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Abstract
Lung cancer is the leading cause of cancer-related deaths. Small cell lung cancer (SCLC) accounts for 15–25% of all lung cancers. It exhibits a rapid doubling time and a high degree of invasiveness. Additionally, overexpression of c-Kit occurs in 70% of SCLC patients. In this study, we evaluated an antibody-drug conjugate (ADC) that targets c-Kit, which is a potential therapeutic agent for SCLC. First, we generated and characterized 4C9, a fully human antibody that targets c-Kit and specifically binds to SCLC cells expressing c-Kit with a binding affinity of KD = 5.5 × 10−9 M. Then, we developed an ADC using DM1, a microtubule inhibitor, as a payload. 4C9-DM1 efficiently induced apoptosis in SCLC with an IC50 ranging from 158 pM to 4 nM. An in vivo assay using a xenograft mouse model revealed a tumor growth inhibition (TGI) rate of 45% (3 mg/kg) and 59% (5 mg/kg) for 4C9-DM1 alone. Combination treatment with 4C9-DM1 plus carboplatin/etoposide or lurbinectedin resulted in a TGI rate greater than 90% compared with the vehicle control. Taken together, these results indicate that 4C9-DM1 is a potential therapeutic agent for SCLC treatment.
Highlights
Lung cancer is the leading cause of cancer-related deaths in the Western world and is classified into two groups: small cell lung cancer (SCLC) and non-SCLC (NSCLC) [1]
Most SCLC patients already present with metastatic disease outside of the chest, at the time of diagnosis, which results in premature death [12]
4C9 antibody binding was saturated at 50 ng/mL in c-Kit-positive SCLC cell lines
Summary
Lung cancer is the leading cause of cancer-related deaths in the Western world and is classified into two groups: small cell lung cancer (SCLC) and non-SCLC (NSCLC) [1]. SCLC is distinctly different from extrapulmonary small cell carcinoma with respect to disease progression, prognosis, and etiology [3]. Tumor protein p53, retinoblastoma protein, NOTCH, MYC, and phosphatidylinositol 3-kinase (PI3K) are aberrantly mutated in SCLC; well-established etiological factors, such as EGFR mutations that occur in NSCLC, have not been identified [7,8,9,10]. Most SCLC patients already present with metastatic disease outside of the chest, at the time of diagnosis, which results in premature death [12]. Most SCLC patients are current or former heavy smokers, which is associated with a high tumor mutational burden, with C:G > A:T transversions being the most common type of base substitutions [13,14]
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