Eradicating mesothelin-positive human gastric and pancreatic tumors in xenograft models with optimized anti-mesothelin antibody–drug conjugates from synthetic antibody libraries
| Autor: | Michael Hsiao, Jhih-Wei Jian, Chiao-Yun Hsieh, Yong Alison Wang, Yueh-Liang Tsou, Chia-Ning Shen, Yu Chung-Ming, Hung-Ju Hsu, Hong-Sen Chen, Kuo Wei-Ying, Fei-Hung Hung, Tung Chao-Ping, Chi-Yung Chen, Hung-Pin Peng, Pei-Hsun Tsai, Simon Shih-Hsien Chuang, An-Suei Yang, Chiu Yi-Kai, Su-I Lin, Yu-Chuan Huang |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Immunoconjugates medicine.medical_treatment Mice SCID Protein Engineering Targeted therapy Mice 0302 clinical medicine Mice Inbred NOD Pancreatic tumor Molecular Targeted Therapy Multidisciplinary biology Chemistry Tumor Burden Synthetic antibody Treatment Outcome Mesothelin 030220 oncology & carcinogenesis Injections Intravenous Heterografts Medicine Antibody Science Drug development GPI-Linked Proteins Article 03 medical and health sciences Stomach Neoplasms In vivo Cell Line Tumor medicine Animals Humans Mesothelin Positive Molecular engineering Cancer medicine.disease Complementarity Determining Regions Xenograft Model Antitumor Assays Pancreatic Neoplasms body regions Disease Models Animal 030104 developmental biology Immunoglobulin G Cancer research biology.protein |
| Zdroj: | Scientific Reports, Vol 11, Iss 1, Pp 1-15 (2021) Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | 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: | OpenAIRE |
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