Rinne Sara S, Vargas Daniela Burnes, Seo Shin, Veach Darren, McDevitt Michael R, Vaughn Brett A, Xu Hong, Guo Hong-Fen, Fung Edward K, de Stanchina Elisa, Miranda Ileana C, Larson Steven M, Cheung Nai Kong V, Cheal Sarah M
Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, New York.
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
J Nucl Med. 2025 Jun 12. doi: 10.2967/jnumed.125.269601.
Radioimmunotherapy using Ac, a highly cytotoxic α-particle emitter, has potential for treating advanced breast cancer, especially human epidermal growth factor receptor 2 (HER2)-positive cases. We use a pretargeted radioimmunotherapy (PRIT) approach consisting of a 3-step intravenous regimen (step 1: bispecific anti-HER2/anti-DOTA antibody; step 2: clearing agent; step 3: Ac-radiolabeled DOTA, or [Ac]Ac-Pr). Our goal was to establish curative Ac-PRIT with high therapeutic indices. The impact of [Ac]Ac-Pr specific activity was evaluated in the BT-474 breast xenograft model. We tested the effects of [Ac]Ac-Pr dosing during PRIT on tumor-targeting efficiency and tissue biodistribution. Using a Ac-PRIT regimen consisting of a ratio of 1.19 nmol of bispecific antibody to 0.60-0.66 nmol of [Ac]Ac-Pr, we evaluated therapy in the BT-474 model and a patient-derived xenograft model. BT-474-tumor-bearing mice were treated with 1 or 2 cycles of Ac-PRIT (37 kBq/cycle) separated by 1 wk. A dose escalation study was performed on the BT-474 model to establish an absorbed radiation dose of approximately 40 Gy (relative biological effectiveness [RBE], 5) as a nephrotoxic dose, as no such histologic findings were observed in prior studies at the 20.7-Gy (RBE, 5) renal dose level. In the BT-474 model, 100% (20/20) achieved complete responses and histologic cure in 17 of 20 (85%) of the treated animals. One-cycle and 2-cycle treatments were equally effective. Treatments were well tolerated, with no chronic radiation toxicity documented during necropsy at 175 d. Dosimetry estimates (RBE, 5) per 37 kBq administered for tumors and kidneys were 210 and 3.5 Gy, respectively. In the patient-derived xenograft model, a single Ac-PRIT treatment led to 60% (3/5) complete response and prolonged survival (>93 d) versus no treatment (30 d; = 0.0185). Lastly, a Ac-PRIT regimen was identified that induces severe chronic nephrotoxicity (41.4 Gy/592 kBq; RBE, 5). Safe and effective Ac-PRIT regimens were developed in 2 preclinical models of advanced HER2-positive human breast cancer with tumor cure without dose-limiting nephrotoxicity. This study establishes crucial preclinical dosimetry benchmarks for Ac-PRIT and provides a compelling rationale for its advancement into the clinic.
使用锕（Ac）进行的放射免疫疗法，锕是一种具有高度细胞毒性的α粒子发射体，在治疗晚期乳腺癌方面具有潜力，尤其是人表皮生长因子受体2（HER2）阳性病例。我们采用一种预靶向放射免疫疗法（PRIT）方法，该方法由三步静脉注射方案组成（步骤1：双特异性抗HER2/抗DOTA抗体；步骤2：清除剂；步骤3：Ac标记的DOTA，即[Ac]Ac-Pr）。我们的目标是建立具有高治疗指数的治愈性Ac-PRIT。在BT-474乳腺异种移植模型中评估了[Ac]Ac-Pr比活的影响。我们测试了PRIT期间[Ac]Ac-Pr给药对肿瘤靶向效率和组织生物分布的影响。使用由1.19 nmol双特异性抗体与0.60 - 0.66 nmol [Ac]Ac-Pr的比例组成的Ac-PRIT方案，我们在BT-474模型和患者来源的异种移植模型中评估了治疗效果。携带BT-474肿瘤的小鼠接受1或2个周期的Ac-PRIT治疗（37 kBq/周期），间隔1周。在BT-474模型上进行了剂量递增研究，以确定约40 Gy（相对生物效应[RBE]，5）的吸收辐射剂量作为肾毒性剂量，因为在先前20.7 Gy（RBE，5）肾剂量水平的研究中未观察到此类组织学结果。在BT-474模型中，100%（20/20）的治疗动物实现了完全缓解，20只中有17只（85%）实现了组织学治愈。单周期和双周期治疗同样有效。治疗耐受性良好，在175天尸检时未记录到慢性辐射毒性。每37 kBq给药的肿瘤和肾脏剂量学估计值（RBE，5）分别为210和3.5 Gy。在患者来源的异种移植模型中，单次Ac-PRIT治疗导致60%（3/5）的完全缓解并延长了生存期（>93天），而未治疗组为30天（P = 0.0185）。最后，确定了一种诱导严重慢性肾毒性的Ac-PRIT方案（41.4 Gy/592 kBq；RBE，5）。在晚期HER2阳性人类乳腺癌的2个临床前模型中开发出了安全有效的Ac-PRIT方案，实现了肿瘤治愈且无剂量限制性肾毒性。本研究为Ac-PRIT建立了关键的临床前剂量学基准，并为其进入临床提供了令人信服的理论依据。
Zotero 插件