期刊
LIFE SCIENCES
卷 80, 期 22, 页码 2005-2014出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.lfs.2007.02.043
关键词
tissue distribution; anti-Fas monoclonal antibody; collagen-induced arthritis; monkey; pharmacokinetics
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 I-125-labeled R-125224 (I-125-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 I-125-R-125224 to Fas antigen in cynomolgus monkeys. Semi-micro autoradioluminograms of anti 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. Kd 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-I 25224 cross-reacts with the monkey Fas antigen. (c) 2007 Published by Elsevier Inc.
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