Abstract A088: Radiopharmaceutical therapy for pancreatic cancer: Engineered anti-prostate stem cell antigen (PSCA) antibody demonstrates targeted imaging and antitumor effects in a syngeneic mouse model of pancreatic ductal adenocarcinoma (PDAC)
Authors: Chen Bao Ying , Ahmed Saad N. , Salazar Felix , Jaiswal Sunidhi , Farshbaf Masoud , Chean Jennifer , Sherman Anakim , Hong Teresa , Yazaki Paul J. , Olafsen Tove , Zettlitz Kirstin A. , Wu Anna M. 
Published: January 2024

Abstract
Introduction: Human prostate stem cell antigen (hPSCA) is a cell surface protein that is overexpressed in pancreatic cancer but minimally expressed in normal tissues, making it ideal as a therapeutic marker for targeted radiopharmaceutical therapy (TRT). Humanized anti-PSCA A2 scFv-Fc2 antibody was engineered with a double mutation (A2DM, t1/2 12 h) in the FcRn binding site for rapid clearance through the liver and reduced bone marrow toxicity to improve the therapeutic index. The potential of A2DM antibody was investigated for targeted anti-PSCA imaging and radiopharmaceutical therapy in a syngeneic mouse model of PDAC (pancreatic ductal adenocarcinoma). Methods: Human PSCA (hPSCA) knock-in (KI) were engrafted subcutaneously with KPC cells overexpressing hPSCA (KPC-hPSCA) in both imaging and therapy studies. For imaging, anti-PSCA A2DM and an isotype control (anti-CD20) antibody were conjugated with p-SCN-Bn-Deferoxamine (SCN-DFO) and radiolabeled with 89Zr. Groups of hPSCA KI mice bearing subcutaneous KPC-hPSCA tumors (n = 5, tumor sizes: 150 mm3 – 180 mm3) were i.v. injected with 89Zr-A2DM, isotype control or blocking control (administered activity: 1.5 MBq/10 µg protein). ImmunoPET was acquired with a small animal PET/CT scanner at 21 h post-injection. Ex vivo biodistribution was conducted and %ID/g was calculated based on decay-corrected standards. For therapy, A2DM was conjugated with p-SCN-Bn-CHX-A”-diethylenetriaminepentaacetic acid (p-SCN-Bn-CHX-A”-DTPA) and radiolabeled with 177Lu. Groups of hPSCA KI mice bearing subcutaneous KPC-hPSCA tumors (n = 10, tumor sizes: 30-55 mm3) were i.v. injected with 177Lu-A2DM (administered activity: 17.8 MBq/10 µg) or saline. Tumor sizes and body weights were measured every 2-3 days. Results: PET imaging and biodistribution results of KPC-hPSCA tumor-bearing mice demonstrated excellent tumor uptake (15.6 ± 0.6 %ID/g) which was significantly higher than tumor uptake of isotype control (10.7 ± 1.0 %ID/g, p&lt;0.0001) or in tumors blocked with 70-fold excess cold antibody (8.6 ± 1.3 %ID/g, p&lt;0.0001). These results suggest that A2DM binds to PSCA-positive tumors in a predominately antigen-specific manner. Therapy studies with KPC-hPSCA tumor-bearing mice demonstrated significant tumor growth inhibition in mice treated with 177Lu-A2DM (tumor size at day 25: 105 ± 63 mm3) compared to saline-treated (tumor size at day 25: 1143 ± 754 mm3, p&lt;0.0001). Results suggest the therapeutic potential of 177Lu-A2DM for TRT in pancreatic cancer. Minimal body weight loss was observed in both the 177Lu-A2DM and saline-treated groups, suggesting that the 177Lu therapy was well tolerated. Conclusions: These studies confirm the specific binding of A2DM to PSCA-expressing pancreatic cancer cells and therapeutic activity of 177Lu-A2DM in a mouse model of PDAC. Further studies will formally assess dosimetry and determine the highest activity of 177Lu-A2DM that can be administered to maximize therapeutic efficacy while minimizing normal organ toxicity.
Citation Format: Bao Ying Chen, Saad N. Ahmed, Felix Salazar, Sunidhi Jaiswal, Masoud Farshbaf, Jennifer Chean, Anakim Sherman, Teresa Hong, Paul J. Yazaki, Tove Olafsen, Kirstin A. Zettlitz, Anna M. Wu. Radiopharmaceutical therapy for pancreatic cancer: Engineered anti-prostate stem cell antigen (PSCA) antibody demonstrates targeted imaging and antitumor effects in a syngeneic mouse model of pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A088.