Journal of Liver

Anti-PLVAP monoclonal antibody derived therapeutics for hepatocellular carcinoma

2^nd International Conference on Hepatology

May 09-11, 2016 Chicago, USA

K J Kao, Yun-Hsing Wang, Vincent P Chuang and Andrew T Huang

Koo Foundation Sun Yat-Sen Cancer Center, Taiwan

Posters & Accepted Abstracts: J Liver

Abstract:

To seek new treatment target for hepatocellular carcinoma (HCC), gene expression profiling was conducted on 18 pairs of HCC and adjacent liver. Genes showing extreme differential expression between paired isogenic tumor and liver tissues were investigated. PLVAP was identified as a top gene showing such differential expression. High PLVAP expression was confirmed in 150 HCC. Using laser-captured microdissection and quantitative RT-PCR, PLVAP was found to expressed by tumor vascular endothelial cells and not detectible in tumor cells, hepatocytes and blood vessels of normal liver. To exploit PLVAP as a specific target for treatment, we developed a recombinant anti-mouse PLVAP Fab fragment co-expressing human tissue factor (TF) to induce thrombosis and ischemic necrosis of HCC. Hep3B xenograft in SCID mice was used for the study. Infusion of anti-PLVAP Fab-TF into tumor feeding artery induced tumor vascular thrombosis and extensive tumor necrosis at doses between 2.5 μg and 12 μg. Tumor growth was suppressed for 40 days after one treatment. No systemic toxicity was noted. Systemic IV administration was ineffective. The results indicate that anti-PLVAP Fab-TF should be infused into tumor feeding artery for therapeutic effect, and may be used to treat HCC without chemotherapeutic agents and drawback of high viscosity of emulsion used for TACE. Subsequently, a recombinant anti-human PLVAP Fab-TF was generated and tested preclinically in primates at doses from 0.03 to 10 mg/kg. The results showed that hepatic artery administration could be tolerated up to 1 mg/kg. There were transient elevation of ALT, prolonged prothrombin time (<20 seconds), and reduced platelet counts (<50%). There were no significant changes of bilirubin, ALP, aPTT, creatinine and BUN. The preclinical primate study supports feasibility of clinical trial in HCC patients.

Biography :

Email: kjkao@kfsyscc.org