Yu Lin, Lu Ying, Yao Yuqin, Liu Yu, Wang Yuxi, Lai Qinhuai, Zhang Ruirui, Li Wenting, Wang Ruixue, Fu Yuyin, Tao Yiran, Yi Shuli, Gou Lantu, Chen Ligong, Yang Jinliang
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.
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.
Oncotarget. 2017 Dec 26;9(4):5197-5207. doi: 10.18632/oncotarget.23708. eCollection 2018 Jan 12.
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. , 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. 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.
小细胞肺癌（SCLC）是一种具有高度侵袭性和转移性的肺癌亚型，此前一直没有有效的靶向治疗方法。CD56是一种在大多数SCLC上高度表达的细胞表面标志物，是治疗这种侵袭性癌症的一个有前景的治疗靶点。在本研究中，我们制备了一种名为promiximab的新型抗CD56抗体，其特点是具有高亲和力、内化作用和肿瘤特异性。然后，通过还原链间二硫键将promiximab与一种强效DNA烷化剂多卡霉素偶联，得到promiximab-多卡霉素（promiximab-DUBA）偶联物。质谱分析表明，promiximab-DUBA的平均药物与抗体比率（DAR）约为2.04。promiximab-DUBA对SCLC细胞系NCI-H526、NCI-H524和NCI-H69具有强烈的抑制作用，IC50值分别为0.07 nmol/L、0.18 nmol/L和0.29 nmol/L。在抗肿瘤活性方面，promiximab-DUBA以每三天5 mg/kg和10 mg/kg的剂量共给药三次，足以诱导NCI-H526肿瘤相对于用promiximab对照治疗持续消退。大多数情况下，直到用promiximab-DUBA治疗后65天未观察到复发。在NCI-H69皮下异种移植模型中，以5 mg/kg或10 mg/kg的剂量给予promiximab-DUBA后，也观察到肿瘤生长受到显著抑制。此外，promiximab-DUBA治疗后主要器官（肝脏、脾脏、心脏、肺和肾脏）的体重和组织病理学没有显著变化。总之，promiximab-DUBA在小细胞肺癌异种移植模型中具有高效性，为SCLC提供了一种新的免疫治疗方法。
