Construction of 124I-trastuzumab for noninvasive PET imaging of HER2 expression: from patient-derived xenograft models to gastric cancer patients.

Abstract

PURPOSE:

Here, we sought to develop a PET radioligand based on trastuzumab labeled with 124I, 124I-trastuzumab, to evaluate its distribution, internal dosimetry, and initial PET images of HER2-positive lesions in gastric cancer (GC) patients.

METHODS:

In animal studies, micro-PET imaging and bio-distribution were performed to examine the specificity of 124I-trastuzumab in HER2-positive and HER2-negative mouse models. Subsequently, 124I-trastuzumab was applied in human clinic trial. Six gastric cancer patients with metastases underwent 124I-trastuzumab PET imaging, with 18F-FDG PET/CT in each to compare.

RESULTS:

In animal studies, PET imaging of 124I-trastuzumab showed significant higher tumor uptake than that of 124I-IgG1 in HER2-positive PDX mouse models at 24 h. The low tumor uptake of 124I-trastuzumab in HER2-negative PDX models further confirmed the specificity. In human clinical studies, 18 HER2-positive lesions and 11 HER2-negative lesions were evaluated in PET imaging analysis. The detection sensitivity of 124I-trastuzumab was 100% (18/18) at 24 h. The PET images showed significant difference in tumor uptake between HER2-positive and HER2-negative lesions at 24 h (SUVmax 7.83 ± 0.55 vs. 1.75 ± 0.29, p < 0.0001). Quite striking difference in tumor uptake was observed between 124I-trastuzumab and 18F-FDG (SUVmax 1.75 ± 0.29 vs. 6.46 ± 0.44, p < 0.0001) in HER2-negative lesions, further confirming the specific binding of 124I-trastuzumab in HER2-positive lesions. The radiation-absorbed dose was calculated to be 0.3011 ± 0.005 mSv/MBq. No toxicities or adverse effects were observed in any of the patients.

CONCLUSION:

The findings described here demonstrated that 124I-trastuzumab was feasible to detect HER2-positive lesions in primary and metastatic gastric cancer patients and to differentiate HER2-positive and HER2-negative lesions quantitatively.

• Authors: Xiaoyi Guo, Nina Zhou, Zuhua Chen, Teli Liu, Xiaoxia Xu, Xia Lei, Lin Shen, Jing Gao, Zhi Yang, Hua Zhu
• Journal: Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association (Gastric Cancer) Vol. 23 Issue 4 Pg. 614-626 (07 2020) ISSN: 1436-3305 [Electronic] Japan
• PMID: 31919745 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents, Immunological
• Iodine Radioisotopes
• Iodine-124
• Radiopharmaceuticals
• Fluorodeoxyglucose F18
• ERBB2 protein, human
• Receptor, ErbB-2
• Trastuzumab

Topics

• Adult
• Aged
• Animals
• Antineoplastic Agents, Immunological (chemistry, therapeutic use)
• Apoptosis
• Cell Proliferation
• Female
• Fluorodeoxyglucose F18 (metabolism)
• Humans
• Iodine Radioisotopes (chemistry)
• Male
• Mice
• Middle Aged
• Positron-Emission Tomography (methods)
• Radiopharmaceuticals (metabolism)
• Receptor, ErbB-2 (metabolism)
• Stomach Neoplasms (diagnostic imaging, drug therapy, metabolism, pathology)
• Trastuzumab (chemistry, therapeutic use)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays