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

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.

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.

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.

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.