Abstract 1572: Preclinical activity and safety of STRO-004, a novel ADC targeting tissue factor for solid tumors

Abstract Tissue Factor (TF) is a type I transmembrane protein that is aberrantly expressed in multiple solid tumor indications including cervical, head and neck, non-small cell lung, and pancreatic cancers. Its expression is associated with poor prognosis and has been linked to pro-tumorigenic activities such as metastasis, inflammation, and angiogenesis. Under normal physiological conditions, TF plays an important role in blood clotting and, as such, is broadly expressed in many normal tissues, typically in the subendothelium. Upon endothelial damage, TF can combine with clotting factors in circulation to initiate a coagulation cascade, thus constituting a "hemostatic envelope". TF-targeted vedotin ADCs are approved in metastatic cervical cancer and in clinical testing across a range of solid tumor indications. However, toxicities such as peripheral neuropathy, epistasis, and ocular toxicities have been dose-limiting. We have developed STRO-004, a novel TF-targeted ADC with a DAR8 β-glucoronidase-exatecan linker-payload, with enhanced potency and safety in preclinical models. STRO-004 is a TF-targeted ADC, engineered for a wider therapeutic index. The ADC is constructed on an antibody that has been designed to avoid interference in the blood coagulation pathways, thus reducing the potential risk for bleeding. The anti-TF antibody is conjugated to exatecan, a topoisomerase 1 inhibitor, via a β-glucoronidase-cleavable linker (SC3417) at a drug-to-antibody ratio (DAR) of 8. The drug-linker is site-specifically conjugated to the non-natural amino acid p-azidomethylphenylalanine (pAMF) incorporated at optimized sites within the antibody (Ab) sequence using Xpress CF+TM. In preclinical xenograft models, STRO-004 demonstrates potent, dose-dependent activity from 0.25-7.5 mg/kg, including in models with low and heterogeneous levels of TF expression. STRO-004 was evaluated in patient-derived xenograft (PDx) models of cancers with prevalent TF expression and demonstrated 50% overall response rate and 70% disease control rate across all models after single dose treatment. Exploratory toxicology studies show that STRO-004 has a favorable safety profile in cynomolgous monkeys up to 50 mg/kg, the highest dose tested. In circulation, STRO-004 demonstrated extended half-life, low clearance, and stable drug-linkage. Consistent with this finding, only low levels of free exatecan could be detected. Based on these promising preclinical observations, STRO-004 is advancing to IND-enabling studies for the treatment of TF expressing malignancies. Citation Format: Andrew McGeehan, Helena Kiefel, Brian Vuillemenot, Guifen Xu, Sihong Zhou, Grace Lee, Mark Armanini, Xiaofan Li, Krishna Bajjuri, Miao Wen, Cuong Tran, Jeff Hanson, Daniel Calarese, Amandeep Gakhal, Hanspeter Gerber, Werner Rubas, Gang Yin, Alice Yam. Preclinical activity and safety of STRO-004, a novel ADC targeting tissue factor for solid tumors [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 1572.