Mesothelin-targeted alpha therapy in PDAC with [225Ac]Ac-Macropa-PEG6-Amatuximab

IF 3 4区医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING

Nuclear medicine and biology Pub Date : 2026-03-01 Epub Date: 2026-01-28 DOI:10.1016/j.nucmedbio.2026.109606

Syed Qaiser Shah , Ralph Santos-Oliveira , Madeeha Shabnam , DeryaIlem-Ozdemir

{"title":"Mesothelin-targeted alpha therapy in PDAC with [225Ac]Ac-Macropa-PEG6-Amatuximab","authors":"Syed Qaiser Shah , Ralph Santos-Oliveira , Madeeha Shabnam , DeryaIlem-Ozdemir","doi":"10.1016/j.nucmedbio.2026.109606","DOIUrl":null,"url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) continues to be deadly and resistant to traditional treatments. Overexpressed in >80% of PDACs, mesothelin is an ideal target for antibody-based α-therapy. Actinium-225 (225Ac) produces high-LET α-particles leading to irreparable DNA damage, but its utility has been compromised by unstable chelation with traditional ligands. Here, we engineered a Macropa-enabled, site-specifically [<sup>225</sup>Ac]Ac-Macropa-PEG<sub>6</sub>-Amatuximab, a radioimmunoconjugate against mesothelin. Conjugation and labeling were characterized by MALDI-TOF and SEC-HPLC. In vitro stability, immunoreactivity, and kinetics of binding were tested in mesothelin-positive AsPC-1 cells and subsequently in vivo biodistribution, dosimetry, and therapy in AsPC-1 xenograft-bearing nude mice. Conjugation had an average ratio of 3.6 ± 0.1 for chelator per antibody, radiolabeling efficiency of 96.3 ± 1.1%, and radiochemical purity ≥98%. The radioconjugate was >92% stable after 168 h in serum, with immunoreactivity (82.2 ± 2.8%) and affinity (Kd = 4.3 ± 0.9 nM). It exhibited specific, time-dependent internalization in AsPC-1 cells and minimal nonspecific uptake. In vivo, [<sup>225</sup>Ac]Ac-Macropa-PEG<sub>6</sub>-Amatuximab exhibited prolonged circulation, specific tumor localization (3.9 ± 0.5 to 16.3 ± 2.1% ID/g, 1–168 h), and enhanced tumor-to-blood ratios (0.21–3.40). Blocking with unlabeled Amatuximab decreased tumor uptake by >60%. The tumor absorbed dose (1.82 ± 0.14 Gy/MBq) was 4–20-fold greater than doses to normal organs. Therapeutically, it caused dose-dependent tumor regression (TGI: 58% at 50 kBq; 92% at 150 kBq) and prolonged survival (>60 days vs. 0–1% in controls, <em>p</em> < 0.001). [<sup>225</sup>Ac]Ac-Macropa-PEG<sub>6</sub>-Amatuximab is stable, selective, and therapeutically effective, demonstrating Macropa-based 225Ac chelation as a stable platform for targeted α-therapy of PDAC.</div></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"154 ","pages":"Article 109606"},"PeriodicalIF":3.0000,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nuclear medicine and biology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0969805126000053","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/1/28 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING","Score":null,"Total":0}

引用次数: 0

Abstract

Pancreatic ductal adenocarcinoma (PDAC) continues to be deadly and resistant to traditional treatments. Overexpressed in >80% of PDACs, mesothelin is an ideal target for antibody-based α-therapy. Actinium-225 (225Ac) produces high-LET α-particles leading to irreparable DNA damage, but its utility has been compromised by unstable chelation with traditional ligands. Here, we engineered a Macropa-enabled, site-specifically [²²⁵Ac]Ac-Macropa-PEG₆-Amatuximab, a radioimmunoconjugate against mesothelin. Conjugation and labeling were characterized by MALDI-TOF and SEC-HPLC. In vitro stability, immunoreactivity, and kinetics of binding were tested in mesothelin-positive AsPC-1 cells and subsequently in vivo biodistribution, dosimetry, and therapy in AsPC-1 xenograft-bearing nude mice. Conjugation had an average ratio of 3.6 ± 0.1 for chelator per antibody, radiolabeling efficiency of 96.3 ± 1.1%, and radiochemical purity ≥98%. The radioconjugate was >92% stable after 168 h in serum, with immunoreactivity (82.2 ± 2.8%) and affinity (Kd = 4.3 ± 0.9 nM). It exhibited specific, time-dependent internalization in AsPC-1 cells and minimal nonspecific uptake. In vivo, [²²⁵Ac]Ac-Macropa-PEG₆-Amatuximab exhibited prolonged circulation, specific tumor localization (3.9 ± 0.5 to 16.3 ± 2.1% ID/g, 1–168 h), and enhanced tumor-to-blood ratios (0.21–3.40). Blocking with unlabeled Amatuximab decreased tumor uptake by >60%. The tumor absorbed dose (1.82 ± 0.14 Gy/MBq) was 4–20-fold greater than doses to normal organs. Therapeutically, it caused dose-dependent tumor regression (TGI: 58% at 50 kBq; 92% at 150 kBq) and prolonged survival (>60 days vs. 0–1% in controls, p < 0.001). [²²⁵Ac]Ac-Macropa-PEG₆-Amatuximab is stable, selective, and therapeutically effective, demonstrating Macropa-based 225Ac chelation as a stable platform for targeted α-therapy of PDAC.

