Abstract B016: Noninvasive PET imaging and targeted radiotherapy in a chemotherapy induced senescent KPC model with uPAR and IL-6 immunoconjugates
Authors: Pratt Edwin C , Loor Angelique , Lowe Scott W , Lewis Jason S 
Published: September 2024

Abstract
Development of noninvasive immunoPET imaging agents alongside a targeted alpha therapy companion enables detection and intervention of pancreatic ductal adenocarcinoma (PDAC). As many patients undergo chemotherapy with combinations including gemcitabine and nab- paclitaxel (GnabP) we sought to identify an imaging strategy leveraging chemotherapy and enriching the detection of murine PDAC tumors arising in KRAS/p53 mutant (KPC) mice. Two cancer and senescence relevant antigens are urokinase plasminogen activator receptor (uPAR) and interleukin-6 (IL-6) – as such these antigens are expressed at elevated levels in basal PDAC but further induced following induction of tumor cell senescence using the drug combination Trametinib and Palbociclib (TP). Using immunoPET antibodies both antigens were detected in KPC tumors with high tumor-to-pancreas ratios. Targeted alpha therapy in KPC tumors with a muPAR antibody achieved static tumor sizes in KPC mice to 30 days. Desferoxamine(DFO)-muPAR was prepared as done previously and radiolabeled with Zirconium-89 and found to be stable in serum 6 days with &gt; 94% activity bound. Mice were imaged 3 weeks after KPC implant with 20 µg [89Zr]Zr-DFO-muPAR at 24, 72, and 144h post injection. Tumor uptake of 14.7 % injected dose per gram (% ID/g) for TP treated KPC tumors was higher than the 10.6 % ID/g for KPC tumors alone, with tumor to pancreas ratio up from 10.8 to 15.2. Next the muPAR antibody was conjugated with a macropa-PEG8-Tz-TCO for targeted alpha therapy. Mice were given a single dose of 0.6 µCi 225Ac IgG1 non-targeted, muPAR targeted or the combination with TP therapy. Biweekly tumor measurements and weights in combination with weekly pooled CBC analysis showed mice given [225Ac]Ac- macropa-PEG8-muPAR and TP saw static tumor sizes through 30 days, while TP, non-targeted IgG and [225Ac]Ac-macropa-PEG8-muPAR alone to a lesser extent. Median survival did not match tumor growth based on tumor ulceration euthanasia guidelines. We have shown the combination TP with targeted alpha therapy can better reduce tumor burden in the KPC model compared to single arms, though further optimization is needed. Under identical conditions an anti-murine IL-6 antibody was also developed. PET imaging with 20 µg of [89Zr]Zr-DFO-mIL6 identified KPC tumors 1, 2, or 3 weeks post implant including 48 hours post implant. Terminal biodistribution confirmed high tumor uptake of 20% injected dose per gram across all weeks tested. In another cohort flank KPC mice were either treated with GnabP or the TP combination. After one week of therapy, [89Zr]Zr-DFO-mIL6 imaging identified mice treated with GnabP to have nearly twice the antigen abundance compared to TP and untreated groups. These data match prior work with [89Zr]Zr-DFO-siltuximab in a human PDAC model. Together we have shown both IL-6 and uPAR can be promising imaging targets for the detection of pancreatic cancer, with clinical relevance for human cancers, and that targeted alpha therapy with a single dose can best delay tumor growth in combination with senescence inducing therapy.
Citation Format: Edwin C Pratt, Angelique Loor, Scott W Lowe, Jason S Lewis. Noninvasive PET imaging and targeted radiotherapy in a chemotherapy induced senescent KPC model with uPAR and IL-6 immunoconjugates [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B016.