Biodistribution of HuCC49DeltaCH2-beta-galactosidase in colorectal cancer xenograft model.
Antibody-enzyme conjugate (AbE) has been widely studied for site-specific prodrug activation in tumors. The purpose of this study is to characterize the pharmacokinetics and tissue distribution of HuCC49DeltaCH2-beta-galactosidase conjugate. HuCC49DeltaCH2 and beta-galactosidase were chemically conjugated and injected into a LS 174T colon cancer xenograft model. A colorimetric assay was developed to quantify the HuCC49DeltaCH2-beta-galactosidase levels in plasma and tissues. The HuCC49DeltaCH2-beta-galactosidase conjugate distributed into tumor tissue as early as 6h with the tumor/blood ratio of 5. This favored distribution of conjugate activity in the tumor tissue which was maintained up to 4 days post conjugate injection, while the conjugate was cleared rapidly from blood and other normal tissues (heart, spleen, lung, liver, kidney and stomach). At a high dose of 3000 U/kg, HuCC49DeltaCH2-beta-galactosidase conjugate saturated the antigen binding sites and yielded decreased tumor/normal tissue ratios compared to 1500 U/kg. These data suggest that HuCC49DeltaCH2-beta-galactosidase specifically target to the tumors to increase tumor selectivity.
Yu
Yanke
Y
Department of Pharmaceutical Sciences, College of Pharmacy, The University of Michigan, Ann Arbor, MI 48109, United States.
Fang
Lanyan
L
Sun
Duxin
D
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000912:Antibodies, Neoplasm / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D000951:Antigens, Neoplasm / Q000276:immunology; D001666:Binding Sites, Antibody; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000276:immunology / Q000378:metabolism*; D003124:Colorimetry; D005260:Female; D006023:Glycoproteins / Q000276:immunology; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D001616:beta-Galactosidase / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; C091202:B72.3 antibody; D006023:Glycoproteins; D018796:Immunoconjugates; C047052:tumor-associated antigen 72; D001616:beta-Galactosidase