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

• Published in: International journal of cancer 2003-07, Vol.105 (6), p.873-881
• Main Authors: Chrastina, Adrián, Závada, Jan, Parkkila, Seppo, Kaluz, Štefan, Kaluzová, Milota, Rajčáni, Július, Pastorek, Jaromír, Pastoreková, Silvia
• Format: Article
• Language: English
• Subjects: Animal tumors. Experimental tumors; Animals; Antibodies, Monoclonal - metabolism; Antibodies, Monoclonal - pharmacokinetics; Antibody Specificity; Antigens, Neoplasm - immunology; Antigens, Neoplasm - metabolism; Autoradiography; biodistribution; Biological and medical sciences; Biomarkers, Tumor - immunology; Biomarkers, Tumor - metabolism; Carbonic Anhydrase IX; Carbonic Anhydrases - immunology; Carbonic Anhydrases - metabolism; Carcinoma - enzymology; Carcinoma - metabolism; Carcinoma - pathology; Cell Hypoxia; Colorectal Neoplasms - enzymology; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Experimental tumors, general aspects; HT29 Cells; Humans; hypoxia; Immunohistochemistry; Iodine Radioisotopes; Kinetics; M75 monoclonal antibody; Medical sciences; Mice; Mice, Nude; Neoplasm Proteins - immunology; Neoplasm Proteins - metabolism; pharmacokinetics; Tissue Distribution; Tumor Cells, Cultured; tumor targeting; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.11142

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 125I‐labeled M75, including equilibrium dissociation constant, hypoxia‐related binding to various cell lines and internalization, were analyzed in vitro. Biodistribution of 125I‐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 125I‐M75 was described using a 2‐compartment model. Blood clearance showed a distribution phase t1/2(α) = 3.4 hr and an elimination phase t1/2(β) = 55.3 hr postinjection. Despite predominant CA IX localization in less accessible perinecrotic regions, 125I‐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. © 2003 Wiley‐Liss, Inc.