Abstract A122: Elevated expression of ALPP and ALPG in KRAS-mutated pancreatic adenocarcinoma and therapeutic targeting with a bispecific T-cell engager

Abstract Alkaline phosphatase, placental type (ALPP), and its isozyme, germ cell type (ALPG), have been reported to exhibit aberrant expression in various solid tumors, ovarian cancer, endometrial cancer, gastric cancer and lung adenocarcinoma et al. Through pan-cancer RNA-sequencing analysis, we identified elevated transcriptional levels of both ALPP and ALPG in pancreatic adenocarcinoma (PAAD), whereas minimal expression was observed in normal pancreatic tissue or adjacent non-tumorous regions. Given the established role of KRAS mutations as a molecular hallmark of PAAD, we further investigated the association between KRAS mutational status and ALPP/ALPG expression. Our analysis revealed a statistically significant upregulation of ALPP/ALPG in KRAS-mutated PAAD, a correlation not observed in other tumor types. Immunohistochemical validation confirmed elevated ALPP/ALPG protein expression in both pancreatic cancer cell lines and primary human tumor specimens. In preclinical studies, EM1032, a novel ALPP/ALPG x CD3 bispecific T-cell engager demonstrated potent redirected T-cell cytotoxicity against the KRAS.G12V mutated PAAD cell line. In vivo, EM1032 in combination with a pan-KRAS inhibitor showed potent tumor growth inhibition in a xenografted mice model. Post-treatment histopathological analysis revealed a marked increase in tumor-infiltrating lymphocytes (TILs) concomitant with a reduction in ALPP-positive tumor cells, suggesting an immune-mediated antitumor mechanism. These findings support the therapeutic potential of EM1032 as a targeted immunotherapy for KRAS-mutated PAAD, particularly in tumors exhibiting elevated ALPP/ALPG expression. Further clinical investigation is warranted to evaluate its translational applicability. Citation Format: Zelong Ma, Beilei Shi, Weiqing Guo, Li Hu, Yixuan Li, Shiyong Gong, Xuan Wu, Danqing Wu. Elevated expression of ALPP and ALPG in KRAS-mutated pancreatic adenocarcinoma and therapeutic targeting with a bispecific T-cell engager [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A122.