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Cryptophycin-55/52 based antibody-drug conjugates: Synthesis, efficacy, and mode of action studies.
Lai, Qinhuai; Wu, Mengdan; Wang, Ruixue; Lai, Weirong; Tao, Yiran; Lu, Ying; Wang, Yuxi; Yu, Lin; Zhang, Ruirui; Peng, Yujia; Jiang, Xiaohua; Fu, Yuyin; Wang, Xin; Zhang, Zhixiong; Guo, Cuiyu; Liao, Wei; Zhang, Yiwen; Kang, Tairan; Chen, Hao; Yao, Yuqin; Gou, Lantu; Yang, Jinliang.
Afiliación
  • Lai Q; State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, PR China.
  • Wu M; State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, PR China.
  • Wang R; State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, PR China.
  • Lai W; State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, PR China.
  • Tao Y; State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, PR China.
  • Lu Y; State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, PR China; West China School of Public Health and West China Fourth Hospital, Healthy Food Evaluation Research Center/ Sichuan University, Chengdu, PR
  • Wang Y; Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, PR China.
  • Yu L; State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, PR China; Department of Clinical Laboratory, Mianyang Central Hospital, Mianyang, PR China.
  • Zhang R; State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, PR China.
  • Peng Y; State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, PR China.
  • Jiang X; State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, PR China.
  • Fu Y; State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, PR China.
  • Wang X; State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, PR China.
  • Zhang Z; State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, PR China.
  • Guo C; State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, PR China.
  • Liao W; The 32265 Army Hospital of PLA, Guangzhou, PR China.
  • Zhang Y; State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, PR China.
  • Kang T; College of Pharmacy and Biological Engineering, Chengdu University, Chengdu, PR China.
  • Chen H; State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, PR China.
  • Yao Y; State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, PR China; West China School of Public Health and West China Fourth Hospital, Healthy Food Evaluation Research Center/ Sichuan University, Chengdu, PR
  • Gou L; State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, PR China.
  • Yang J; State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, PR China; Research Unit of Gene and Immunotherapy, Chinese Academy of Medical Sciences, Beijing, PR China. Electronic address: jinliangyang@scu.edu.c
Eur J Med Chem ; 199: 112364, 2020 Aug 01.
Article en En | MEDLINE | ID: mdl-32402935
Cryptophycin-52 (CR52), a tubulin inhibitor, exhibits promising antitumor activity in vitro (picomolar level) and in mouse xenograft models. However, the narrow therapeutic window in clinical trials limits its further development. Antibody-drug conjugate (ADC), formed by coupling cytotoxic compound (payload) to an antibody via a linker, can deliver drug to tumor locations in a targeted manner by antibody, enhancing the therapeutic effects and reducing toxic and side effects. In this study, we aim to explore the possibility of CR52-based ADC for tumor targeted therapy. Due to the lack of a coupling site in CR52, its prodrug cryptophycin-55 (CR55) containing a free hydroxyl was synthesized and conjugated to the model antibody trastuzumab (anti-HER2 antibody drug approved by FDA for breast cancer therapy) via the linkers based on Mc-NHS and Mc-Val-Cit-PAB-PNP. The average drug-to-antibody ratios (DARs) of trastuzumab-CR55 conjugates (named T-L1-CR55, T-L2-CR55, and T-L3-CR55) were 3.50, 3.29, and 3.35, respectively. These conjugates exhibited potent cytotoxicity in HER2-positive tumor cell lines with IC50 values at low nanomolar levels (0.58-1.19 nM). Further, they displayed significant antitumor activities at the doses of 10 mg/kg in established ovarian cancer (SKOV3) and gastric cancer (NCI-N87) xenograft models without overt toxicities. Finally, the drug releases were analyzed and the results indicated that T-L3-CR55 was able to effectively release CR55 and further epoxidized to CR52, which may be responsible for its best performance in antitumor activities. In conclusion, our results demonstrated that these conjugates have the potential for tumor targeted therapy, which provides insights to further research the CR55/CR52-based ADC for tumor therapy.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inmunoconjugados / Depsipéptidos / Trastuzumab / Lactamas / Lactonas / Antineoplásicos Límite: Animals / Female / Humans Idioma: En Revista: Eur J Med Chem Año: 2020 Tipo del documento: Article Pais de publicación: Francia
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inmunoconjugados / Depsipéptidos / Trastuzumab / Lactamas / Lactonas / Antineoplásicos Límite: Animals / Female / Humans Idioma: En Revista: Eur J Med Chem Año: 2020 Tipo del documento: Article Pais de publicación: Francia