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.
Highlights
Small cell lung cancer (SCLC) is a much aggressive form of lung cancer that characterized by poor prognosis and rapid progress, which accounts for approximately 13-15% of all newly diagnosed lung cancer cases [1,2,3]
Through hybridoma and humanization technology, we generated the new anti-CD56 antibody promiximab and it was characterized by the following properties
Promiximab can bind to the CD56 expressed on the surface of NCI-H526, NCI-H524 and NCI-H69 SCLC cells
Summary
Small cell lung cancer (SCLC) is a much aggressive form of lung cancer that characterized by poor prognosis and rapid progress, which accounts for approximately 13-15% of all newly diagnosed lung cancer cases [1,2,3]. Small cell lung cancer (SCLC) is a much aggressive form of lung cancer that characterized by poor prognosis and rapid progress, which accounts for approximately 13-. Targeted therapies for non-small cell lung cancer (NSCLC) have been made great successes in the last decade [6]. ADCs (Antibody Drug Conjugates), which are formed by monoclonal antibodies, linkers and chemotherapy drugs, have better targeting tumor effects but less toxic side effects than traditional chemotherapy drugs [9, 10]. ADCs have been paid more attentions and there have been two drugs approved by the FDA (Food and Drug Administration) including Adctris® for systemic anaplastic large cell lymphoma (SALCL) [11] and Kadcyla® for HER2-positive breast cancer [12]. A few attempts to develop ADCs have been made to treat SCLC [13,14,15]
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