PO.ET08.02 · 实验与分子治疗
一种新型NTSR1靶向α放射治疗药物SKL35501在HCT116结直肠肿瘤模型中展现出强效抗肿瘤疗效
A novel NTSR1-targeting alpha radiotherapeutic SKL35501 demonstrating potent anti-tumor efficacy in HCT116 colorectal tumor model
该海报暂无可下载的资料
AACR 官方页面
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：使用α发射体Actinium-225（225Ac）的放射性药物疗法（RPT）正在成为治疗晚期实体瘤的一种有前景的治疗方法。神经降压素受体1（NTSR1）在胰腺导管腺癌、结直肠癌、食管癌、胃癌、胆道癌和头颈部鳞状细胞癌等侵袭性癌症中高表达，代表了RPT的一个有吸引力的靶点。SKL35501是225Ac标记的NTSR1配体，开发作为治疗药物。本研究使用HCT116细胞系评估了SKL35501的临床前特性。在此，我们展示了在结直肠肿瘤模型中良好的体外药理学、体内生物分布和体内抗肿瘤活性。
方法：使用摄取和集落形成实验，在表达NTSR1的HCT116人结直肠癌细胞中评估了SKL35501的体外细胞摄取/内化和细胞毒性。在HCT116异种移植模型中，跨多个剂量水平（0、7.5、15和30 kBq）评估了单次静脉给药后的体内生物分布和抗肿瘤疗效。通过体重和血液学参数评估安全性。
结果：SKL35501在HCT116细胞中表现出快速、时间依赖性、NTSR1介导的摄取，>90%的细胞相关活性被内化，并在集落形成实验中显示出剂量依赖性的集落形成抑制。在体内，SKL35501表现出强大而持续的肿瘤蓄积（24小时时31 %ID/g，滞留至168小时），同时从非靶器官快速清除。单次给药产生了剂量依赖性的肿瘤生长抑制，在≥15 kBq剂量下到第75天出现部分肿瘤消退。与载体相比，所有SKL35501剂量水平均显著延长了生存期（p=0.0005）。毒性是短暂和可逆的，表现为轻度血液学抑制和<10%的体重减轻，两者均在数周内恢复。
结论：SKL35501是一种高效的、首创的、225Ac标记的NTSR1靶向α放射治疗药物，展现出卓越的肿瘤选择性、持久的肿瘤滞留、强效的抗肿瘤活性和良好的安全性。这些临床前发现有力地支持使用SKL35501推进至针对NTSR1阳性晚期实体瘤患者的首次人体（FIH）试验。
查看英文原文 English abstract
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.
利益披露 Disclosure
J. Na, None..
T. Lee, None..
S. Jeon, None..
H. Lee, None..
S. Lee, None..
S. Hwang, None..
J. Park, None.