Biodistribution and pharmacokinetics of 125I-labeled monoclonal antibody M75 specific for carbonic anhydrase IX, an intrinsic marker of hypoxia, in nude mice xenografted with human colorectal carcinoma.
Carbonic anhydrase IX (CA IX) is frequently expressed in human carcinomas and absent from the corresponding normal tissues. Strong induction by tumor hypoxia predisposes CA IX to serve as a target for cancer diagnostics and therapy. Here we evaluated targeting properties and pharmacokinetics of CA IX-specific monoclonal antibody (MAb) M75. Binding parameters of (125)I-labeled M75, including equilibrium dissociation constant, hypoxia-related binding to various cell lines and internalization, were analyzed in vitro. Biodistribution of (125)I-M75 in nude mice bearing HT-29 human colorectal carcinoma xenografts with hypoxic pattern of CA IX expression was studied by measurements of radioactivity in dissected tissues and macroautoradiography of tissue sections. Pharmacokinetics of intravenously administered (125)I-M75 was described using a 2-compartment model. Blood clearance showed a distribution phase t(1/2)(alpha) = 3.4 hr and an elimination phase t(1/2)(beta) = 55.3 hr postinjection. Despite predominant CA IX localization in less accessible perinecrotic regions, (125)I-M75 exhibited specific accumulation in xenograft, with a mean uptake of 15.3 +/- 3.6% of injected dose per gram of tumor tissue at 48 hr postadministration. Specificity of M75 localization was confirmed by low tumor uptake of control antibody. Altogether, our data demonstrate that M75 MAb is a promising tool for selective immunotargeting of hypoxic human tumors that express CA IX.
Chrastina
Adrián
A
Centre of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovak Republic.
Závada
Jan
J
Parkkila
Seppo
S
Kaluz
Stefan
S
Kaluzová
Milota
M
Rajcáni
Július
J
Pastorek
Jaromír
J
Pastoreková
Silvia
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000493:pharmacokinetics*; D000918:Antibody Specificity; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D001345:Autoradiography; D014408:Biomarkers, Tumor / Q000276:immunology* / Q000378:metabolism; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000276:immunology* / Q000378:metabolism; D002277:Carcinoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D007457:Iodine Radioisotopes; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000276:immunology* / Q000378:metabolism; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D007457:Iodine Radioisotopes; C475102:M75 monoclonal antibody; D009363:Neoplasm Proteins; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases