RT01: A first-in-class theranostic radionuclide drug conjugate (RDC) with zirconium-89 and lutetium-177 targeting tissue factor.

Abstract

e15151 Background: Tissue factor (TF) is highly expressed in various solid tumors, including pancreatic, cervical, and lung cancers, and is a key driver of tumor invasion and metastasis. While TF-targeted antibody-drug conjugates (ADCs) have validated this target, their efficacy can be limited by tumor heterogeneity and low antigen expression. The Nanolattix research team developed RT01-Zr89 and RT01-177Lu as a first-in-class oncology theranostic pair targeting TF. This approach is designed to overcome ADC limitations through synergistic therapy and potent killing of tumor cells even in heterogeneous populations. Methods: We evaluated the cytotoxicity, in vivo tumor-suppressive activity, and safety of RT01 using in vitro tumor cell lines (including low TF-expressing models) and tumor-bearing mouse models. Both PET/CT and SPECT/CT imaging analysis were utilized to monitor real-time drug distribution and "dynamic spatial distribution" post-injection, validating the integrated diagnostic and therapeutic functions. Results: In vitro experiments demonstrated that RT01 significantly killed both high and low TF-expressing tumor cells. In tumor-bearing mouse models, a single dose of RT01-177Lu (200 uCi) achieved a maximum mean tumor uptake of 35.29% ID/cc at 96 hours. Tumor shrinkage began on day 6, with a therapeutic effect lasting over 50 days and a tumor inhibition rate of 75.3%. Imaging analysis confirmed specific accumulation in xenograft tumors. RT01-Zr89 studies suggest its effectiveness as a companion imaging diagnosis. Anatomical and pathological examinations revealed no damage to major organs, and no grade 3 or higher adverse reactions were observed. Conclusions: RT01-Zr89 and RT01-177Lu demonstrate outstanding efficacy and safety in preclinical studies as a novel theranostic strategy to overcome resistance in solid tumors. Based on these results, an investigator-initiated clinical trial (IIT) has been initiated.