.png){kind=icon}
.png){kind=icon}
Return
Mesothelin-targeted alpha therapy in PDAC with [225Ac]Ac-Macropa-PEG6-Amatuximab
.png){kind=icon}
PRE
AI
S
R
M
N
DOI：10.1016/j.nucmedbio.2026.109606.png)
.png){kind=icon}
Original request for help.png){kind=icon}
Share.png){kind=icon}
Save
Abstract
En 中文
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.
Journal
IF:
3
Papers:
3.7K
Citations:
3.2K
Organization
Cited Papers