title: Tissue distribution of humanized anti-human Fas monoclonal antibody (R-125224) based on fas antigen-antibody reaction in collagen-induced arthritis monkeys.
abstract: R-125224 is a novel humanized anti-human Fas monoclonal antibody prepared from HFE7A, which is a monoclonal mouse IgG anti-Fas antibody, by grafting the mouse complementarity-determining regions to human IgG, presently being developed as a drug for treatment of rheumatoid arthritis. In the present study, we investigated the tissue distribution of radioactivity in cynomolgus monkeys with collagen-induced arthritis at the arm joint (CIA monkeys) after intravenous administration of (125)I-labeled R-125224 ((125)I-R-125224). At 168 h after administration, we observed a high radioactivity in the bone marrow, thymus, lungs, liver, adrenals, spleen, ovaries, axillary lymph node and mesenteric lymph node compared to the radioactivity in the plasma. These tissues and organs in human are reported to express Fas antigen, strongly suggesting a specific binding of (125)I-R-125224 to Fas antigen in cynomolgus monkeys. Semi-micro autoradioluminograms of arm joint showed that radioactivity is detected in pharmacological site, such as the bone marrow and articular cavity at 168 h. The kinetics in binding of R-125224 to activated monkey lymphocytes and hepatocytes was also investigated. K(d) values of activated lymphocytes and hepatocytes were 1.51+/-0.08 and 0.60+/-0.11 nM, respectively, which were similar to those values in human lymphocytes and hepatocytes, demonstrating that R-125224 cross-reacts with the monkey Fas antigen.
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.
authors.forename: Motoko
authors.initials: M
authors.lastname: Saito
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yoshigae
authors.forename: Junichi
authors.initials: J
authors.lastname: Nakayama
authors.forename: Yukie
authors.initials: Y
authors.lastname: Ogawa
authors.forename: Masahiko
authors.initials: M
authors.lastname: Ohtsuki
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kurihara
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Ikeda
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology; D001853:Bone Marrow / Q000378:metabolism; D003429:Cross Reactions; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000097:blood / Q000378:metabolism*; D000882:Haplorhini; D006801:Humans; D007457:Iodine Radioisotopes / Q000032:analysis; D007596:Joints / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism; D008252:Macaca fascicularis; D051379:Mice; D016719:Radioimmunodetection; D013154:Spleen / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents; D053222:Fas Ligand Protein; D007457:Iodine Radioisotopes; C411023:anti-Fas monoclonal antibody