Anti-serum albumin domain antibodies for extending the half-lives of short lived drugs
Anti-serum albumin domain antibodies for extending the half-lives of short lived drugs
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DOI：
10.1093/protein/gzm067
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发表时间：
2008-05-01
影响因子：
2.4
通讯作者：
Tomlinson, Ian M.
中科院分区：
文献类型：
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作者：
Holt, Lucy J.;Basran, Amrik;Tomlinson, Ian M.
我们已经使用噬菌体展示来分离一系列与小鼠、大鼠和/或人血清白蛋白（SA）结合并且可以在细菌、酵母或哺乳动物细胞培养物中以非常高的水平表达的人域抗体（dAb）。与具有小于45分钟的终末半衰期的非SA结合dAb相反，这些12 kDa“AlbudAb”的半衰期可以匹配SA本身的半衰期。为了证明AlbudAb用于延长治疗药物的半衰期，我们创建了白细胞介素-1受体拮抗剂（IL-1 ra）与AlbudAb的融合物。可溶性IL-1 ra是IL-1信号传导的有效抑制剂，其被批准用于治疗类风湿性关节炎，但具有相对短的体内半衰期。在这里，我们表明，虽然AlbudAb/IL-1 ra融合具有相似的体外效力，但由于其延长的血清半衰期，其体内功效可以显著提高。AlbudAb可能用于产生许多不同药物的一系列长半衰期版本，以改善其给药方案和/或临床效果。
We have used phage display to isolate a range of human domain antibodies (dAbs) that bind to mouse, rat and/or human serum albumin (SA) and can be expressed at very high levels in bacterial, yeast or mammalian cell culture. In contrast to non-SA-binding dAbs, which have terminal half-lives of less than 45 min, the half-lives of these 12 kDa `AlbudAbs' can match the half-life of SA itself. To demonstrate the use of AlbudAbs for extending the half-lives of therapeutic drugs, we created a fusion of the interleukin-1 receptor antagonist (IL-1ra) with an AlbudAb. Soluble IL-1ra is potent inhibitor of IL-1 signalling that is approved for the treatment of rheumatoid arthritis but has a relatively short in vivo half-life. Here we show that although the AlbudAb/IL-1ra fusion has a similar in vitro potency, its in vivo efficacy can be dramatically improved due to its extended serum half-life. AlbudAbs could potentially be used to generate a range of long half-life versions of many different drugs in order to improve their dosing regimen and/or clinical effect.