机构:[1]Department of Nuclear Medicine, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, China.[2]State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital &[3] Institute, Beijing 100142, China.
Mucin 17 (MUC17), a transmembrane mucin, is overexpressed in pancreatic cancer and is associated with tumor proliferation and metastasis. CD3 is an indispensable molecule on the surface of T lymphocytes, which is associated with T cell activation and participates in immune responses. Here, we developed a bispecific T-cell engager radiotracer, 89Zr-M17C3, targeting MUC17 and CD3, to enable noninvasive PET imaging of both tumor cells and T-cell infiltration in pancreatic cancer. 89Zr-M17C3 was synthesized by conjugating AMG199 with zirconium-89 and verified for its radiochemical purity and in vitro stability. The 89Zr-M17C3 probe demonstrated excellent radiochemical purity (>99%) and stability (maintained ≥99% over 120 h). Cellular uptake assays and binding affinity studies were conducted to evaluate the probe's specificity for MUC17 and CD3. Micro-PET/CT imaging and biodistribution studies were performed in MUC17-expressing nude mice and CD3 humanized mice to assess probe uptake in tumors and T-cell-infiltrated tissues. In MUC17-expressing AsPC-1 tumors, probe uptake was significantly higher than in MUC17-negative PANC-1 tumors (SUVmax: 2.26 ± 0.18 vs 1.13 ± 0.14, P < 0.001) and was confirmed to be MUC17-dependent through blocking studies. In CD3 humanized mice, the probe was able to visualize both T-cell infiltration and MUC17-positive tumors, with peak uptake in AsPC-1 tumors (SUVmax: 2.35 ± 0.46) and spleen (SUVmax: 2.19 ± 0.40) at 216 h. Immunohistochemical analysis confirmed the spatial correlation between MUC17 expression and CD3-positive T-cell infiltration in AsPC-1 tumors but not in PANC-1 tumors. In summary, the 89Zr-M17C3 radiotracer exhibited high affinity for MUC17 and CD3 and successfully differentiated MUC17-positive tumors from MUC17-negative tumors while simultaneously providing insight into the T-cell distribution. This study highlights the potential of 89Zr-M17C3 as a versatile imaging tool to support patient stratification and therapeutic monitoring in tumor-targeted immunotherapy, particularly for bispecific T-cell engager-based approaches such as AMG199.
基金:
National Natural Science
Foundation of China (grant numbers: 92359203, 82171973,
82171980), Youth Talent Support Program (grant number:
A002863), Science Foundation of Peking University Cancer
Hospital (grant number: JC202308), Science and Technology
Department of Sichuan Province project (grant number:
2024NSFSC0668), Affiliated Hospital of North Sichuan
Medical College Research and development project (grant
number: 2023LC004), and Research development Fund
project of North Sichuan Medical College (grant number:
CBY21-QA31, CBY21-QA40).
语种:
外文
PubmedID:
中科院(CAS)分区:
出版当年[2025]版:
大类|2 区医学
小类|2 区药学3 区医学:研究与实验
最新[2025]版:
大类|2 区医学
小类|2 区药学3 区医学:研究与实验
第一作者:
第一作者机构:[1]Department of Nuclear Medicine, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, China.
共同第一作者:
通讯作者:
推荐引用方式(GB/T 7714):
Wen Dan,Wang Qi,Ding Jin,et al.Construction of Bispecific T-Cell Engager Radiotracer and Its Micro-PET Evaluation in Pancreatic Cancer[J].Molecular Pharmaceutics.2025,doi:10.1021/acs.molpharmaceut.5c00072.
APA:
Wen Dan,Wang Qi,Ding Jin,Wang Zilei,Lin Shiyu...&Yang Zhi.(2025).Construction of Bispecific T-Cell Engager Radiotracer and Its Micro-PET Evaluation in Pancreatic Cancer.Molecular Pharmaceutics,,
MLA:
Wen Dan,et al."Construction of Bispecific T-Cell Engager Radiotracer and Its Micro-PET Evaluation in Pancreatic Cancer".Molecular Pharmaceutics .(2025)