Abstract Image

查看原文本刊更多论文

[225Ac] ac - macropa - peg6 -阿玛妥昔单抗靶向间皮素治疗PDAC。

胰腺导管腺癌（PDAC）仍然是致命的和抵抗传统治疗。间皮素在80%的pdac中过表达，是基于抗体的α-治疗的理想靶点。锕-225 （225Ac）产生高let α-颗粒，导致不可修复的DNA损伤，但其效用已被传统配体的不稳定螯合所损害。在这里，我们设计了Macropa-enabled，位点特异性[225Ac] ac - macropa - peg6 - amuximab，一种针对间皮素的放射免疫偶联物。用MALDI-TOF和SEC-HPLC对偶联和标记进行了表征。在间皮素阳性的AsPC-1细胞中测试了其体外稳定性、免疫反应性和结合动力学，随后在携带AsPC-1异种移植物的裸鼠体内进行了生物分布、剂量测定和治疗。每个抗体螯合剂的平均偶联率为3.6±0.1，放射标记效率为96.3±1.1%，放射化学纯度≥98%。该放射偶联物在血清中放置168 h后稳定性为>92%，具有免疫反应性（82.2±2.8%）和亲和力（Kd = 4.3±0.9 nM）。它在AsPC-1细胞中表现出特异性的、时间依赖性的内化和最小的非特异性摄取。在体内，[225Ac] ac - macropa - peg6 - amuximab表现出延长循环，特异性肿瘤定位（3.9±0.5至16.3±2.1% ID/g, 1-168 h），提高肿瘤与血液比率（0.21-3.40）。用未标记的阿玛妥昔单抗阻断可使肿瘤摄取降低约60%。肿瘤吸收剂量（1.82±0.14 Gy/MBq）是正常器官吸收剂量的4 ~ 20倍。在治疗上，它引起了剂量依赖性肿瘤消退（TGI在50 kBq时为58%，在150 kBq时为92%）和延长生存期（60天，对照组为0-1%，p 225Ac）。ac - macropa - peg6 - amuximab是稳定的、选择性的和治疗有效的，表明基于macropa的225Ac螯合是靶向α-治疗PDAC的稳定平台。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Nuclear medicine and biology 医学-核医学

CiteScore

6.00

自引率

9.70%

发文量

479

审稿时长

51 days

期刊介绍： Nuclear Medicine and Biology publishes original research addressing all aspects of radiopharmaceutical science: synthesis, in vitro and ex vivo studies, in vivo biodistribution by dissection or imaging, radiopharmacology, radiopharmacy, and translational clinical studies of new targeted radiotracers. The importance of the target to an unmet clinical need should be the first consideration. If the synthesis of a new radiopharmaceutical is submitted without in vitro or in vivo data, then the uniqueness of the chemistry must be emphasized. These multidisciplinary studies should validate the mechanism of localization whether the probe is based on binding to a receptor, enzyme, tumor antigen, or another well-defined target. The studies should be aimed at evaluating how the chemical and radiopharmaceutical properties affect pharmacokinetics, pharmacodynamics, or therapeutic efficacy. Ideally, the study would address the sensitivity of the probe to changes in disease or treatment, although studies validating mechanism alone are acceptable. Radiopharmacy practice, addressing the issues of preparation, automation, quality control, dispensing, and regulations applicable to qualification and administration of radiopharmaceuticals to humans, is an important aspect of the developmental process, but only if the study has a significant impact on the field. Contributions on the subject of therapeutic radiopharmaceuticals also are appropriate provided that the specificity of labeled compound localization and therapeutic effect have been addressed.