| Autor: |
Hung-Ju Hsu, Chao-Ping Tung, Chung-Ming Yu, Chi-Yung Chen, Hong-Sen Chen, Yu-Chuan Huang, Pei-Hsun Tsai, Su-I Lin, Hung-Pin Peng, Yi-Kai Chiu, Yueh-Liang Tsou, Wei-Ying Kuo, Jhih-Wei Jian, Fei-Hung Hung, Chiao-Yun Hsieh, Michael Hsiao, Simon Shih-Hsien Chuang, Chia-Ning Shen, Yong Alison Wang, An-Suei Yang |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Předmět: |
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| Zdroj: |
Scientific Reports, Vol 11, Iss 1, Pp 1-15 (2021) |
| Druh dokumentu: |
article |
| ISSN: |
2045-2322 |
| DOI: |
10.1038/s41598-021-94902-1 |
| Popis: |
Abstract Mesothelin (MSLN) is an attractive candidate of targeted therapy for several cancers, and hence there are increasing needs to develop MSLN-targeting strategies for cancer therapeutics. Antibody–drug conjugates (ADCs) targeting MSLN have been demonstrated to be a viable strategy in treating MSLN-positive cancers. However, developing antibodies as targeting modules in ADCs for toxic payload delivery to the tumor site but not to normal tissues is not a straightforward task with many potential hurdles. In this work, we established a high throughput engineering platform to develop and optimize anti-MSLN ADCs by characterizing more than 300 scFv CDR-variants and more than 50 IgG CDR-variants of a parent anti-MSLN antibody as candidates for ADCs. The results indicate that only a small portion of the complementarity determining region (CDR) residues are indispensable in the MSLN-specific targeting. Also, the enhancement of the hydrophilicity of the rest of the CDR residues could drastically increase the overall solubility of the optimized anti-MSLN antibodies, and thus substantially improve the efficacies of the ADCs in treating human gastric and pancreatic tumor xenograft models in mice. We demonstrated that the in vivo treatments with the optimized ADCs resulted in almost complete eradication of the xenograft tumors at the treatment endpoints, without detectable off-target toxicity because of the ADCs’ high specificity targeting the cell surface tumor-associated MSLN. The technological platform can be applied to optimize the antibody sequences for more effective targeting modules of ADCs, even when the candidate antibodies are not necessarily feasible for the ADC development due to the antibodies’ inferior solubility or affinity/specificity to the target antigen. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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