Abstract 4778: ADCE-T02: A first-in-class topoisomerase-1 inhibitor based antibody drug conjugate against tissue factor demonstrates excellent preclinical efficacy and tolerability

Abstract Tissue factor (TF, F3, coagulation factor III, thromboplastin, or CD142) is a 47-kDa transmembrane glycoprotein. In normal tissues TF expression is limited to the perivascular compartment where it is the cell surface receptor for the serine protease factor VIIa (FVIIa). Functionally, the TF/FVIIa complex converts the inactive zymogen Factor X (FX) to FXa triggering initiation of the extrinsic coagulation protease cascade. TF is overexpressed in a wide range of solid tumors, including pancreatic, cervical, and colorectal cancer as well as non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC), which in combination with efficient receptor internalization makes TF an ideal antibody-drug conjugate (ADC) target. The TF-ADC tisotumab-vedotin (Tivdak®) has been approved for treatment of cervical cancer but is associated with serious side effects including ocular toxicities, peripheral neuropathy, and bleeding. ADCE-T02 is a first-in-class Topoisomerase-1 inhibitor TF-ADC composed of a humanized anti-TF IgG1 monoclonal antibody (Ab-754), conjugated via a novel T1000 linker moiety to the Topoisomerase-1 inhibitor Exatecan payload at a drug-to-antibody ratio (DAR) of 4. ADCE-T02 binds with high affinity to human recombinant TF protein and multiple TF positive cell lines. Binding of ADCE-T02 to TF on the cell surface triggers internalization, resulting in intracellular exatecan release and cancer cell death. In addition, ADCE-T02 induces potent bystander cytotoxicity in TF negative cancer cells when cocultured with TF positive cells in vitro. In contrast to tisotumab, Ab-754 does not inhibit FXa activation and demonstrates reduced effect in coagulation assays in vitro. ADCE-T02 induces antibody-dependent cellular cytotoxicity but not antibody-dependent cellular phagocytosis or complement-dependent cytotoxicity. In vivo, ADCE-T02 shows strong anti-tumor activity in a wide range of solid tumor models including pancreatic cancer, esophageal squamous cell carcinoma, NSCLC and HNSCC and is well tolerated in non-human primate toxicology studies with no evidence of ocular toxicity, peripheral neuropathy, or bleeding. In summary, ADCE-T02 constitutes a novel first-in-class Topoisomerase-1 inhibitor ADC targeting TF with a potentially enhanced therapeutic and safety profile. A phase I clinical study of ADCE-T02 in patients with advanced solid tumors is currently ongoing (Clinical Trial ID NCT06597721). Citation Format: Thomas Tuxen Poulsen, Yue Zhang, Jianjian Zhang, Huiyan Shi, Shu-Hui Liu, Xun Meng, Mette Gillberg, Dominik Mumberg. ADCE-T02: A first-in-class topoisomerase-1 inhibitor based antibody drug conjugate against tissue factor demonstrates excellent preclinical efficacy and tolerability [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 4778.