Promiximab-duocarmycin, a new CD56 antibody-drug conjugates, is highly efficacious in small cell lung cancer xenograft models

// Lin Yu 1, * , Ying Lu 1, * , Yuqin Yao 1, 2 , Yu Liu 1 , Yuxi Wang 1 , Qinhuai Lai 1 , Ruirui Zhang 1 , Wenting Li 1 , Ruixue Wang 1 , Yuyin Fu 1 , Yiran Tao 1 , Shuli Yi 1 , Lantu Gou 1 , Ligong Chen 3 and Jinliang Yang 1 1 State 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 2 Research Center for Occupational Respiratory Diseases, West China School of Public Health/No.4 West China Teaching Hospital, Sichuan University, Chengdu 610041, P.R. China 3 Pharmacology & Pharmaceutical Sciences School of Medicine/Collaborative Innovation Center for Biotherapy, Tsinghua University, Beijing 100084, China * These authors have contributed equally to this work Correspondence to: Jinliang Yang, email: jlyang01@163.com Keywords: CD56; small cell lung cancer; antibody-drug conjugates; duocarmycins Received: March 16, 2017      Accepted: March 29, 2017      Published: December 26, 2017 ABSTRACT 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.