Development and characterization of clinical-grade 89Zr-trastuzumab for HER2/neu immunoPET imaging.
The anti-human epidermal growth factor receptor 2 (HER2/neu) antibody trastuzumab is administered to patients with HER2/neu-overexpressing breast cancer. Whole-body noninvasive HER2/neu scintigraphy could help to assess and quantify the HER2/neu expression of all lesions, including nonaccessible metastases. The aims of this study were to develop clinical-grade radiolabeled trastuzumab for clinical HER2/neu immunoPET scintigraphy, to improve diagnostic imaging, to guide antibody-based therapy, and to support early antibody development. The PET radiopharmaceutical (89)Zr-trastuzumab was compared with the SPECT tracer (111)In-trastuzumab, which we have tested in the clinic already.


METHODS
Trastuzumab was labeled with (89)Zr and (for comparison) with (111)In. The minimal dose of trastuzumab required for optimal small-animal PET imaging and biodistribution was determined with human HER2/neu-positive or -negative tumor xenograft-bearing mice.


RESULTS
Trastuzumab was efficiently radiolabeled with (89)Zr at a high radiochemical purity and specific activity. The antigen-binding capacity was preserved, and the radiopharmaceutical proved to be stable for up to 7 d in solvent and human serum. Of the tested protein doses, the minimal dose of trastuzumab (100 microg) proved to be optimal for imaging. The comparative biodistribution study showed a higher level of (89)Zr-trastuzumab in HER2/neu-positive tumors than in HER2/neu-negative tumors, especially at day 6 (33.4 +/- 7.6 [mean +/- SEM] vs. 7.1 +/- 0.7 percentage injected dose per gram of tissue). There were good correlations between the small-animal PET images and the biodistribution data and between (89)Zr-trastuzumab and (111)In-trastuzumab uptake in tumors (R(2) = 0.972).


CONCLUSIONS
Clinical-grade (89)Zr-trastuzumab showed high and HER2/neu-specific tumor uptake at a good resolution.
Dijkers
Eli C F
EC
Department of Hospital and Clinical Pharmacy, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Kosterink
Jos G W
JG
Rademaker
Anna P
AP
Perk
Lars R
LR
van Dongen
Guus A M S
GA
Bart
Joost
J
de Jong
Johan R
JR
de Vries
Elisabeth G E
EG
Lub-de Hooge
Marjolijn N
MN
D000818:Animals; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D004355:Drug Stability; D006801:Humans; D007150:Immunohistochemistry; D007553:Isotope Labeling; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D011786:Quality Control; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D014018:Tissue Distribution; D000068878:Trastuzumab; D015040:Zirconium
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D015040:Zirconium; C571668:zirconium-89-trastuzumab