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

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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.

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Abbreviations

HER2:

Human epidermal receptor type 2

GC:

Gastric cancer

GEC:

Gastroesophageal junction cancer

IHC:

Immunohistochemistry

i.v.:

Intravenous injection

h :

Hour

SISH/CISH/FISH:

Silver, chromogenic, or fluorescent in situ hybridization

SPECT:

Single-photon emission computed tomography

PET:

Positron emission tomography

DFO:

Desferrioxamine

NOTA:

S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid

PDX:

Patient-derived tumor xenograft

radio-TLC:

Radioactive thin-layer chromatography scanner

HPLC:

High-performance liquid chromatography

p.i.:

Post-injection

d :

Day

SUVmax:

The maximum single-voxel standardized uptake value

ROIs:

Regions of interest

%ID/g:

Percent injected dose per gram

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Author information

Correspondence to Zhi Yang or Hua Zhu.

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Conflicts of interests

The authors declare no potential conflict of interests.

Ethical approval

All procedures in this study were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and its later versions. Informed consent, or its equivalent, was obtained from all patients included in the study. The clinical study was approved by the Ethics Committee of the Beijing Cancer Hospital (Ethics Approval License: 2018KT48).

Human and animal rights

All institutional and national guidelines for the care and use of laboratory animals were followed.

Informed consent

Informed consent was obtained from the 6 individual participants included in this study.

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Guo, X., Zhou, N., Chen, Z. et al. Construction of 124I-trastuzumab for noninvasive PET imaging of HER2 expression: from patient-derived xenograft models to gastric cancer patients. Gastric Cancer (2020) doi:10.1007/s10120-019-01035-6

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Keywords

  • 124I-trastuzumab
  • PET/CT
  • Gastric cancer
  • HER2