Benjamin B Kasten1, Rebecca C Arend2, Ashwini A Katre3, Harrison Kim4, Jinda Fan4, Soldano Ferrone5, Kurt R Zinn4, Donald J Buchsbaum3. 1. Department of Radiology, University of Alabama at Birmingham, Birmingham, AL. Electronic address: benjaminkasten@uabmc.edu. 2. Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL. 3. Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL. 4. Department of Radiology, University of Alabama at Birmingham, Birmingham, AL. 5. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Abstract
INTRODUCTION: Novel therapies that effectively kill both differentiated cancer cells and cancer initiating cells (CICs), which are implicated in causing chemotherapy-resistance and disease recurrence, are needed to reduce the morbidity and mortality of ovarian cancer. These studies used monoclonal antibody (mAb) 376.96, which recognizes a B7-H3 epitope expressed on ovarian cancer cells and CICs, as a carrier molecule for targeted α-particle radioimmunotherapy (RIT) in preclinical models of human ovarian cancer. METHODS: mAb 376.96 was conjugated to the chelate 2-(4-isothiocyanotobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamoylmethyl)-cyclododecane (TCMC) and radiolabeled with 212Pb, a source of α-particles. In vitro Scatchard assays determined the specific binding of 212Pb-376.96 to adherent differentiated or non-adherent CIC-enriched ES-2 and A2780cp20 ovarian cancer cells. Adherent ovarian cancer cells and non-adherent CIC-enriched tumorspheres treated in vitro with 212Pb-376.96 or the irrelevant isotype-matched 212Pb-F3-C25 were assessed for clonogenic survival. Mice bearing i.p. ES-2 or A2780cp20 xenografts were injected i.p. with 0.17-0.70MBq 212Pb-376.96 or 212Pb-F3-C25 and were used for in vivo imaging, ex vivo biodistribution, and therapeutic survival studies. RESULTS: 212Pb-376.96 was obtained in high yield and purity (>98%); Kd values ranged from 10.6-26.6nM for ovarian cancer cells, with 104-105 binding sites/cell. 212Pb-376.96 inhibited the clonogenic survival of ovarian cancer cells up to 40 times more effectively than isotype-matched control 212Pb-F3-C25; combining 212Pb-376.96 with carboplatin significantly decreased clonogenic survival compared to either agent alone. In vivo imaging and biodistribution analysis 24h after i.p. injection of 212Pb-376.96 showed high peritoneal retention and tumor tissue accumulation (28.7% ID/g in ES-2 ascites, 73.1% ID/g in A2780cp20 tumors); normal tissues showed lower and comparable uptake for 212Pb-376.96 and 212Pb-F3-C25. Tumor-bearing mice treated with 212Pb-376.96 alone or combined with carboplatin survived 2-3 times longer than mice treated with 212Pb-F3-C25 or non-treated controls. CONCLUSION: These results support additional RIT studies with 212Pb-376.96 for future evaluation in patients with ovarian cancer.
INTRODUCTION: Novel therapies that effectively kill both differentiated cancer cells and cancer initiating cells (CICs), which are implicated in causing chemotherapy-resistance and disease recurrence, are needed to reduce the morbidity and mortality of ovarian cancer. These studies used monoclonal antibody (mAb) 376.96, which recognizes a B7-H3 epitope expressed on ovarian cancer cells and CICs, as a carrier molecule for targeted α-particle radioimmunotherapy (RIT) in preclinical models of humanovarian cancer. METHODS: mAb 376.96 was conjugated to the chelate 2-(4-isothiocyanotobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamoylmethyl)-cyclododecane (TCMC) and radiolabeled with 212Pb, a source of α-particles. In vitro Scatchard assays determined the specific binding of 212Pb-376.96 to adherent differentiated or non-adherent CIC-enriched ES-2 and A2780cp20 ovarian cancer cells. Adherent ovarian cancer cells and non-adherent CIC-enriched tumorspheres treated in vitro with 212Pb-376.96 or the irrelevant isotype-matched 212Pb-F3-C25 were assessed for clonogenic survival. Mice bearing i.p. ES-2 or A2780cp20 xenografts were injected i.p. with 0.17-0.70MBq 212Pb-376.96 or 212Pb-F3-C25 and were used for in vivo imaging, ex vivo biodistribution, and therapeutic survival studies. RESULTS:212Pb-376.96 was obtained in high yield and purity (>98%); Kd values ranged from 10.6-26.6nM for ovarian cancer cells, with 104-105 binding sites/cell. 212Pb-376.96 inhibited the clonogenic survival of ovarian cancer cells up to 40 times more effectively than isotype-matched control 212Pb-F3-C25; combining 212Pb-376.96 with carboplatin significantly decreased clonogenic survival compared to either agent alone. In vivo imaging and biodistribution analysis 24h after i.p. injection of 212Pb-376.96 showed high peritoneal retention and tumor tissue accumulation (28.7% ID/g in ES-2ascites, 73.1% ID/g in A2780cp20 tumors); normal tissues showed lower and comparable uptake for 212Pb-376.96 and 212Pb-F3-C25. Tumor-bearing mice treated with 212Pb-376.96 alone or combined with carboplatin survived 2-3 times longer than mice treated with 212Pb-F3-C25 or non-treated controls. CONCLUSION: These results support additional RIT studies with 212Pb-376.96 for future evaluation in patients with ovarian cancer.
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