Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Chemistry, Hunter College of the City University of New York, New York, New York.
Clin Cancer Res. 2019 Jan 15;25(2):868-880. doi: 10.1158/1078-0432.CCR-18-1650. Epub 2018 Oct 23.
Interest in targeted alpha-therapy has surged due to α-particles' high cytotoxicity. However, the widespread clinical use of this approach could be limited by on-/off-target toxicities. Here, we investigated the inverse electron-demand Diels-Alder ligation between an Ac-labeled tetrazine radioligand and a -cyclooctene-bearing anti-CA19.9 antibody (5B1) for pretargeted α-radioimmunotherapy (PRIT) of pancreatic ductal adenocarcinoma (PDAC). This alternative strategy is expected to reduce nonspecific toxicities as compared with conventional radioimmunotherapy (RIT). A side-by-side comparison of Ac-PRIT and conventional RIT using a directly Ac-radiolabeled immunoconjugate evaluates the therapeutic efficacy and toxicity of both methodologies in PDAC murine models.
A comparative biodistribution study of the PRIT versus RIT methodology underscored the improved pharmacokinetic properties (e.g., prolonged tumor uptake and increased tumor-to-tissue ratios) of the PRIT approach. Cerenkov imaging coupled to PRIT confirmed the biodistribution of Ac-radioimmunoconjugate but-importantly-further allowed for the monitoring of Ac's radioactive daughters' redistribution. Human dosimetry was extrapolated from the mouse biodistribution and confirms the clinical translatability of Ac-PRIT. Furthermore, longitudinal therapy studies performed in subcutaneous and orthotopic PDAC models confirm the therapeutic efficacy of Ac-PRIT with the observation of prolonged median survival compared with control cohorts. Finally, a comparison with conventional RIT highlighted the potential of Ac-PRIT to reduce hematotoxicity while maintaining therapeutic effectiveness.
The ability of Ac-PRIT to deliver a radiotherapeutic payload while simultaneously reducing the off-target toxicity normally associated with RIT suggests that the clinical translation of this approach will have a profound impact on PDAC therapy.
由于 α 粒子具有高细胞毒性，靶向 α 疗法的兴趣大增。然而，这种方法的广泛临床应用可能会受到靶内/靶外毒性的限制。在这里，我们研究了 Ac 标记的四嗪放射性配体与携带抗 CA19.9 的 -环辛烯之间的逆电子需求 Diels-Alder 连接，用于胰腺导管腺癌 (PDAC) 的预靶向 α 放射免疫治疗 (PRIT)。与传统放射免疫治疗 (RIT) 相比，这种替代策略预计会降低非特异性毒性。通过直接 Ac 放射性标记免疫缀合物对 Ac-PRIT 和常规 RIT 进行并排比较，评估了这两种方法在 PDAC 小鼠模型中的治疗效果和毒性。
PRIT 与 RIT 方法的比较生物分布研究强调了 PRIT 方法改善的药代动力学特性（例如，延长肿瘤摄取和增加肿瘤与组织的比值）。与 PRIT 相结合的 Cerenkov 成像证实了 Ac 放射性免疫缀合物的生物分布，但更重要的是，允许监测 Ac 的放射性子体的再分布。从小鼠生物分布外推的人类剂量学证实了 Ac-PRIT 的临床可转化性。此外，在皮下和原位 PDAC 模型中进行的纵向治疗研究证实了 Ac-PRIT 的治疗效果，与对照组相比观察到中位生存期延长。最后，与常规 RIT 的比较突出了 Ac-PRIT 减少血液毒性同时保持治疗效果的潜力。
Ac-PRIT 能够输送放射治疗有效载荷，同时减少与 RIT 相关的非靶毒性，这表明该方法的临床转化将对 PDAC 治疗产生深远影响。
