Alpha radioimmunotherapy using (225)Ac-proteus-DOTA for solid tumors - safety at curative doses.
Alpha radioimmunotherapy using (225)Ac-proteus-DOTA for solid tumors - safety at curative doses.
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DOI：
10.7150/thno.48810
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发表时间：
2020
期刊：
影响因子：
12.4
通讯作者：
Larson SM
中科院分区：
文献类型：
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作者：
Cheal SM;McDevitt MR;Santich BH;Patel M;Yang G;Fung EK;Veach DR;Bell M;Ahad A;Vargas DB;Punzalan B;Pillarsetty NVK;Xu H;Guo HF;Monette S;Michel AO;Piersigilli A;Scheinberg DA;Ouerfelli O;Cheung NV;Larson SM
这是使用225 Ac及其治疗诊断对111 In的基于α的预靶向放射免疫治疗（PRIT）的初步报告。我们将我们的新型肿瘤靶向DOTA-半抗原PRIT系统称为“蛋白-DOTA”或“Pr”。在此，我们报告了放射化学发展、放射药理学和肿瘤抗原结合的化学计量学的第一批结果，包括Pr-PRIT方法（如α-DOTA-PRIT）的比活性、抗肿瘤功效和正常组织毒性的作用。在结直肠癌（GPA 33）、乳腺癌（HER 2）和神经母细胞瘤（GD 2）的三种实体人类癌症异种移植物模型中进行了一系列α-DOTA-PRIT治疗研究，包括在约20周时对选择的存活者的慢性毒性进行评价。研究方法：在SW 1222荷瘤小鼠中的初步生物分布实验显示，225 Ac不能被用于177 Lu或90 Y的当前DOTA-Bn半抗原有效地预靶向，导致体内肿瘤摄取差。因此，我们合成了Pr，其由用于225 Ac的空DOTA螯合物组成，通过短的聚乙二醇接头连接到用于皮摩尔抗DOTA螯合物单链可变片段（scFv）结合的镥络合的DOTA。Pr用225 Ac和其显像替代物111 In放射性标记。体外研究验证了[225 Ac]Pr的抗DOTA scFv识别，并进行体内生物分布和清除研究以评估半抗原适用性和体内靶向效率。结果：静脉注射（i. v.）在小鼠中施用225 Ac或111 In放射性标记的Pr显示快速的肾清除和最小的正常组织保留。体内预靶向研究显示Pr的高肿瘤蓄积（在24 h p.i. [225 Ac]Pr和[111 In]Pr）和正常组织中相对较低的摄取（注射后24小时，所有平均值均≤ 1.4% IA/g）。在高达296 kBq/小鼠的给药活性下，单独的[225 Ac]Pr或预先靶向的[225 Ac]Pr均未达到最大耐受剂量（MTD）。由α-DOTA-PRIT与huA 33-C825双特异性抗肿瘤/抗DOTA-半抗原抗体（BsAb）、抗HER 2-C825 BsAb或hu 3F 8-C825 BsAb（分别靶向GPA 33、HER 2或GD 2）组成的单周期治疗非常有效。在GPA 33模型中，未观察到完全反应（CR），但α-DOTA-PRIT治疗的动物的延长的总体存活为42天，而仅[225 Ac]Pr为25天GD 2组CR（7/7，100%）和组织学治愈（4/7，57%）; HER 2组CR（7/19，37%）和组织学治愈（10/19，56%），无急性或慢性毒性。结论：[225 Ac]Pr及其成像生物标志物[111 In]Pr证明了α-DOTA-PRIT治疗诊断应用的最佳放射药理学行为。对于疗效和毒性的初步评价，在所有三个系统中进行了单周期治疗方案。未观察到组织学毒性，因此未观察到MTD。在给药动物中观察到延长的总生存期、CR和组织学治愈。与使用抗肿瘤IgG抗体的RIT相比，[225 Ac]Pr具有大大改善的安全性特征。最终，这些数据将用于指导[225 Ac]Pr的毒性和疗效研究的临床开发，目标是提供大剂量的致命辐射，以实现无毒性治愈的高概率。
This is the initial report of an α-based pre-targeted radioimmunotherapy (PRIT) using 225Ac and its theranostic pair, 111In. We call our novel tumor-targeting DOTA-hapten PRIT system “proteus-DOTA” or “Pr.” Herein we report the first results of radiochemistry development, radiopharmacology, and stoichiometry of tumor antigen binding, including the role of specific activity, anti-tumor efficacy, and normal tissue toxicity with the Pr-PRIT approach (as α-DOTA-PRIT). A series of α-DOTA-PRIT therapy studies were performed in three solid human cancer xenograft models of colorectal cancer (GPA33), breast cancer (HER2), and neuroblastoma (GD2), including evaluation of chronic toxicity at ~20 weeks of select survivors. Methods: Preliminary biodistribution experiments in SW1222 tumor-bearing mice revealed that 225Ac could not be efficiently pretargeted with current DOTA-Bn hapten utilized for 177Lu or 90Y, leading to poor tumor uptake in vivo. Therefore, we synthesized Pr consisting of an empty DOTA-chelate for 225Ac, tethered via a short polyethylene glycol linker to a lutetium-complexed DOTA for picomolar anti-DOTA chelate single-chain variable fragment (scFv) binding. Pr was radiolabeled with 225Ac and its imaging surrogate, 111In. In vitro studies verified anti-DOTA scFv recognition of [225Ac]Pr, and in vivo biodistribution and clearance studies were performed to evaluate hapten suitability and in vivo targeting efficiency. Results: Intravenously (i.v.) administered 225Ac- or 111In-radiolabeled Pr in mice showed rapid renal clearance and minimal normal tissue retention. In vivo pretargeting studies show high tumor accumulation of Pr (16.71 ± 5.11 %IA/g or 13.19 ± 3.88 %IA/g at 24 h p.i. for [225Ac]Pr and [111In]Pr, respectively) and relatively low uptake in normal tissues (all average ≤ 1.4 %IA/g at 24 h p.i.). Maximum tolerated dose (MTD) was not reached for either [225Ac]Pr alone or pretargeted [225Ac]Pr at administered activities up to 296 kBq/mouse. Single-cycle treatment consisting of α-DOTA-PRIT with either huA33-C825 bispecific anti-tumor/anti-DOTA-hapten antibody (BsAb), anti-HER2-C825 BsAb, or hu3F8-C825 BsAb for targeting GPA33, HER2, or GD2, respectively, was highly effective. In the GPA33 model, no complete responses (CRs) were observed but prolonged overall survival of treated animals was 42 d for α-DOTA-PRIT vs. 25 d for [225Ac]Pr only (P < 0.0001); for GD2, CRs (7/7, 100%) and histologic cures (4/7, 57%); and for HER2, CRs (7/19, 37%) and histologic cures (10/19, 56%) with no acute or chronic toxicity. Conclusions: [225Ac]Pr and its imaging biomarker [111In]Pr demonstrate optimal radiopharmacologic behavior for theranostic applications of α-DOTA-PRIT. For this initial evaluation of efficacy and toxicity, single-cycle treatment regimens were performed in all three systems. Histologic toxicity was not observed, so MTD was not observed. Prolonged overall survival, CRs, and histologic cures were observed in treated animals. In comparison to RIT with anti-tumor IgG antibodies, [225Ac]Pr has a much improved safety profile. Ultimately, these data will be used to guide clinical development of toxicity and efficacy studies of [225Ac]Pr, with the goal of delivering massive lethal doses of radiation to achieve a high probability of cure without toxicity.