Promiximab-duocarmycin, a new CD56 antibody-drug conjugates, is highly efficacious in small cell lung cancer xenograft models
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Lin Yu1,*, Ying Lu1,*, Yuqin Yao1,2, Yu Liu1, Yuxi Wang1, Qinhuai Lai1, Ruirui Zhang1, Wenting Li1, Ruixue Wang1, Yuyin Fu1, Yiran Tao1, Shuli Yi1, Lantu Gou1, Ligong Chen3 and Jinliang Yang1
1State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, P.R. China
2Research Center for Occupational Respiratory Diseases, West China School of Public Health/No.4 West China Teaching Hospital, Sichuan University, Chengdu 610041, P.R. China
3Pharmacology & Pharmaceutical Sciences School of Medicine/Collaborative Innovation Center for Biotherapy, Tsinghua University, Beijing 100084, China
*These authors have contributed equally to this work
Jinliang Yang, email: [email protected]
Keywords: CD56; small cell lung cancer; antibody-drug conjugates; duocarmycins
Received: March 16, 2017 Accepted: March 29, 2017 Published: December 26, 2017
Small cell lung cancer (SCLC) is of a highly invasive and metastatic lung cancer subtype and there had not been effective targeted therapies. CD56, a cell surface marker highly expressed on most SCLC, is a promising therapeutic target for treatment of this aggressive cancer. In this study, we generated a novel anti-CD56 antibody named promiximab, characterized by high affinity, internalization and tumor specificity. Then, the promiximab was conjugated with a potent DNA alkylating agent duocarmycin via reduced interchain disulfides to yield the promiximab-Duocarmycin (promiximab-DUBA) conjugates. Mass spectrometry analysis showed promiximab-DUBA had an average DAR (Drug-to-Antibody Ratio) of about 2.04. In vitro, promiximab-DUBA exerted strong inhibitory effects on SCLC cell lines NCI-H526, NCI-H524 and NCI-H69, with IC50 values of 0.07 nmol/L, 0.18 nmol/L and 0.29 nmol/L, respectively. In vivo antitumor activity, promiximab-DUBA at the dose of 5 mg/kg and 10 mg/kg every three days with a total of three times were sufficient to induce sustained regression of NCI-H526 tumors over control treatment with promiximab. Mostly, no recurrence was observed until 65 days post treatment with promiximab-DUBA. In the NCI-H69 subcutaneous xenograft model, significant inhibition of tumor growth was also observed following administration of promiximab-DUBA at the dose of 5 mg/kg or 10 mg/kg. Moreover, body weight and histopathology of major organs (liver, spleen, heart, lung and kidney) showed no significant changes after treatment of promiximab-DUBA. In conclusion, promiximab-DUBA is highly efficacious in small cell lung cancer xenograft models, and provides a new immunotherapy approach for SCLC.
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