Treatment of experimental pancreatic cancer with 213-Bismuth-labeled chimeric antibody to single-strand DNA

Abstract

Background: Novel approaches to treatment of pancreatic cancer (PCa) are urgently needed. A chimeric monoclonal antibody (mAb) chTNT3 binds to single-strand DNA (ssDNA) and RNA released from the non-viable cells in fast growing tumors. Here the authors investigated whether radioimmunotherapy (RIT) using chTNT3 mAb radiolabeled with 213-Bismuth (²¹³Bi) could be effective in treatment of experimental PCa. Methods: Two human PCa cell lines, Panc1 and MiaPaCa-2, were used for in vitro experiments. The xenografts in mice were established using MiaPaCa-2 cells. Therapy compared ²¹³Bi-chTNT3 (700 μCi) to gemcitabine or cisplatin, untreated controls and ‘cold’ chTNT3. Results: RIT abrogated the tumors growth while tumors in control groups grew aggressively. Chemotherapy was less effective than RIT and toxic to mice while RIT did not have any side effects. Conclusions: RIT with ²¹³Bi-chTNT3 was safe and effective in the treatment of experimental PCa in comparison with chemotherapy. This makes α-RIT targeting ssDNA a promising modality for further development.

Keywords::

• 213-Bismuth
• cisplatin
• gemcitabine
• intracellular antigens
• pancreatic cancer
• radioimmunotherapy
• single-strand DNA

Financial & competing interests disclosure

This work was supported by NIH grant CA156088 to ED and by European Commission (AM and FB).

No writing assistance was utilized in the production of this manuscript.

Key issues

• Pancreatic cancer (PCa), the fourth leading cause of cancer deaths, is a ‘silent killer’ which often metastasizes before the primary tumor is detected, resulting in a 5-year survival rate of only 4%. Gemcitabine and erlotinib, the US FDA-approved drugs for PCa treatment, improve median survival by less than 6 months in advanced stage patients, underscoring the need for alternative approaches.

• Radioimmunotherapy (RIT) relies on antigen–antibody binding to deliver cytotoxic doses of α or β radiation to tumor cells. RIT has been successfully used to treat refractory and recurrent lymphomas, with two FDA-approved radiolabeled monoclonal antibodies (mAb) targeting CD20 (Zevalin^® and Bexxar^®).

• RIT targeting of intracellular antigens, which become available for mAb binding in aggressively growing tumors as a result of fast cellular turnover, was suggested two decades ago as an alternative to targeting surface antigens. The advantage of this approach is that mAbs to intracellular antigens have very low cross-reactivity with surface antigens on healthy tissues, allowing high specificity and low toxicity of treatment. A radiolabeled human-mouse chimeric mAb chTNT3 to single-strand DNA (ssDNA) and RNA has already been approved in China for patients with advanced lung cancer.

• In mice bearing MiaPaCa-2 PCa xenografts cells, the therapeutic experiments compared α-particle emitter ²¹³bismuth-labeled chTNT3 antibody (700 μCi) to gemcitabine or cisplatin, untreated controls and to ‘cold’ chTNT3. RIT abrogated the tumors growth, while the tumors in control groups grew aggressively. Chemotherapy was less effective than RIT and toxic to mice, while RIT did not have any side effects. RIT with ²¹³Bi-chTNT3 was safe and effective in treatment of experimental PCa in comparison with chemotherapy. This makes α-RIT targeting ssDNA a promising modality for further development.

Notes