Tissue distribution of humanized anti-human Fas monoclonal antibody (R-125224) based on fas antigen-antibody reaction in collagen-induced arthritis monkeys
Tissue distribution of humanized anti-human Fas monoclonal antibody (R-125224) based on fas antigen-antibody reaction in collagen-induced arthritis monkeys
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DOI：
10.1016/j.lfs.2007.02.043
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发表时间：
2007-05-08
期刊：
影响因子：
6.1
通讯作者：
Ikeda, Toshihiko
中科院分区：
文献类型：
--
作者：
Saito, Motoko;Yoshigae, Yasushi;Ikeda, Toshihiko
R-125224是一种新的人源化抗人Fas单克隆抗体，它是从HFE 7A制备的，HFE 7A是一种单克隆小鼠IgG抗Fas抗体，通过将小鼠互补决定区移植到人IgG上，目前正在开发作为治疗类风湿性关节炎的药物。在本研究中，我们研究了I-125标记的R-125224（I-125-R-125224）静脉给药后患胶原诱导关节炎的食蟹猴（CIA猴）的放射性组织分布。给药后168 h，我们在骨髓、胸腺、肺、肝脏、肾上腺、脾脏、卵巢、腋窝淋巴结和肠系膜淋巴结中观察到的放射性高于血浆中的放射性。据报道，这些人体组织和器官表达Fas抗原，强烈表明I-125-R-125224与食蟹猴中Fas抗原特异性结合。抗关节半微量放射自发光显示168 h时在骨髓和关节腔等药理部位检测到放射性。还研究了R-125224与活化猴淋巴细胞和肝细胞结合的动力学。活化淋巴细胞和肝细胞的Kd值分别为1.51 +/- 0.08和0.60 +/- 0.11 nM，与人淋巴细胞和肝细胞中的值相似，表明R-I 25224与猴Fas抗原交叉反应。(c)2007年由Elsevier Inc.出版
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.