Biodistributions of 177Lu- and 111In-labeled 7E11 antibodies to prostate-specific membrane antigen in xenograft model of prostate cancer and potential use of 111In-7E11 as a pre-therapeutic agent for 177Lu-7E11 radioimmunotherapy.
BACKGROUND
Prostate-specific membrane antigen is a transmembrane glycoprotein highly expressed in many prostate cancers and can be targeted with radiolabeled antibodies for diagnosis and treatment of this disease. To serve as a radioimmunotherapeutic agent, a kinetically inert conjugate is desired to maximize tumor uptake and tumor radiation dose with minimal nonspecific exposure to bone marrow and other major organs.


METHODS
In this study, we assessed the pharmacokinetics and biodistribution of the 7E11 monoclonal antibody (MAb) radiolabeled with the lutetium-177 ((177)Lu)-tetraazacyclododecanetetraacetic acid conjugate system ((177)Lu-7E11) versus those of the 7E11 MAb radiolabeled with the indium-111 ((111)In)/glycyl-tyrosyl-(N,-diethylenetriaminepentaacetic acid)/lysine hydrochloride conjugate system ((111)In-7E11, also known as ProstaScint) to determine the feasibility of using (111)In-7E11 as a pre-therapeutic agent for (177)Lu-7E11 radioimmunotherapy. Pharmacokinetic and biodistribution studies of (177)Lu-7E11 in lymph node cancer of the prostate (LNCaP) xenograft mice were performed at 2, 8, 12, 24, 72, and 168 h after radiopharmaceutical administration. For (111)In-7E11, pharmacokinetic and biodistribution studies were performed at 8, 24, and 72 h. Parallel studies of (177)Lu-7E11 in non-tumor-bearing mice at 8, 24, and 72 h post-injection served as controls. Gamma scintigraphy was performed, followed by autoradiography and tissue counting, to demonstrate and quantify the distributions of radioconjugated MAb in the tumor and normal tissues.


CONCLUSIONS
Both (177)Lu- and (111)In-7E11 conjugates demonstrated an early blood pool phase in which uptake was dominated by the blood, lung, spleen and liver, followed by uptake and retention of the radiolabeled antibody in the tumor which was most prominent at 24 h. Total accumulation of radioconjugated MAb in tumor at 24 h was greater in the case of (177)Lu-7E11 in comparison to that of (111)In-7E11. Continued accumulation in tumor was observed for the entire time course studied for both (177)Lu-7E11 and (111)In-7E11. The liver was the only major organ demonstrating a significant difference in accumulation between the two conjugates. In conclusion, pharmacokinetic and biodistribution studies of (177)Lu-7E11 in LNCaP xenograft mouse models support its potential application as a radioimmunotherapeutic agent targeting prostate cancer, and the distribution and tumor uptake of (111)In-7E11 appear to be similar to those of (177)Lu-7E11, supporting its use as a pre-therapeutic tool to assess the potential accumulation of (177)Lu-7E11 radioimmunotherapeutic at sites of prostate cancer. However, the different accumulation patterns of the (111)In and (177)Lu immunoconjugates in liver will likely prevent the use of (111)In-7E11 as a true dosimetry tool for (177)Lu-7E11 radioimmunotherapy.
Pan
Mei-Hsiu
MH
Center for Molecular and Functional Imaging, Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94143, USA.
Gao
Dong-Wei
DW
Feng
Jinjin
J
He
Jiang
J
Seo
Youngho
Y
Tedesco
John
J
Wolodzko
John G
JG
Hasegawa
Bruce H
BH
Franc
Benjamin L
BL
D000818:Animals; D000911:Antibodies, Monoclonal; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007205:Indium Radioisotopes / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008099:Liver / Q000378:metabolism; D008187:Lutetium / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D017430:Prostate-Specific Antigen / Q000276:immunology*; D011471:Prostatic Neoplasms / Q000532:radiotherapy*; D016499:Radioimmunotherapy / Q000379:methods*; D011868:Radioisotopes / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; D007205:Indium Radioisotopes; D011868:Radioisotopes; D008187:Lutetium; D017430:Prostate-Specific Antigen