Abstract 2115: SIM0680, a potent antibody-drug conjugate for the treatment of solid tumors expressing ENPP3

Abstract Introduction: The ATP- and cGAMP-hydrolysing ecto-nucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3 or CD203c) is an extracellular enzyme which has been implicated in checkpoint regulation of innate immune responses. Analysis of data in The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) indicates elevated expression of ENPP3 in multiple solid tumors compared to normal tissues. Moreover, immunohistochemistry studies suggest that the expression of ENPP3 on healthy epithelial lining is polarized toward the lumen of internal organs but becomes disorganized and non-apical after malignant transformation. This spatial distribution of expression could make ENPP3 an ideal target for antibody therapies, which may have access to CD203c exclusively on tumor cells and not on healthy tissues. Results: We have developed an antibody-drug conjugate, SIM0680, which is a fully humanized antibody that binds a membrane-proximal epitope on ENPP3 with high affinity and is coupled to a payload through a proprietary linker. Immunohistochemistry confirmed strong expression of ENPP3 in liver, renal, and colorectal carcinomas. SIM0680 had potent and specific cytotoxic activity against cell lines originating from these tissues and displaying various levels of ENPP3 expression. Consistent with the observed in vitro efficacy, SIM0680 demonstrated strong single-dose and dose-dependent anti-tumor activity in vivo against multiple cell line- and patient-derived renal cell and hepatocellular carcinoma xenografts in mice, without causing significant weight loss. Similar potent anti-tumor efficacy was observed in human myeloid and megakaryoblastic leukemia models. Conclusion: Our findings underscore the potential of targeting the apically restricted tumor antigen ENPP3 with antibody therapy and support clinical development of SIM0680 as a novel therapeutic modality for treatment of ENPP3-positive solid tumors. Citation Format: Abdullah Emran, Yutian Zhang, Yi Yang, Liting Xue, Lu Gong, Amin Al-Shami, Yayuan Fu, Renhong Tang. SIM0680, a potent antibody-drug conjugate for the treatment of solid tumors expressing ENPP3 [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 2115.