SEZ6 靶向 PET 成像与 α 粒子放射性免疫治疗对小细胞肺癌检测与治疗的有效性研究
SEZ6-Targeted PET Imaging and Alpha-Particle Radioimmunotherapy is Effective for Detection and Treatment of Small Cell Lung Cancer.
作者
作者单位
- National Cancer Institute Bethesda, Maryland United States.
- National Cancer Institute MD United States.
- National Institutes of Health Bethesda, MD United States.
- National Institutes of Health BETHESDA, MD United States.
- National Cancer Institute Bethesda, MD United States.
摘要
中文
小细胞肺癌(SCLC)仍然是最致命的恶性肿瘤之一,尽管治疗手段不断进步,其五年生存率仍不足 10%。SEZ6(seizure-related gene 6)是一种 I 型跨膜蛋白,在神经内分泌肿瘤中优先表达,近期已成为一个有前景的治疗靶点,这一点得到了针对 SEZ6 的抗体药物偶联物在复发 SCLC 中展现临床活性的支持。本研究开发并评估了一种人源化抗 SEZ6 单克隆抗体,用于 SEZ6 靶向正电子发射计算机断层扫描(PET)成像与 α 粒子放射性免疫治疗。患者组织免疫组织化学检测确认 SEZ6 呈强表达且与分期无关。细胞研究证实 SEZ6 受体密度高,支持抗体高亲和力结合与快速受体介导的内吞。低抗体剂量给予 [89Zr]Zr-DFO-SEZ6-Ab 后,尽管肿瘤内 SEZ6 水平较高,却表现出快速的肝脾清除与极低的肿瘤摄取。这一模式与活跃的胞外域脱落及可溶性抗原在肿瘤微环境中的局部蓄积相一致,形成了细胞外抗原陷阱,限制了有效的靶点结合。增加抗体剂量可克服这一障碍,显著提高异种移植瘤中的肿瘤摄取。[225Ac]Ac-Macropa-SEZ6-Ab 治疗诱导了肿瘤完全消退,而联合给予 ATR 抑制剂 berzosertib 可在更低放射性活度下增强疗效且不增加毒性。上述结果共同表明,肿瘤局部 SEZ6 脱落是 SEZ6 靶向治疗的生物学屏障,明确了克服该屏障的给药策略,并证实了 SEZ6 导向 α 粒子放射性免疫治疗在 SCLC 中具有强大的抗肿瘤活性。
English
Small cell lung cancer (SCLC) remains one of the most lethal malignancies, with a five-year survival of <10% despite advances in treatment. Seizure-related gene 6 (SEZ6), a type I transmembrane protein preferentially expressed in neuroendocrine tumors, has recently emerged as a promising therapeutic target, supported by clinical activity of SEZ6-targeted antibody-drug conjugates in relapsed SCLC. Here, we developed and evaluated a humanized anti-SEZ6 monoclonal antibody for SEZ6-targeted positron emission tomography (PET) imaging and α-particle radioimmunotherapy. Immunohistochemistry of patient tissues confirmed strong, stage-independent SEZ6 expression. Cell-based studies demonstrated high SEZ6 receptor densities, supporting high-affinity antibody binding and rapid receptor-mediated internalization. [89Zr]Zr-DFO-SEZ6-Ab administered at low antibody mass exhibited rapid hepatosplenic clearance with minimal tumor uptake despite high intratumoral levels. This pattern was consistent with active ectodomain shedding and local accumulation of soluble antigen within the tumor microenvironment, creating an extracellular antigen sink and limiting effective target engagement. Increasing the antibody mass overcame this barrier, dramatically increasing tumor uptake in xenografts. Treatment with [225Ac]Ac-Macropa-SEZ6-Ab induced complete tumor regression, while co-administration of the ATR inhibitor berzosertib enhanced efficacy at lower radioactivity doses without added toxicity. Together, these findings identify tumor-localized SEZ6 shedding as a biological barrier to SEZ6-targeted therapy, define dosing strategies to overcome it, and demonstrate potent antitumor activity of SEZ6-directed α-particle radioimmunotherapy in SCLC.
分类与指标
- 研究类型
- 基础研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 22.6
- 新锐分区
- 1区