发展motavizumab, ultra-potent抗体预防呼吸道合胞病毒感染的上、下呼吸道。

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吴H, Pfarr DS,约翰逊,Brewah是的,伍兹RM, Patel NK,白色WI,年轻的摩根富林明,齐纳尔PA

发展motavizumab, ultra-potent抗体预防呼吸道合胞病毒感染的上、下呼吸道。

J杂志。2007年5月4日,368 (3):652 - 65。Epub 2007 2月20。

PubMed ID

17362988 (在PubMed

]

文摘

呼吸道合胞病毒(RSV)是病毒的主要原因在婴幼儿毛细支气管炎和肺炎。目前,palivizumab是唯一批准的单克隆抗体(mAb)预防RSV。但是,一小部分患者不受palivizumab保护;此外,palivizumab不能有效地抑制RSV复制上呼吸道。我们报告的开发和表征motavizumab, ultra-potent, affinity-matured,人性化马伯源自palivizumab。几个palivizumab变异,提高体外RSV的中和了44-fold生成;然而,体内预防棉花有这些抗体授予的老鼠只有在palivizumab双重的改善能力。这意想不到的小增加体内效力是由贫穷引起血清药物动力学以及所导致的肺bio-availability出人意料地广泛组织约束力。后续分析显示,三个氨基酸的变化产生的亲和力成熟明显增加各种组织的非特异性结合。我们的研究结果表明,k(上)简况突变更容易启动非特异性绑定事件比k(关上)简况突变。 Reversion of these three residues to the original sequences greatly diminished the tissue binding. The resulting mAb, motavizumab, binds to RSV F protein 70-fold better than palivizumab, and exhibits about a 20-fold improvement in neutralization of RSV in vitro. In cotton rats, at equivalent concentrations, motavizumab reduced pulmonary RSV titers to up to 100-fold lower levels than did palivizumab and, unlike palivizumab, motavizumab very potently inhibited viral replication in the upper respiratory tract. This affinity-enhanced mAb is being investigated in pivotal clinical trials. Importantly, our engineering process offers precious insights into the improvement of other therapeutic mAbs.

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药物

Motavizumab