Abstract 593: c-MET targeted theranostic Raptamers for early diagnosis of lung cancer

Abstract Histological screening of tumor biopsies is the gold standard for identifying actionable biomarkers, but is invasive and non-representative, especially for patients with advanced or inaccessible tumors. Imaging with targeted positron emission tomography (PET) may provide a more complete view of the cancer and guide therapy. PET imaging, with a targeting ligand, is preferred for evaluating tumor avidity of new radiolabeled molecular entities. Raptamers (aptamers with amino acid-like functionality) combine attractive attributes of small molecules and monoclonal antibodies (mAbs) in targeted delivery of radionuclides. Like mAbs, Raptamers can provide low nM to pM binding affinities with very low off-rates. Unlike mAbs, they are smaller (with a potentially broader volume of distribution), are manufactured synthetically (less expensive and more consistency), and are more stable. Radionuclide-labeled Raptamers (Radiomers®) can be used for both imaging and therapeutics. We are developing a Radiomer to image, and potentially treat, c-Met over-expressing cancers with minimal off-target effects. c-Met protein is over-expressed in non-small cell lung cancer (NSCLC); with up to 70% in adenocarcinomas (ADCs) and 40% in squamous cell carcinomas (SCCs). Overexpression promotes tumor growth, angiogenesis, invasion and metastasis. The expression level of c-Met correlates with response to c-Met-targeted therapy. The discovery campaign identified multiple high-affinity Raptamers for c-Met, confirmed using biolayer interferometry, and a lead candidate was selected. For surrogate studies, we conjugated Raptamers with a fluorescent tag (Cy5) at the 5’ end. Cy5-Raptamers showed internalization into c-Met+ cells and accumulated, in vivo, in c-Met+ tumors in mice. Additional modifications on the 3’ end improved the biodistribution profile. We then optimized click chemistry reaction conditions to conjugate a DOTA chelator at the 5’ end of Raptamers with a high degree of reproducibility and purity. Stability tests confirmed in vitro integrity of the DOTA conjugates, followed by successful radiolabeling trials with 86Ga and 177Lu. The tests showed higher loading efficiency of Lu over Ga, but we were able to proceed with further studies using both isotopes. 177Lu-Radiomers demonstrated cell surface binding and rapid clearance in mice. 177Lu-Radiomers also showed promising biodistribution in tumor bearing mouse models. hese studies provide the first proof-of-concept data of Radiomers in targeted molecular imaging of cancer. Molecular imaging can potentially allow detection and monitoring of lung cancers with abnormal alterations of c-Met in real time. Also, Radiomers can focus radioactive decay to the vicinity of or within the tumor cells, leading to therapeutic options. In this way, Radiomers can potentially target any cell-surface neo-antigen and open up new diagnostic and therapeutic paradigms in cancer. Citation Format: Sougata Dey, Uksha Saini, Stephanie Vega, Secondra L. Holmes, Nancy Ward, Atul Varadhachary, Dev Chatterjee. c-MET targeted theranostic Raptamers for early diagnosis of lung 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 593.