Phase I Study of ^99mTc-ADAPT6, a Scaffold Protein–Based Probe for Visualization of HER2 Expression in Breast Cancer

Abstract

Radionuclide molecular imaging of human epidermal growth factor receptor type 2 (HER2) expression may help to stratify breast and gastroesophageal cancer patients for HER2-targeting therapies. Albumin-binding domain-derived affinity proteins (ADAPTs) are a new type of small (46-59 amino acids) protein useful as probes for molecular imaging. The aim of this first-in-humans study was to evaluate the biodistribution, dosimetry, and safety of the HER2-specific 99m Tc-ADAPT6. Methods: Twenty-nine patients with primary breast cancer were included. In 22 patients with HER2-positive (n 5 11) or HER2-negative (n 5 11) histopathology, an intravenous injection of 385 125 MBq of 99m Tc-ADAPT6 was performed, randomized to an injected protein mass of either 500 g (n 5 11) or 1,000 g (n 5 11). Planar scintigraphy followed by SPECT imaging was performed after 2, 4, 6, and 24 h. An additional cohort (n 5 7) was injected with 165 29 MBq (injected protein mass, 250 g), and imaging was performed after 2 h only. Results: Injections of 99m Tc-ADAPT6 were well tolerated at all mass levels and not associated with adverse effects. 99m Tc-ADAPT6 cleared rapidly from the blood and most other tissues. The normal organs with the highest accumulation were the kidney, liver, and lung. Effective doses were 0.009 0.002 and 0.010 0.003 mSv/MBq for injected protein masses of 500 and 1,000 g, respectively. Injection of 500 g resulted in excellent discrimination between HER2-positive and HER2-negative tumors as early as 2 h after injection (tumor-to-contralateral breast ratio, 37 19 vs. 5 2; P , 0.01). The tumor-to-contralateral breast ratios for HER2-positive tumors were significantly (P , 0.05) higher for an injected mass of 500 g than for either 250 or 1,000 g. Conclusion: Injections of 99m Tc-ADAPT6 are safe and associated with low absorbed and effective doses. A protein dose of 500 g is preferable for discrimination between tumors with high and low expression of HER2. Further studies are justified to evaluate whether 99m Tc-ADAPT6 can be used as an imaging probe to stratify patients for HER2-targeting therapy in areas where PET imaging is not readily available.