Abstract 6021: Lutetium-177 (177Lu) radiolabeled engineered antibody fragment against human prostate stem cell antigen (hPSCA) demonstrates targeting and antitumor effects in a syngeneic mouse model of pancreatic ductal adenocarcinoma (PDAC)

Abstract Introduction: hPSCA is a cell surface protein overexpressed in PDAC but minimally expressed in normal tissues, making it a promising therapeutic marker for targeted radiopharmaceutical therapy (TRT). Anti-hPSCA A2 scFv-Fc2DM antibody (A2DM) was engineered with a double mutation in the FcRn binding site for rapid blood clearance to the liver, reducing bone marrow and kidney radiotoxicity. The potential of using 177Lu radiolabeled A2DM antibody for targeted anti-hPSCA imaging and TRT was investigated in a syngeneic mouse model of PDAC. Methods: hPSCA knock-in mice were engrafted subcutaneously with KPC cells overexpressing hPSCA (KPC-hPSCA). ImmunoPET with zirconium-89 (89Zr) radiolabeled with A2DM was conducted to confirm in vivo targeting. For imaging, A2DM and an isotype control (anti-CD20) antibody were radiolabeled with 89Zr. Mice (n = 5; tumor sizes: 150 mm3 - 180 mm3) were i. v. injected with 89Zr-A2DM or 89Zr-isotype control (administered activity: 1. 5 MBq/10 µg) or co-injected with excess cold antibody. ImmunoPET was acquired at 21 h post-injection. Ex vivo biodistribution was conducted and %ID/g was calculated based on decay-corrected standards. For therapy, KPC-hPSCA tumor bearing mice (n = 8 - 9, average tumor sizes: 20. 1 ± 5. 1 mm3) was i. v. injected with 177Lu-A2DM (administered activity: 17. 8 MBq/10 µg or 9. 25 MBq/10 µg) or saline. Tumor sizes and body weights measured every 2-3 days. Results: 89Zr immunoPET and biodistribution of A2DM demonstrated significantly higher tumor uptake (15. 6 ± 0. 6 %ID/g) than theisotype control (10. 7 ± 1. 0 %ID/g, p= 0. 0001) or blocked control with 70-fold excess cold antibody (8. 6 ± 1. 3 %ID/g, p 0. 0001), suggesting A2DM binds to hPSCA-positive tumors in an antigen-specific manner. Therapy studies show tumor growth inhibition in a dose-dependent manner when treated with 17. 8 MBq of 177Lu-A2DM (tumor size at day 25: 178 ± 119 mm3) or 9. 25 MBq of 177Lu-A2DM (tumor size at day 25: 309 ± 182 mm3) (tumor size at day 25: 740 ± 317 mm3, p= 0. 006, 0. 04 respectively, compared to saline). Median survival was significantly improved in mice treated with high dose of 17. 8 MBq 177Lu-A2DM compared to saline-treated group (48 vs. 25 days, p= 0. 002). Median survival of mice treated with low dose 9. 25 MBq of 177Lu-A2DM showed a trend towards improved survival but results were not significant (48 vs. 34 days, p= 0. 25). Minimal weight loss observed in the 177Lu-A2DM and saline groups, suggesting the 177Lu therapy was well tolerated. Conclusions: 89Zr immunoPET studies confirmed specific targeting of A2DM to KPC-hPSCA tumors in vivo. 177Lu-A2DM therapeutic studies demonstrated significant tumor growth delay in a dose-dependent manner. Future studies will explore dose fractionation strategies, with the aim to enhance tumor growth control for PDAC. Citation Format: Bao Ying Chen, Masoud Farshbaf, Felix B. Salazar, Saad N. Ahmed, Sunidhi Jaiswal, Jennifer Chean, Anakim Sherman, Teresa Hong, Paul J. Yazaki, Tove Olafsen, Kirstin A. Zettlitz, Anna M. Wu. Lutetium-177 (177Lu) radiolabeled engineered antibody fragment against human prostate stem cell antigen (hPSCA) demonstrates targeting and antitumor effects in a syngeneic mouse model of pancreatic ductal adenocarcinoma (PDAC) abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6021.