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 124 I, 124 I-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 124 I-trastuzumab in HER2-positive and HER2-negative mouse models. Subsequently, 124 I-trastuzumab was applied in human clinic trial. Six gastric cancer patients with metastases underwent 124 I-trastuzumab PET imaging, with 18 F-FDG PET/CT in each to compare. Results In animal studies, PET imaging of 124 I-trastuzumab showed significant higher tumor uptake than that of 124 I-IgG1 in HER2-positive PDX mouse models at 24 h. The low tumor uptake of 124 I-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 124 I-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 124 I-trastuzumab and 18 F-FDG (SUVmax 1.75 ± 0.29 vs. 6.46 ± 0.44, p < 0.0001) in HER2-negative lesions, further confirming the specific binding of 124 I-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. ConclusionThe findings described here demonstrated that 124 I-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.Xiaoyi Guo, Nina Zhou, and Zuhua Chen have contributed equally to this work.

Prospects and Clinical Perspectives of Total-Body PET Imaging Using Plastic Scintillators

“…44 Sc-DOTA-ZHER2:342, 72-CAIX, 55,56 Integrin 59 PSMA, 69 SST2R 64 iv. Can be used in dual analysis with 2 radiotracers "pairs": 124 I-trastuzumab/ 18 F-FDG 70 This unique feature of the aforementioned radionuclides over the standard 2g radionuclides, which emit additional prompt g (eg, 44 Sc, 66 Ga, 82 Rb, 124 I) provides another rationale for the application of the TB-PET concept.…”

A Preliminary Clinical Trial to Evaluate 64Cu-NOTA-Trastuzumab as a Positron Emission Tomography Imaging Agent in Patients with Breast Cancer

“…To overcome these limitations, a diagnostic method using positron emission tomography (PET) has been studied. Clinical trials of antibodies such as Trastuzumab labeled with radioisotopes, including 124 I and 89 Zr, have been conducted [9,11,12], demonstrating HER2 expression capability of lesions in patients with HER2 expressing tumors [9,11,12]. Moreover, the use of HER2-targeted PET imaging, using 64 Cutetra-azacyclododecanetetra-acetic acid (DOTA)-Trastuzumab has been attempted [5,6,11,13,14]; related clinical trials in the United States and Japan showed effective identi cation of HER2 expression in breast cancer patients [5,6,13,14].…”

A Microdose Clinical Trial to Evaluate 64Cu-NOTA-Trastuzumab as a Positron Emission Tomography Imaging Agent in Patients with Breast Cancer

“…To overcome these limitations, a diagnostic method using positron emission tomography (PET) has been studied. Clinical trials of isotopes, such as 124 I and 89 Zr that were labeled with antibodies such as trastuzumab, have been conducted [9,11,12]. The trials were able to demonstrate that they can quantify HER2 expression of lesions in patients with HER2 expressing tumors [9,11,12].…”

“…Clinical trials of isotopes, such as 124 I and 89 Zr that were labeled with antibodies such as trastuzumab, have been conducted [9,11,12]. The trials were able to demonstrate that they can quantify HER2 expression of lesions in patients with HER2 expressing tumors [9,11,12]. In addition, the use of HER2 targeted PET imaging using 64 Cu-tetra-azacyclododecanetetra-acetic acid (DOTA)-Trastuzumab has been attempted [5,6,11,13,14].…”