Abstract 577: First-in-class Claudin 18.2 targeting radiopeptide, 64Cu-PD-29875 and 177Lu-PD-29875, exhibit promising theranostic potential in a pancreatic cancer xenograft model
Authors: Shota Tsuchida, Yoshihide Mizukoshi, Shintaro Kato, Hiroko Inaba, Rie Komura, Miho Satake, Yuki Sato, Naoki Kanazawa, Hayato Yanagida, Hidetomo Kitamura, Kentaro Suzuki, Keisuke Matsuhara, Satoshi Matsushima, Masato Murakami
Journal: Cancer Research (2025)

Introduction: Claudin 18.2 (CLDN18.2) is one of the tight junction proteins essential for maintaining the gastric mucosal barrier, preventing gastric acid leakage through paracellular space. Although CLDN18.2 is physiologically expressed in gastric mucosal cells and restricted localization at tight junction, it is overexpressed and exposed on the surface of cancer cells in several tumor types, including pancreatic, esophageal, and gastric cancers, which indicates CLDN18.2 is attractive molecule for cancer targeting. PD-29875 is a novel macrocyclic peptide targeting CLDN18.2 and can be labeled with radionuclides such as cupper (64Cu) and lutetium (177Lu), which enables tumor-specific PET imaging and therapy. This study reports the theranostic potential of PD-29875 for a pancreatic cancer xenograft model. Materials and Methods: PD-29875 was discovered using Peptide Discovery Platform System (PDPS), a proprietary screening system of PeptiDream. Binding affinity and CLDN18.2 selectivity of PD-29875 was measured by cell-based assay. For in vivo evaluation, we used a xenograft model in which BxPC3 (PDAC cell line) which overexpressed CLDN18.2 was subcutaneously transplanted into nude mice. To assess biodistribution, 64Cu-PD-29875 or 177Lu-PD-29875 was dosed to BxPC3 xenograft mice, and the percentage of injected dose in tumors and major organs was quantified by cut and count method. To evaluate whether PET imaging can detect tumors, 64Cu-PD-29875 was dosed to BxPC3 xenograft mice and PET scanning was performed. For therapeutic experiment, 177Lu-PD-29875 was dosed to BxPC3 xenograft mice and tumor volume and body weight were measured for 48 days after dosing. Results: Cell-based assay revealed that 64Cu-PD-29875 exhibit a strong binding to HEK293-hCLDN18.2 OE cell line, but not HEK293-hCLDN18.1 OE and parental HEK293 cell line, demonstrating that PD-29875 is selectively binding to hCLDN18.2. In in vivo biodistribution experiment, 64Cu-PD-29875 and 177Lu-PD-29875 showed a strong accumulation in the tumors and were still highly retained in the tumor at 24 hours after dosing, in contrast, accumulation in the normal stomach was markedly lower, suggesting PD-29875 distinguishes physiological and tumor-expressed CLDN18.2. In PET imaging, 64Cu-PD-29875 clearly detected tumors, consistent with the biodistribution data. In therapeutic experiment, 177Lu-PD-29875 was well tolerated and improved mouse overall survival compared with control animals for 62 days after transplantation, which suggests a robust tumor growth inhibition of 177Lu-PD-29875 administration. Conclusion: PD-29875 has preferable properties for imaging and therapy with radionuclides for theranostic use in CLDN18.2 expressing solid tumors including pancreatic cancer. Citation Format: Shota Tsuchida, Yoshihide Mizukoshi, Shintaro Kato, Hiroko Inaba, Rie Komura, Miho Satake, Yuki Sato, Naoki Kanazawa, Hayato Yanagida, Hidetomo Kitamura, Kentaro Suzuki, Keisuke Matsuhara, Satoshi Matsushima, Masato Murakami. First-in-class Claudin 18.2 targeting radiopeptide, 64Cu-PD-29875 and 177Lu-PD-29875, exhibit promising theranostic potential in a pancreatic cancer xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 577.