Abstract
BackgroundROBO1 is a membrane protein that functions in axon guidance. ROBO1 contributes to tumour metastasis and angiogenesis and may have potential as a target protein of immunotherapy because ROBO1 is specifically expressed at high levels in hepatocellular carcinoma. In this study, we examined biodistribution and radioimmunotherapy (RIT) using a radioisotope-labelled anti-ROBO1 monoclonal antibody (MAb) against hepatocellular carcinoma models.MethodsROBO1-positive HepG2 human hepatocellular carcinoma xenograft nude mice were used in this study. We conjugated anti-ROBO1 MAb with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and the conjugates were labelled with 111In and 90Y. To study biodistribution, the 111In-DOTA-anti-ROBO1 MAb was injected into HepG2 xenograft mice via the tail vein. To evaluate any antitumour effect, a RIT study was performed, and the 90Y-DOTA-anti-ROBO1 MAb was injected via the tail vein. Tumour volume, mouse weight, and blood cell count were periodically measured throughout the experiments. The tumours and organs of mice were collected, and a histopathological analysis was carried out.ResultsThe tumour uptake of 111In-anti-ROBO1 MAb in HepG2 xenograft mice was 15.0% ± 0.69% injected dose per gram at 48 h after injection.Immunotherapy with cold-anti-ROBO1 MAb (70 μg) did not cause a significant antitumour effect. RIT with 6.7 MBq of 90Y-anti-ROBO1 MAb caused significant tumour growth suppression. Transient body weight loss and bone-marrow suppression were observed. Histopathological analyses of tumours revealed the fatal degeneration of tumour cells, significant reduction of the Ki-67 index, and an increase of the apoptosis index. Normal organs showed no significant injury, but a transient reduction of hematopoietic cells was observed in the spleen and in the sternal bone marrow.ConclusionsThese results suggest that RIT with 90Y-anti-ROBO1 MAb is a promising treatment for ROBO1-positive hepatocellular carcinoma.
Highlights
ROBO1 is a membrane protein that functions in axon guidance
Competitive ELISA revealed that anti-ROBO1, DOTA-anti-ROBO1, and 90Y- and 111In-anti-ROBO1 inhibited the binding of horse radish peroxidase (HRP)-anti-ROBO1 to the sROBO1 antigen, in a dose-dependent manner
IC50 values for anti-ROBO1, DOTA-anti-ROBO1, and 111In-anti-ROBO1 were 0.41, 0.44, and 0.60 μg/mL, respectively. These results indicate that the DOTA-anti-ROBO1 and 90Y- and 111In-anti-ROBO1 possess similar potency as that of the anti-ROBO1
Summary
ROBO1 is a membrane protein that functions in axon guidance. ROBO1 contributes to tumour metastasis and angiogenesis and may have potential as a target protein of immunotherapy because ROBO1 is expressed at high levels in hepatocellular carcinoma. We examined biodistribution and radioimmunotherapy (RIT) using a radioisotope-labelled anti-ROBO1 monoclonal antibody (MAb) against hepatocellular carcinoma models. Hepatocellular carcinoma (HCC) is a malignant tumour derived from hepatocytes. The primary treatments for HCC are surgical resection, transplantation, and chemoembolisation. An oral multikinase inhibitor, is the standard medicine administered for advanced HCC. Sorafenib treatment does not result in remission or improved survival [1]. Systemic chemotherapy has no survival benefit [1,3]. The development of more effective therapeutic drugs for HCC is required
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