Treatment of experimental pancreatic cancer with 213-Bismuth-labeled chimeric antibody to single-strand DNA in combination with cisplatin and gemcitabine

Pancreatic cancer (PCa), the 4th leading cause of cancer deaths, has a notoriously poor prognosis with the 5-year survival rate of only 4%. Novel approaches to its treatment 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 and already showed promise in treatment of lung and brain cancers. Methods: We investigated whether the combination of radioimmunotherapy (RIT), using chTNT3 mAb radiolabeled with the powerful alpha-emitter 213-Bismuth (213Bi), with gemcitabine or cisplatin will provide a viable treatment for experimental PCa. The pancreatic xenografts in nude mice were established using human MiaPaCa-2 cells. Results: Pre-treatment of MiaPaCa-2 cells and tumors with chemotherapy resulted in considerable killing of tumor cells and subsequent release of ssDNA (LDH and crystal violet assays). However, chemotherapy also damaged the blood vessels in the tumors preventing the increase in uptake of radiolabeled chTNT3 mAb as per biodistribution and microSPECT/CT. Therapy experiments compared 213Bi-chTNT3 alone (700 Ci), combination of 700 Ci 213Bi-chTNT3 with 3 days pretreatment with gemcitabine or cisplatin, untreated controls, “cold” chTNT3 and chemotherapeutic agents alone. Sixty five days observation period demonstrated that RIT abrogated the growth of MiaPaCa-2 tumors, while tumors grew aggressively in control groups. Chemotherapy was significantly less effective than RIT in slowing down tumor growth and was very toxic while RIT was not. Discussion: We demonstrated that RIT with 213Bi-labeled antibody to ssDNA was safe and effective in treatment of experimental PCa in comparison with two chemotherapeutic drugs. This makes alpha-RIT targeting ssDNA a promising modality for translation into the clinic.

BRYAN R. A.;  JIANG Z.;  JANDL T;  STRAUSS J;  KOBA W;  ONYEDIKA C;  MORGENSTERN Alfred;  BRUCHERTSEIFER Frank;  SELLERS R.;  EPSTEIN A;  DADACHOVA E.; 

2013-06-27

Oak Ridge National Laboratory

JRC82746

https://register.ornl.gov/2013/TATS/index.shtml,    https://publications.jrc.ec.europa.eu/repository/handle/JRC82746,