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|Title:||Radioimmunotherapy of pancreatic cancer with 213Bi-labeled antibodies to intranuclear histones|
|Authors:||DADACHOVA E.; BRYAN R. A.; JIANG Z.; JANDL T; STRAUSS J; KOBA W; SELLERS R.; MORGENSTERN Alfred; BRUCHERTSEIFER Frank; EPSTEIN A|
|Citation:||EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING vol. 39 no. Supplement 2 p. 155-156|
|Type:||Articles in periodicals and books|
|Abstract:||Aim: Pancreatic cancer (PC) remains one of the deadliest cancers with very poor prognosis. New effective methods for therapy of the advanced disease are urgently needed. Targeting of intracellular antigens (IntA) is an alternative to targeting surface antigens in radioimmunotherapy (RIT). IntA become accessible for antibody binding in aggressively growing tumors as a result of fast cellular turnover. The advantage of this approach is that antibodies to IntA have low cross-reactivity with surface antigens on healthy tissue, which leads to high specificity and low toxicity of treatment. Materials and Methods: We targeted histones - intranuclear proteins associated with DNA - with chimeric antibody chTNT3 which has been already tested in clinical trials of other cancers. chTNT3 was radiolabeled with 213Bi. The pancreatic xenografts in nude mice were established using MiaPaCa2 cell line. We also hypothesized that pre-treating tumors with chemotherapeutic agents such as cisplatin or gemcitabine will make some tumor cells non-viable thus making more of the intranuclear histones accessible for radiolabeled specific mAb which should result in increased tumor uptake and better therapy results. Results: Pre-treatment of tumors with chemotherapeutic agents resulted in considerable killing of the tumor cells and subsequent release of IntA. However, chemotherapy also damaged the blood vessels in the tumors as per immunohistochemical analysis thus preventing the increase in uptake of radiolabeled chTNT3 mAb according to the biodistribution and microSPECT/CT results. Based on these observations, RIT experiments compared 213Bi-chTNT3 alone with untreated controls, “cold” chTNT3 and chemotherapeutic agents alone. Sixty days observation period after treatment administration demonstrated that RIT abrogated the growth of MiaPaCa2 tumors, while tumors grew aggressively in control groups. Chemotherapy was significantly less effective than RIT in slowing down tumor growth and was very toxic to mice while RIT did not have any side effects. Conclusions: We demonstrated that RIT with 213Bi-labeled antibody to intranuclear histones was safe and effective in treatment of experimental pancreatic cancer in comparison with two chemotherapeutic drugs which currently constitute standard of care for patients with metastatic PC. This makes alpha-RIT targeting intranuclear histones a promising modality for translation into the clinic.|
|JRC Directorate:||Nuclear Safety and Security|
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