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

The Journal of Nuclear Medicine

article

Olga Bragina¹  Vladimir Chernov¹  Alexey Schulga²  Elena Konovalova³  Eugeniy Garbukov⁴  Anzhelika Vorobyeva²  Anna Orlova²  Liubov Tashireva⁵  Jens Sörensen⁶  Roman Zelchan¹  Anna Medvedeva¹  Sergey Deyev²  Vladimir Tolmachev² 

[1] Department of Nuclear Medicine, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences;Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University;Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences;Department of General Oncology, Cancer Research Institute, Tomsk National Research Medical Center Russian Academy of Sciences;Department of General and Molecular Pathology, Tomsk National Research Medical Center;Radiology and Nuclear Medicine, Department of Surgical Sciences, Uppsala University

关键词: HER2;    DARPin G3;    99mTc;    SPECT;    phase I;   

DOI  :  10.2967/jnumed.121.262542

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

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 99mTc-(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 μg of 99mTc-(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. 99mTc-(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 μg was significantly (P < 0.05) lower than the uptake after injection of 1,000 μg. 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 99mTc-(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 99mTc-(HE)3-G3.

【 授权许可】

CC BY