86/90Y-based theranostics targeting tissue factor in a pancreatic tumor model

134 Objectives: Pancreatic cancer (PaCa) is the second most frequent digestive cancer in the US. It is one of the most aggressive malignancies in the world, with a median survival time of less than 6 months and a 5-year overall survival rate of less than 6%. The poor prognosis of PaCa is largely due to its advanced stage at diagnosis, with >80% of patients presenting with locally advanced or metastatic disease, and the lack of efficient therapeutic options. The survival rate for PaCa can only be improved if early diagnosis can be achieved and a better PaCa therapeutic strategy is developed. The development of an efficient, multifunctional PaCa theranostic system is urgently needed to improve PaCa patient management. In that context, the possibility of using a radioactive theranostic pair such as 86/90Y, with identical radiolabeling chemistry, attached to a same targeted moiety is extremely attractive. Overexpression of tissue factor (TF) has been associated with increased tumor growth, tumor angiogenesis, and metastatic potential in many malignancies, including pancreatic cancer. TF is expressed on 77% of pancreatic intraepithelial neoplasms, with no expression on health adjacent ductal tissue, and on 91% of intraductal papillary mucinous neoplasms, with higher expression indicating more extensive dysplasia. We propose the use of a TF-targeted monoclonal antibody (ALT836) conjugated with the pair 86/90Y as a theranostic agent against pancreatic cancer. Methods: The anti-TF antibody, ALT836 (Altor Bioscience Corp) was conjugated with diethylenetriaminepentaacetic acid (DTPA) for radiolabeling with two yttrium isotopes: 86Y (t1/2: 14.7 h, a positron emitter) and 90Y (t1/2: 64 h, a higher energy beta-emitter). Serial PET imaging with the positron-emitter 86Y-DTPA-ALT836 was conducted to map the biodistribution and investigate the pharmacokinetics of the tracer in BXPC-3 tumor-bearing mice. For therapeutic studies, four groups were employed: 90Y-DTPA-ALT836 (120 µCi, 45 µg), 90Y-DTPA-IgG (an isotype control, 120 µCi, 45 µg), ALT836 only (45 µg), and PBS only. Tumor growth and mouse body weight were monitored for 15 days. Blood analyses were performed in all groups at 0, 7, and 15 days post-injection, and histological analysis also compared tumors and main organs pre- and post-therapy. Cerenkov luminescence imaging was also performed for the 90Y-injected mice throughout the course of the study to qualitatively map the biodistribution of 90Y-DTPA-ALT836. Results: The uptake of 86Y-DTPA-ALT836 in BXPC-3 xenograft tumors was high and increased over time (from 8.6 ± 2.4 %ID/g at 4 h p.i. to 27.3 ± 11.1 %ID/g at 48 h, n=5), with the liver showing the highest off-target accumulation at around 11.5 %ID/g at all time points. Ex vivo biodistribution studies further verified this trend, with tumor uptake of 34.8 ± 14.9 %ID/g. Cerenkov imaging demonstrated persistent uptake of 90Y-DTPA-ALT836 in the BXPC-3 tumors throughout the entire study. In therapeutic studies, 90Y-DTPA-ALT836 was found to slow tumor growth relative to the control groups and had significantly smaller (p<0.05) tumor volumes at 13 days p.i. Histological analysis of ex vivo tissues revealed significant damage to the treated tumors. Conclusions: The use of the 86/90Y theranostic pair allows PET imaging with excellent tumor-to-background contrast and treatment of TF-expressing pancreatic tumors. While promising therapeutic outcomes were achieved, the treatment with 90Y-DTPA-ALT836 requires further investigation in order to identify optimum injection and dosage regimen and to minimize off-target doses.