med, Affiliated Hosp 1, Bone Marrow Transplantat Ctr, Hangzhou 310009, Peoples R China 5.Chinese Acad Sci, Zhejiang Canc Hosp, Hangzhou Inst Med, Dept Lymphat Oncol, Hangzhou 310022, Peoples R China 6.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China 7.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Chem Biol, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Guo, Yu,Song, Yi,Wang, Hanlin,et al. Rational engineering of degradation tail-driven CELMoD-antibody conjugates for precision malignancy therapy[J]. ACTA PHARMACEUTICA SINICA B,2025,15(12):6510-6528. |
| APA | Guo, Yu.,Song, Yi.,Wang, Hanlin.,Lu, Yang.,Zhang, Jingyu.,...&Dong, Xiaowu.(2025).Rational engineering of degradation tail-driven CELMoD-antibody conjugates for precision malignancy therapy.ACTA PHARMACEUTICA SINICA B,15(12),6510-6528. |
| MLA | Guo, Yu,et al."Rational engineering of degradation tail-driven CELMoD-antibody conjugates for precision malignancy therapy".ACTA PHARMACEUTICA SINICA B 15.12(2025):6510-6528. |
入库方式： OAI收割
来源：上海药物研究所
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