Abstract
Hepatocellular carcinoma (HCC) is characterized by alterations in multiple genes. High expression of CD147 on the surface of HCC cells promotes proliferation. The monoclonal antibody HAb18 recognizes CD147. We constructed an oncolytic adenoviral vector to express HAb18 (ZD55-HAb18) in HCC cells. Interleukin 24 (IL24) was co-expressed through the use of an F2A linker. ZD55-HAb18-IL24 decreased HCC cell viability to a greater degree than either ZD55-HAb18 or ZD55-IL24 alone. ZD55-HAb18-IL24 also induced apoptosis and autophagy in PLC/PRF/5 HCC cells. Intratumoral injection of ZD55-HAb18-IL24 repressed tumor growth in a PLC/PRF/5 xenograft model. Our results suggest that antibody-antitumor gene conjugation elicited a stronger antitumor effect than the antibody alone, and that this strategy could broaden the applications of antibody-based therapies in HCC.
Highlights
Hepatocellular carcinoma (HCC) is a multi-factorial disease that involves cross-talk between several pathways [1]
Our results indicate oncolytic adenoviruses carrying a combination of a therapeutic monoclonal antibody and a cytokine may be effective HCC therapies
Examination of CD147 expression in several HCC cell lines revealed higher CD147 mRNA and protein expression in cancer cells compared to normal human hepatocytes (QSG-7701 cells) (Figure 1B and 1C)
Summary
Hepatocellular carcinoma (HCC) is a multi-factorial disease that involves cross-talk between several pathways [1]. Combination approaches for HCC therapy based on multi-targeted conjugates have significant advantages [2]. Combination endostatin/sFlt-1 antiangiogenic gene therapy was shown to be highly effective in a rat model of HCC [3]. Complete eradication of HCC was achieved by combined vasostatin gene therapy and B7H3-mediated immunotherapy [4]. Drozdzik et al demonstrated that a suicide gene in combination with interleukin-12 was more efficient than therapy with one gene alone in a murine model of HCC [5]. HAb18 is secreted by hybridoma cells in BALB/c mice immunized with human HCC tissue extracts. Xu et al reported that blocking CD147 with HAb18 mAb inhibited HCC growth and metastasis in vivo [13]
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