用于前列腺癌的新型高亲和力PSMA靶向放射性配体177Lu-PSMA-3D1015的开发与评价

Background: The clinical efficacy of PSMA targeted RLT for metastatic PCa has been well established by Pluvicto®. However, the suboptimal characteristics of existing agents, such as short tumor retention and rapid clearance, may limit the efficiency of radiation energy from ¹⁷⁷Lu decay. The small molecular compound, 3D1015, is a newly designed PSMA-targeted ligand with high affinity. Its radiolabeled product, 177 Lu-PSMA-3D1015 (hereafter “3D1015”), has been developed to prolong its retention in the tumor tissue, and has shown excellent tumor inhibition effect at low dose, along with great safety profile. Method: The binding affinity of ligand to PSMA was evaluated using LNCaP cells via FACS-based competition assay, with PSMA-617 as a reference. In vivo biodistribution and efficacy were assessed in LNCaP xenograft B-NDG mice by calculating uptake (%ID/g) and measuring TGI (%) across dose groups. A single-dose toxicity study in SD rats was conducted to determine the dose tolerance and identify target toxic organs. An exploratory study further investigated the dosimetry and safety of 3D1015 in patients with PSMA-positive mCRPC who had failed SOCs. Eligible patients received a single administration of 3D1015 (10 mCi, i.v. ) then underwent qSPECT/CT at different timepoints. Results: IC₅₀ values were 1.47 nM for 3D1015 ligand and 4.11 nM for PSMA-617. Radiolabeling with ¹⁷⁷Lu under mild conditions achieved >97% RCP. Biodistribution studies revealed rapid and sustained tumor uptake of 3D1015, reaching 36.50 %ID/g at 120 h, with renal excretion indicated by high kidney exposure (max: 59.47 %ID/g at 72 h). Efficacy studies demonstrated dose-dependent efficacy (TGI: 80.0%, 98.3%, and 99.8% at 0.1, 0.5, and 1.0 mCi/mouse, respectively). A dose of 0.5 mCi 3D1015 achieved superior TGI versus 1.0 mCi 177 Lu-PSMA-617 (TGI: 94.0%). Toxicity study identified the spleen as the primary target organ, with a MTD of 15 mCi/kg; transient toxicities in body weight, food intake, and hematology were fully reversible. Two patients received a single dose of 10 mCi of 3D1015. SPECT/CT imaging indicated that the drug was primarily excreted via the hepatobiliary/intestinal route rather than the renal excretion pathway as shown in the previous animal toxicity research. Uptake of 3D1015 was observed in all pre-identified lesions till 216 h. Mean absorbed dose in kidneys, submandibular and parotid glands, liver, spleen, and bone marrow was 0.80, 1.35, 0.44, 1.12, and 0.12 mGy/MBq, respectively. No > G2 TRAEs occurred. A 14% decline of PSA was observed in 1pts after one dose of 10mCi infusion. Conclusion: 177 Lu-PSMA-3D1015 exhibits high PSMA affinity and prolonged retention in tumor, potentially driving potent efficacy at lower doses. Its distinct hepatobiliary excretion profile differentiates it from existing therapies. These findings address key limitations of current RLTs, and further clinical trials are ongoing.