Properties of human IgG1s engineered for enhanced binding to the neonatal Fc receptor (FcRn)
Properties of human IgG1s engineered for enhanced binding to the neonatal Fc receptor (FcRn)
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DOI：
10.1074/jbc.m604292200
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发表时间：
2006-08-18
影响因子：
4.8
通讯作者：
Wu, Herren
中科院分区：
文献类型：
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作者：
Dall'Acqua, William F.;Kiener, Peter A.;Wu, Herren
我们在这里描述的功能的影响，在IgG结合新生儿Fc受体的增加。我们以系统的方式定义了人源化抗呼吸道合胞病毒（RSV）单克隆抗体（MEDI-524）的FcRn结合增强与食蟹猴中相应生物学后果之间的关系。将三重突变M252 Y/S254 T/T256 E（YTE）引入MEDI-524的Fc部分。尽管这些取代不影响MEDI-524与其同源抗原结合并抑制RSV复制的能力，但在pH 6.0下，它们导致其与食蟹猴和人FcRn的结合增加10倍。在两种情况下，在pH 7.4下，MEDI-524-YTE均从FcRn中有效释放。我们发现，与MEDI-524相比，MEDI-524-YTE在食蟹猴中的血清半衰期持续增加近4倍。这是迄今为止描述的灵长类动物中IgG的最大半衰期改善。我们首次证明，这些持续的血清水平导致肺生物利用度增加高达4倍。重要的是，我们还建立了我们的非人灵长类动物模型与人类相关。最后，我们报告了YTE三重取代提供了一种调节针对人整联蛋白α（v）β（3）的人源化IgG 1的抗体依赖性细胞介导的细胞毒性（ADCC）活性的方法。因此，YTE取代允许同时调节给定人IgG 1的血清半衰期、组织分布和活性。
We describe here the functional implications of an increase in IgG binding to the neonatal Fc receptor. We have defined in a systematic fashion the relationship between enhanced FcRn binding of a humanized anti-respiratory sincytial virus (RSV) monoclonal antibody (MEDI-524) and the corresponding biological consequences in cynomolgus monkeys. The triple mutation M252Y/S254T/T256E (YTE) was introduced into the Fc portion of MEDI-524. Whereas these substitutions did not affect the ability of MEDI-524 to bind to its cognate antigen and inhibit RSV replication, they resulted in a 10-fold increase in its binding to both cynomolgus monkey and human FcRn at pH 6.0. MEDI-524-YTE was efficiently released from FcRn at pH 7.4 in both cases. We show that MEDI-524-YTE consistently exhibited a nearly 4-fold increase in serum half-life in cynomolgus monkeys when compared with MEDI-524. This constituted the largest half-life improvement described to date for an IgG in a primate. For the first time, we demonstrate that these sustained serum levels resulted in an up to 4-fold increase in lung bioavailability. Importantly, we also establish that our non-human primate model is relevant to human. Finally, we report that the YTE triple substitution provided a means to modulate the antibody-dependent cell-mediated cytotoxicity (ADCC) activity of a humanized IgG1 directed against the human integrin alpha(v)beta(3). Therefore, the YTE substitutions allow the simultaneous modulation of serum half-life, tissue distribution and activity of a given human IgG1.