Abstract 1782: Preclinical development of iSAP-0909: A novel self-assembled fluorescent contrast agent targeting XIAP for image-guided surgery in bladder cancer

Abstract Background: Fluorescence-guided surgery as an intraoperative optical imaging technique offers surgeons real-time guidance on for tumor delineation. However, there is still a pressing clinical need for next-generation tumor-targeted fluorescent imaging agents that exhibit enhanced specificity, sensitivity, and photostability. iSAP-0909 is developed as an experimental peptide-based tumor-targeting fluorescent agent employing an in vivo self-assembly approach for adjunctive diagnosis and intraoperative localization in non-muscle-invasive bladder and other solid tumors. Method: This research involved extensive preclinical studies, comprising in vitro assays on human bladder cancer cells, Ex vivo near-infrared (NIR) imaging on clinical bladder cancer specimens, in vivo imaging evaluation on mouse orthotopic bladder cancer model, and comprehensive toxicity studies on rats and dogs. Results: iSAP-0909 is a novel peptide-conjugated NIR fluorescent cyanine dye targeting X-linked inhibitor of apoptosis protein (XIAP). The peptide binding activates downstream caspase enzyme, promoting cleavage of iSAP-0909 to initiate self-assembly process. Hereby, formation of β-sheet structure-enriched nanofibers within tumor cells is triggered, resulting in enhanced accumulation and retention of the cyanine dye. In vitro uptake and retention assays indicated that iSAP-0909 has notably higher tumor cell selectivity greater than HAL (by 5.4 fold), and showcases prolonged intracellular retention. Ex vivo imaging studies on human bladder revealed that iSAP-0909 distinctly delineates tumor boundaries and minor lesions through fluorescence imaging, with specificity of 97.96% and sensitivity of 99.58% derived from 338 clinical specimens. In an orthotopic tumor model derived from KU19-19 (human bladder cancer cell), iSAP-0909 achieved detection rate of 83.3% within 4 hours post-administration at a pharmacologically active dose, and the resulting signal-to-noise ratio was 7.53. Repeat-dose toxicology and safety pharmacology studies in rats and dogs indicated no adverse effects for iSAP-0909, suggesting favorable tolerability and no-observed genotoxic risk. Toxicokinetic analysis also reflected minimal plasma drug exposure (≤0.5%/BQL). Conclusion: iSAP-0909 represents a novel self-assembled fluorescent contrast agent, demonstrating high specificity and sensitivity for bladder tumor tracing. This probe offers potential clinical advantages in localizing malignant lesions in patients with bladder cancer. The FDA has granted clinical approval of iSAP-0909 (IND 172343). Concurrently, an investigator initiated trial (IIT) study is underway to assess the safety and feasibility of imaging following intravenous administration of iSAP-0909 in cancer patients. Citation Format: Min Han, Gantian Lyu, Yuzhen Qian, Hongwei An, Yingbin Zhang, Lin Fu, Hao Wang. Preclinical development of iSAP-0909: A novel self-assembled fluorescent contrast agent targeting XIAP for image-guided surgery in bladder cancer [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 1782.