Development and clinical evaluation of [⁶⁸Ga]Ga-NODAGA-ADAPT6 as a novel HER2-targeted PET radiotracer for breast cancer imaging and treatment monitoring.

Abstract

Accurate assessment of human epidermal growth factor receptor type 2 (HER2) expression is crucial for diagnosis, treatment planning, and monitoring of breast cancer patients. A ⁶⁸Ga-labeled tracer based on the albumin-binding domain-derived affinity protein 6 (ADAPT6) was developed to evaluate HER2 expression in breast cancer. The gene encoding ADAPT6 was modified with N-terminal (GHEHEHEDANS) and C-terminal (GSSC) extensions to enhance its functionality. The precursor was synthesized, purified, and characterized, followed by radiolabeling with ⁶⁸Ga to produce [⁶⁸Ga]Ga-NODAGA-ADAPT6. In vivo metabolism and biodistribution studies were performed in HCC1954 (HER2-positive) and MDA-MB-468 (HER2-negative) tumor-bearing mice. Additionally, with ethical approval and informed consent, 22 breast cancer patients underwent [⁶⁸Ga]Ga-NODAGA-ADAPT6 PET imaging to assess HER2 expression in primary and metastatic lesions. The tracer was prepared with a radiochemical purity exceeding 99% and demonstrated high stability in vivo. Micro-PET/CT imaging revealed significant accumulation of the radiotracer in HCC1954 tumors, which was markedly reduced after HER2 blockade with trastuzumab. In contrast, MDA-MB-468 tumors showed minimal uptake. In the clinical study, [⁶⁸Ga]Ga-NODAGA-ADAPT6 PET images displayed varying levels of radiotracer uptake in primary and metastatic lesions, which correlated well with the HER2 expression status determined by pathological analysis. [⁶⁸Ga]Ga-NODAGA-ADAPT6 exhibited excellent pharmacokinetic properties and high specificity for HER2-expressing lesions in PET imaging. These findings highlight its potential as a promising tool for distinguishing different levels of HER2 expression in breast cancer, aiding in personalized treatment strategies.