PET imaging of prostate cancer xenografts with a highly specific antibody against the prostate-specific membrane antigen.
Prostate-specific membrane antigen (PSMA), a transmembrane glycoprotein, is highly expressed by virtually all prostate cancers and is currently the focus of several diagnostic and therapeutic strategies. We have previously reported on the generation of several monoclonal antibodies (mAb) and antibody fragments that recognize and bind with high affinity to the extracellular domain of cell-adherent PSMA. This article reports the in vivo behavior and tumor uptake of the radiolabeled anti-PSMA mAb 3/A12 and its potential as a tracer for PET.


METHODS
The mAb 3/A12 was conjugated with the chelating agent 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) and radiolabeled with (64)Cu. Severe combined immunodeficient mice bearing PSMA-positive C4-2 prostate carcinoma xenografts were used for small-animal PET imaging. Mice with PSMA-negative DU 145 tumors served as controls. For PET studies, each animal received 20-30 microg of radiolabeled mAb corresponding to an activity of 7.6-11.5 MBq. Imaging was performed 3, 24, and 48 h after injection. After the last scan, the mice were sacrificed and tracer in vivo biodistribution was measured by gamma-counting.


RESULTS
Binding of the mAb 3/A12 on PSMA-expressing C4-2 cells was only minimally influenced by DOTA conjugation. The labeling efficiency using (64)Cu and DOTA-3/A12 was 95.3% +/- 0.3%. The specific activity after (64)Cu labeling was between 327 and 567 MBq/mg. After tracer injection, static small-animal PET images of mice with PSMA-positive tumors revealed a tumor-to-background ratio of 3.3 +/- 1.3 at 3 h, 7.8 +/- 1.4 at 24 h, and 9.6 +/- 2.7 at 48 h. In contrast, no significant tracer uptake occurred in the PSMA-negative DU 145 tumors. These results were confirmed by direct counting of tissues after the final imaging.


CONCLUSIONS
Because of the high and specific uptake of (64)Cu-labeled mAb 3/A12 in PSMA-positive tumors, this ligand represents an excellent candidate for prostate cancer imaging and potentially for radioimmunotherapy.
Elsässer-Beile
Ursula
U
Department of Urology, University of Freiburg, Freiburg, Germany.
Reischl
Gerald
G
Wiehr
Stefan
S
Bühler
Patrick
P
Wolf
Philipp
P
Alt
Karen
K
Shively
John
J
Judenhofer
Martin S
MS
Machulla
Hans-Jürgen
HJ
Pichler
Bernd J
BJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics; D003301:Copper Radioisotopes / Q000493:pharmacokinetics; D007089:Image Enhancement / Q000379:methods; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D016513:Mice, SCID; D009928:Organ Specificity; D049268:Positron-Emission Tomography / Q000379:methods*; D017430:Prostate-Specific Antigen / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D003301:Copper Radioisotopes; D019275:Radiopharmaceuticals; D017430:Prostate-Specific Antigen