Journal
ONCOTARGET
Volume 8, Issue 20, Pages 32450-32460Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.10592
Keywords
glypican-3 or GPC3; hepatocellular carcinoma; recombinant immunotoxin; single-domain antibody fragment; mouse xenograft model
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Funding
- Intramural Research Program of the NIH, NCI, Center for Cancer Research
- China Scholarship Council (CSC)
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Glypican-3 (GPC3) is overexpressed in hepatocellular carcinoma (HCC). We constructed a recombinant immunotoxin, HN3-mPE24, which contains a truncated form of Pseudomonas exotoxin A. The toxin portion lacks most of domain II and has seven point mutations in domain III to remove the B-cell epitopes thought to be responsible for causing off-target side effects and immunogenicity. We also fused a bivalent HN3 to mPE24. We tested these two molecules for GPC3 binding and cytotoxicity in HCC cell models. The K-D values of HN3-mPE24 and HN3-HN3-mPE24 for GPC3-expressing tumor cells were 12 nM and 1.4 nM, respectively. The IC50 values of HN3-mPE24 and HN3-HN3-mPE24 for HCC cells were 0.2 nM and 0.4 nM, respectively. We also evaluated their toxicity and anti-tumor efficacy in mice. The maximum tolerated doses of HN3-mPE24 and HN3-HN3-mPE24 were 7 mg kg(-1) and 3.6 mg kg(-1), respectively. We treated mice with 5 mg kg(-1) of HN3-mPE24 intravenously every other day for ten injections. The alpha-fetoprotein level of HN3-mPE24 treated group was approximately 700 fold less than that of the untreated group (1.1 mu g ml(-1) vs. 692.1 mu g ml(-1)). In addition, 25% of the mice treated with HN3-mPE24 survived to the end of this study, which was 105 days after HCC tumor implantation. In conclusion, the HN3-mPE24 immunotoxin caused liver tumor regressions and extended survival with no significant side effects in mice. It is a promising candidate for the treatment of liver cancer that may be readily translated to humans.
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