Development and preclinical studies of64Cu-NOTA-pertuzumab F(ab')2for imaging changes in tumor HER2 expression associated with response to trastuzumab by PET/CT.
We previously reported that microSPECT/CT imaging with111In-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')2of pertuzumab modified with NOTA chelators for complexing64Cu. The effect of the administered mass (5-200 µg) of64Cu-NOTA-pertuzumab F(ab')2was 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 of64Cu-NOTA-pertuzumab F(ab')2on tumor or normal tissue uptake. The predicted total body dose in humans was 0.015 mSv/MBq, a 3.3-fold reduction compared to111In-labeled pertuzumab. MicroPET/CT images revealed specific tumor uptake of64Cu-NOTA-pertuzumab F(ab')2at 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 of64Cu-NOTA-pertuzumab F(ab')2in 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 with64Cu-NOTA-pertuzumab F(ab')2detected changes in HER2 expression in response to trastuzumab while delivering a lower total body radiation dose compared to111In-labeled pertuzumab.
a Department of Pharmaceutical Sciences , University of Toronto , Toronto , ON , Canada.
Karen
K
Lam
a Department of Pharmaceutical Sciences , University of Toronto , Toronto , ON , Canada.
Conrad
C
Chan
a Department of Pharmaceutical Sciences , University of Toronto , Toronto , ON , Canada.|b Department of Medical Imaging , University of Toronto , Toronto , ON , Canada.|c Toronto General Research Institute, University Health Network , Toronto , ON , Canada.
Raymond M
RM
Reilly
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D003301:Copper Radioisotopes / Q000493:pharmacokinetics; D003952:Diagnostic Imaging / Q000379:methods*; D005260:Female; D006571:Heterocyclic Compounds / Q000493:pharmacokinetics; D006573:Heterocyclic Compounds, 1-Ring; D064593:Heterografts; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics*; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000000981:diagnostic imaging*; D000072078:Positron Emission Tomography Computed Tomography / Q000379:methods; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*
D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D003301:Copper Radioisotopes; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D018796:Immunoconjugates; D007140:Immunoglobulin Fab Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; C048993:1,4,7-triazacyclononane-N,N',N''-triacetic acid; C508053:ERBB2 protein, human; C485206:pertuzumab
Copper-64; HER2; PET; molecular imaging; pertuzumab; radiation dosimetry; trastuzumab