Eradicating mesothelin-positive human gastric and pancreatic tumors in xenograft models with optimized anti-mesothelin antibody–drug conjugates from synthetic antibody libraries
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...
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Nature Portfolio
2021
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oai:doaj.org-article:1fd9e8c33c85491783497a53a3cfc8092021-12-02T16:23:42ZEradicating mesothelin-positive human gastric and pancreatic tumors in xenograft models with optimized anti-mesothelin antibody–drug conjugates from synthetic antibody libraries10.1038/s41598-021-94902-12045-2322https://doaj.org/article/1fd9e8c33c85491783497a53a3cfc8092021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-94902-1https://doaj.org/toc/2045-2322Abstract 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.Hung-Ju HsuChao-Ping TungChung-Ming YuChi-Yung ChenHong-Sen ChenYu-Chuan HuangPei-Hsun TsaiSu-I LinHung-Pin PengYi-Kai ChiuYueh-Liang TsouWei-Ying KuoJhih-Wei JianFei-Hung HungChiao-Yun HsiehMichael HsiaoSimon Shih-Hsien ChuangChia-Ning ShenYong Alison WangAn-Suei YangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021) |
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Medicine R Science Q 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 Eradicating mesothelin-positive human gastric and pancreatic tumors in xenograft models with optimized anti-mesothelin antibody–drug conjugates from synthetic antibody libraries |
| description |
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. |
| format |
article |
| author |
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 |
| author_facet |
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 |
| author_sort |
Hung-Ju Hsu |
| title |
Eradicating mesothelin-positive human gastric and pancreatic tumors in xenograft models with optimized anti-mesothelin antibody–drug conjugates from synthetic antibody libraries |
| title_short |
Eradicating mesothelin-positive human gastric and pancreatic tumors in xenograft models with optimized anti-mesothelin antibody–drug conjugates from synthetic antibody libraries |
| title_full |
Eradicating mesothelin-positive human gastric and pancreatic tumors in xenograft models with optimized anti-mesothelin antibody–drug conjugates from synthetic antibody libraries |
| title_fullStr |
Eradicating mesothelin-positive human gastric and pancreatic tumors in xenograft models with optimized anti-mesothelin antibody–drug conjugates from synthetic antibody libraries |
| title_full_unstemmed |
Eradicating mesothelin-positive human gastric and pancreatic tumors in xenograft models with optimized anti-mesothelin antibody–drug conjugates from synthetic antibody libraries |
| title_sort |
eradicating mesothelin-positive human gastric and pancreatic tumors in xenograft models with optimized anti-mesothelin antibody–drug conjugates from synthetic antibody libraries |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/1fd9e8c33c85491783497a53a3cfc809 |
| work_keys_str_mv |
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