Abstract 571: Novel somatostatin receptor type 2 targeted radiopharmaceuticals with improved renal clearance and enhanced tumor retention relative to DOTATATE

Abstract Introduction: Somatostatin receptor type 2 (SSTR2) is highly expressed on a majority of well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and is also expressed in other solid tumors such as small-cell lung cancer (SCLC) and breast cancer, albeit with a lower prevalence. [177Lu]Lu-DOTATATE is an eight amino acid peptide with high affinity for SSTR2 receptor used as a radiopharmaceutical therapy (RPT) for treatment of SSTR2 expressing solid tumors. One limitation of DOTATATE-based RPT is the uptake and extended retention of radiolabeled peptides in the proximal renal tubule cells, increasing the risk for radiation-induced nephropathy. The kidney retention of DOTATATE limits the administered radioactivity and effective radiation dose delivered to the tumors. We report the development of a novel SSTR2 targeted RPT agents, RYZ-SSAs, designed to have enhanced renal clearance and improved tumor exposure compared to [177Lu]Lu-DOTATATE; thereby maximizing the therapeutic potential of SSTR2 RPT by effectively delivering higher radiation doses to tumors while minimizing renal exposure. Methods: RYZ-SSAs are highly selective, potent SSTR2 agonists conjugated to a DOTA chelator, and capable of binding various radioisotopes. The binding affinity to the SSTR1-5 proteins, and the cell binding and internalization in SSTR2 expressing cell lines were determined by radioligand binding assays. Further evaluation by cAMP and b-arrestin recruitment assays were performed in SSTR2 overexpressing CHO cells. Biodistribution studies using SPECT imaging and ex vivo quantification, and efficacy were performed in SSTR2 expressing xenograft models. Results: RYZ-SSAs show high binding affinity to human SSTR2, with sub-nanomolar SSTR2 Ki’s and selectivity of >200-fold against SSTR1/3/4/5 isoforms. The IC50s and EC50s for RYZ-SSAs ranged from single digit nanomolar to sub-nanomolar. In ex vivo mouse biodistribution studies, [177Lu]Lu-RYZ-SSAs were compared with [177Lu]Lu-DOTATATE in a SSTR2 positive NSCLC xenograft. The tumor to kidney ratio based on the mTIACs were 2.1 for DOTATATE and 10.5 for RYZ-SSA1. RYZ-SSA1 demonstrated greater than two-fold increase in tumor retention, and two-fold decrease in renal exposure relative to DOTATATE. A single injection of [225Ac]Ac-RYZ-SSA1 resulted in significant tumor growth inhibition in a NSCLC xenograft model with durable regression and prolonged survival. All treatments were well tolerated. Conclusion: Preclinical in vitro and in vivo data demonstrate that RYZ-SSAs have an improved therapeutic window relative to [177Lu]Lu-DOTATATE. RYZ-SSA1 has the potential to deliver higher radiation doses to tumors while sparing the kidneys without co-administration of amino acids, paving the way for a more effective and convenient RPT treatment regimen for SSTR2 expressing solid tumors. Citation Format: Nicole Bakas, Alain Noncovich, Andrew Hudson, Su-Tang Lo, Lea Nyiranshuti, Patrick Napier, Nicholas Smith, Steven Horton, Samantha Richardson, Terra Miller, Ron Deocareza, Katrina Salvador, Tarsicio Juarez, Charlotte Lorenz, Abhijit Bhat. Novel somatostatin receptor type 2 targeted radiopharmaceuticals with improved renal clearance and enhanced tumor retention relative to DOTATATE [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 571.