A novel NTSR1-targeting alpha radiotherapeutic SKL35501 demonstrating potent anti-tumor efficacy in HCT116 colorectal tumor model

Background: Radiopharmaceutical Therapy (RPT) using the alpha-emitter Actinium-225 ( 225 Ac) is emerging as a promising therapeutic approach for advanced solid tumors. Neurotensin Receptor 1 (NTSR1), highly expressed in aggressive cancers such as pancreatic ductal adenocarcinoma, colorectal cancer, esophageal cancer, gastric cancer, biliary tract cancer, and head and neck squamous cell carcinoma, represents an attractive target for RPT. SKL35501, the 225 Ac-labeled NTSR1 ligand, was developed as the therapeutic agent. This study evaluated the preclinical characteristics of SKL35501 using the HCT116 cell line. Here, we demonstrate favorable in vitro pharmacology, in vivo biodistribution, and in vivo antitumor activity in a colorectal tumor model. Methods: In vitro cellular uptake/internalization and cytotoxicity of SKL35501 were assessed in NTSR1-expressing HCT116 human colorectal carcinoma cells using uptake and colony formation assays. In vivo biodistribution and antitumor efficacy following a single intravenous administration were evaluated in HCT116 xenograft models across multiple dose levels (0, 7.5, 15, and 30 kBq). Safety was assessed by body weight and hematological parameters. Results: SKL35501 demonstrated rapid and time-dependent, NTSR1-mediated uptake in HCT116 cells, with >90% of cell-associated activity internalized, and showed a dose-dependent colony formation inhibition in the colony-formation assay. In vivo , SKL35501 exhibited robust and sustained tumor accumulation (31 %ID/g at 24h, with retention through 168 hours) alongside rapid clearance from non-target organs. A single administration produced dose-dependent tumor growth inhibition, with partial tumor regression at doses ≥15 kBq by Day 75. All SKL35501 dose levels resulted in significantly prolonged survival compared with vehicle (p=0.0005). Toxicity was transient and reversible, characterized by mild hematological suppression and <10% body weight loss, both of which recovered within several weeks. Conclusions: SKL35501 is a highly effective, first-in-class, 225 Ac-labeled NTSR1-targeting alpha radiotherapeutic demonstrating excellent tumor selectivity, durable tumor retention, potent antitumor activity, and a favorable safety profile. These preclinical findings strongly support advancement to the FIH trial for patients with NTSR1-positive advanced solid tumors using the SKL35501.