We previously reported that microSPECT/CT imaging with 111In-labeled
pertuzumab detected decreased HER2 expression in human
breast cancer (BC) xenografts in athymic mice associated with response to treatment with
trastuzumab (
Herceptin). Our aim was to extend these results to PET/CT by constructing F(ab')2 of
pertuzumab modified with
NOTA chelators for complexing 64Cu. The effect of the administered mass (5-200 µg) of 64Cu-NOTA-pertuzumab F(ab')2 was studied in NOD/SCID mice engrafted with HER2-positive SK-OV-3 human
ovarian cancer xenografts. Biodistribution studies were performed in non-
tumor bearing Balb/c mice to predict radiation doses to normal organs in humans. Serial PET/CT imaging was conducted on mice engrafted with HER2-positive and
trastuzumab-sensitive BT-474 or
trastuzumab-insensitive SK-OV-3 xenografted mice treated with weekly doses of
trastuzumab. There were no significant effects of the administered mass of 64Cu-NOTA-pertuzumab F(ab')2 on
tumor or normal tissue uptake. The predicted total body dose in humans was 0.015 mSv/MBq, a 3.3-fold reduction compared to 111In-labeled
pertuzumab. MicroPET/CT images revealed specific
tumor uptake of 64Cu-NOTA-pertuzumab F(ab')2 at 24 or 48 h post-injection in mice with SK-OV-3
tumors. Image analysis of mice treated with
trastuzumab showed 2-fold reduced uptake of 64Cu-NOTA-pertuzumab F(ab')2 in BT-474
tumors after 1 week of
trastuzumab normalized to baseline, and 1.9-fold increased uptake in SK-OV-3
tumors after 3 weeks of
trastuzumab, consistent with
tumor response and resistance, respectively. We conclude that PET/CT imaging with 64Cu-NOTA-pertuzumab F(ab')2 detected changes in HER2 expression in response to
trastuzumab while delivering a lower total body radiation dose compared to 111In-labeled
pertuzumab.