Development of a bispecific antibody-drug conjugate targeting EpCAM and CLDN3 for the treatment of multiple solid tumors
文献类型：期刊论文
| 作者 | Luo, Meiying6; Wang, Xiaohuan5; Yu, Guoji4; Ji, Jing3; Li, Long2,6 ; Song, Fan1,6
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| 刊名 | EXPERIMENTAL HEMATOLOGY & ONCOLOGY
 |
| 出版日期 | 2025-03-08 |
| 卷号 | 14期号:1页码:16 |
| 关键词 | EpCAM CLDN3 Antibody-drug conjugate Dxd Solid tumor |
| DOI | 10.1186/s40164-025-00624-9 |
| 通讯作者 | Ji, Jing(jingji09714@buaa.edu.cn) ; Li, Long(lilong@lnm.imech.ac.cn) ; Song, Fan(songf@lnm.imech.ac.cn) |
| 英文摘要 | Epithelial cell adhesion molecule (EpCAM), a tumor antigen for antibody-drug conjugates (ADCs), is highly expressed in many epithelial cancers. However, the clinical progress of EpCAM ADCs has been challenging, primarily due to their toxicity in normal high-expression tissues such as the gastrointestinal tract. CLDN3 is highly co-expressed with EpCAM in various human malignancies, coupled with its minimal presence in normal tissues, rendering it an ideal target for developing potent therapeutic ADCs. Here, we developed a bispecific ADC (BsADC) targeting EpCAM and CLDN3, designed to avoid toxicity in normal tissues with high EpCAM expression. The parental monoclonal antibodies (mAbs) were screened for high binding and endocytosis activities on tumor cell lines. We then modified them into monovalent structures and selected clones with decreased binding and endocytosis activities. We combined these clones into bispecific antibodies (BsAbs) and finally chose the molecules with restored binding and endocytosis activities as lead molecules. The BsADCs were generated by conjugating the Drutecan (Dxd) to BsAbs via a cleavable linker. These conjugates exhibit potent binding and effectively inhibit the growth of tumor cells with high levels of both EpCAM and CLDN3, indicating their anti-tumor efficacy. Importantly, they show weak binding to cells with high EpCAM but low CLDN3, implying minimal toxicity to normal tissues with elevated EpCAM expression. Moreover, the BsADCs displayed advantageous pharmacokinetics and low toxicity in mice. These findings position the BsADCs targeting EpCAM and CLDN3 as promising candidates for treating multiple solid tumors. |
| WOS关键词 | SURFACE GLYCOPROTEIN ; PROTEIN EXPRESSION ; HUMAN OVARIAN ; EP-CAM ; CLAUDINS ; EGFR |
| 资助项目 | China Postdoctoral Science Foundation |
| WOS研究方向 | Oncology ; Hematology |
| 语种 | 英语 |
| WOS记录号 | WOS:001439610200001 |
| 资助机构 | China Postdoctoral Science Foundation |
| 源URL | [http://dspace.imech.ac.cn/handle/311007/100226]  |
| 专题 | 力学研究所_非线性力学国家重点实验室 |
| 通讯作者 | Ji, Jing; Li, Long; Song, Fan |
| 作者单位 | 1.Univ Chinese Acad Sci, Ctr Mat Sci & Optoelect Engn, Sch Engn Sci, Beijing 100049, Peoples R China 2.Guangzhou Med Univ, Afiliated Canc Hosp, Guangzhou Inst Canc Res, Guangzhou 510095, Peoples R China 3.Beihang Univ, Sch Biol Sci & Med Engn, Beijing 100191, Peoples R China 4.Inner Mongolia Met Mat Res Inst, Yantai 264003, Shandong, Peoples R China 5.Peking Univ Third Hosp, Dept Rehabil Med, 49 North Garden Rd, Beijing 100191, Peoples R China 6.Chinese Acad Sci, Inst Mech, State Key Lab Nonlinear Mech, Beijing Key Lab Engn Construct & Mechanobiol, 15 North Fourth Ring Rd West, Beijing 100190, Peoples R China |
| 推荐引用方式 GB/T 7714 | Luo, Meiying,Wang, Xiaohuan,Yu, Guoji,et al. Development of a bispecific antibody-drug conjugate targeting EpCAM and CLDN3 for the treatment of multiple solid tumors[J]. EXPERIMENTAL HEMATOLOGY & ONCOLOGY,2025,14(1):16. |
| APA | Luo, Meiying,Wang, Xiaohuan,Yu, Guoji,Ji, Jing,Li, Long,&Song, Fan.(2025).Development of a bispecific antibody-drug conjugate targeting EpCAM and CLDN3 for the treatment of multiple solid tumors.EXPERIMENTAL HEMATOLOGY & ONCOLOGY,14(1),16. |
| MLA | Luo, Meiying,et al."Development of a bispecific antibody-drug conjugate targeting EpCAM and CLDN3 for the treatment of multiple solid tumors".EXPERIMENTAL HEMATOLOGY & ONCOLOGY 14.1(2025):16. |
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来源：力学研究所
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