Abstract 5203: Tissue factor targeted radionuclide therapy with 177Lu-FVIIai inhibits tumor growth of human pancreatic cancer xenografts

Abstract

Abstract Introduction: Tissue factor (TF) is involved in cancer processes responsible for aggressiveness and invasiveness and there is a correlation between tumor TF expression, metastatic potential, and patient outcome. The aim of the study was to develop a novel compound for localized TF targeted radionuclide therapy based on Factor VII (FVII), the natural ligand to TF. In the current study, we investigated the biodistribution and therapeutic potential of 177Lu labeled active site inhibited FVIIa (177Lu-FVIIai) for radionuclide therapy targeting TF in an experimental mouse model of pancreatic cancer. Methods: p-SCN-Bn-CHX-A’’-DTPA was conjugated to FVIIai followed by radiolabeling with 177Lu (177Lu-CHX-A’’-DTPA-FVIIai). A pancreas xenograft mouse model (BxPC3) was used to assess the therapeutic potential of 177Lu-FVIIai. NMRI nude mice were injected subcutaneously with BxPC3 cells. When tumors reached 50 mm3, the mice were randomized into groups receiving 177Lu-FVIIai, FVIIai, or vehicle. 177Lu-FVIIai was administered in doses of 15 MBq, 7.5 MBq or 2 x 7.5 MBq (n=8 mice/group). Tumor growth was monitored by 3 weekly measurements. Ex vivo biodistribution of 177Lu-FVIIai was studied in several organs at 1, 4, 24, 72 and 168 hours after injection. The in vivo biodistribution was evaluated by SPECT/CT imaging. Furthermore, competition and dose escalation experiments (1-30 MBq) were performed. Toxicity effects of the treatment with 177Lu-FVIIai were evaluated by hematology. Results: FVIIai was successfully radiolabeled with 177Lu with a high specific activity of 10-25 GBq/µmol after EDTA scavenging and PD-10 purification. No difference in tumor growth was observed between the FVIIai and vehicle groups. Mice receiving 15 MBq 177Lu-FVIIai had a significantly reduced tumor growth from day 0 to day 19 compared with mice from the control groups (425.5±44.8% versus 614.2±49.1%; p=0.02). No significant difference in tumor growth was observed in the groups receiving 7.5 MBq or 2 x 7.5 MBq compared with controls on day 19. There was a significant increase in the survival of mice treated with 7.5 MBq 177Lu-FVIIai compared with the controls (p=0.007). Treatment with 15 and 2 x 7.5 MBq 177Lu-FVIIai did not influence survival. Ex vivo tumor uptake of 177Lu-FVIIai was 1.16±0.04, 1.97±0.18, 1.95±0.07, 1.01±0.06, 0.31±0.02 percent injected dose per gram (%ID/g) at 1, 4, 24, 72 and 168 hours post-injection, respectively. Competition with unlabeled FVIIai 10 minutes before 177Lu-FVIIai injection significantly reduced tumor uptake of 177Lu-FVIIai (from 2.5±0.16 %ID/g to 1.7±0.05 %ID/g; p<0.05). Tumor uptake (%ID/g) of 177Lu-FVIIai was unchanged when varying the dose from 1-30 MBq. A transient decrease in leucocyte counts was observed for the mice receiving 15 and 7.5 MBq 177Lu-FVIIai. Conclusion: FVIIai was successfully radiolabeled with 177Lu. 177Lu-FVIIai showed therapeutic potential in a mouse model of human pancreatic cancer. Citation Format: Mette Munk Jensen, Jesper Fonslet, Camilla S. Knudsen, Troels E. Jeppesen, Andreas I. Jensen, Gregory W. Severin, Carsten H. Nielsen, Andreas Kjær. Tissue factor targeted radionuclide therapy with 177Lu-FVIIai inhibits tumor growth of human pancreatic cancer xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5203. doi:10.1158/1538-7445.AM2017-5203