Phase I Trial of 99mTc-(HE)3-G3, a DARPin-Based Probe for Imaging of HER2 Expression in Breast Cancer

Radionuclide molecular imaging of human epidermal growth factor receptor type 2 (HER2) expression may enable a noninvasive discrimination between HER2-positive and HER2-negative breast cancers for stratification of patients for HER2-targeted treatments. DARPin (designed ankyrin repeat proteins) G3 is a small (molecular weight, 14 kDa) scaffold protein with picomolar affinity to HER2. The aim of this first-in-humans study was to evaluate the safety, biodistribution, and dosimetry of Tc-99m-(HE)(3)-G3. Methods: Three cohorts of patients with primary breast cancer (each including at least 4 patients with HER2-negative and 5 patients with HER2-positive tumors) were injected with 1,000, 2,000, or 3,000 pg of Tc-99m-(HE)(3)-G3 (287 +/- 170 MBq). Whole body planar imaging followed by SPECT was performed at 2, 4, 6, and 24 h after injection. Vital signs and possible side effects were monitored during imaging and up to 7 d after injection. Results: All injections were well tolerated. No side effects were observed. The results of blood and urine analyses did not differ before and after studies. Tc-99m-(HE)(3)-G3 cleared rapidly from the blood. The highest uptake was detected in the kidneys and liver followed by the lungs, breasts, and small intestinal content. The hepatic uptake after injection of 2,000 or 3,000 pg was significantly (P < 0.05) lower than the uptake after injection of 1,000 pg. Effective doses did not differ significantly between cohorts (average, 0.011 +/- 0.004 mSv/MBq). Tumor-to-contralateral site ratios for HER positive tumors were significantly (P < 0.05) higher than for HER2-negative at 2 and 4 h after injection. Conclusion: Imaging of HER2 expression using Tc-99m-(HE)(3)-G3 is safe and well tolerated and provides a low absorbed dose burden on patients. This imaging enables discernment of HER2-positive and HER2-negative breast cancer. Phase I study data justify further clinical development of Tc-99m-(HE)(3)-G3.

Automated summary

The study evaluated the safety, biodistribution, and dosimetry of Tc-99m-(HE)(3)-G3 in breast cancer patients, showing that the imaging method provides a low absorbed dose burden on patients and is safe and well-tolerated.