Abstract
Cetuximab is a chimeric monoclonal antibody, approved to treat patients with metastatic colorectal cancer (mCRC), head and neck squamous cell carcinoma (HNSCC), non-small-cell lung cancer (NSCLC) for years. It functions by blocking the epidermal growth factor receptor (EGFR) from receiving signals or interacting with other proteins. Although the demand for cetuximab for the treatment of cancer patients in clinics is increasing, the complicated techniques involved and its high cost limit its wide applications. Here, a new, cheaper form of cetuximab was generated for cancer gene therapy. This was achieved by cloning the full-length cetuximab antibody into two serotypes of adenoviral vectors, termed as AdC68-CTB and Hu5-CTB. In vivo studies showed that a single dose of AdC68-CTB or Hu5-CTB induced sustained cetuximab expression and dramatically suppressed tumor growth in NCI-H508– or DiFi-inoculated nude mice. In conclusion, gene therapy using adenovirus expressing full-length cetuximab could be a novel alternative method for the effective treatment of colorectal cancer.
Highlights
epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein that plays crucial roles in regulating cell proliferation, migration, invasion, adhesion, differentiation and survival [1,2,3]
We developed replication-defective recombinant adenovirus based on the chimpanzee serotype 68 (AdC68) or human serotype 5 (Hu5), expressing the full-length cetuximab antibody
E1- and E3deleted adenoviral recombinants of Hu5 and AdC68 were developed to express the full-length cetuximab, driven from CASI promoter composed of the cytomegalovirus immediate early promoter (CMV), chimeric chicken-βactin (CAG), and ubiquitin C (UBC) enhancer region
Summary
EGFR is a transmembrane glycoprotein that plays crucial roles in regulating cell proliferation, migration, invasion, adhesion, differentiation and survival [1,2,3]. EGFR is overexpressed in a variety of human cancers, such as mCRC, HNSCC, NSCLC, pancreatic cancer, glioblastoma and ovarian carcinoma [5,6,7,8,9,10]. The binding of cetuximab to EFGR blocks the activation of receptor tyrosine kinase and the downstream signaling pathways, including the RAS-RAF-MEK-MAPK pathway and the PI3K-Akt pathway. The former controls gene transcription, cell cycle progression and cell proliferation, and the latter triggers a series of anti-apoptotic and prosurvival signals [1, 16]. It elicits host antitumor immune responses, including antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated cytotoxicity (CMC) [18, 19]
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