Dall'Acqua William F, Kiener Peter A, Wu Herren
Department of Antibody Discovery and Protein Engineering, MedImmune, Inc., Gaithersburg, Maryland 20878, USA. dall'
J Biol Chem. 2006 Aug 18;281(33):23514-24. doi: 10.1074/jbc.M604292200. Epub 2006 Jun 21.
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 syncytial 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)beta3. Therefore, the YTE substitutions allow the simultaneous modulation of serum half-life, tissue distribution and activity of a given human IgG1.
我们在此描述了IgG与新生儿Fc受体结合增加所产生的功能影响。我们以系统的方式确定了人源化抗呼吸道合胞病毒（RSV）单克隆抗体（MEDI-524）增强的FcRn结合与其在食蟹猴中相应生物学后果之间的关系。三重突变M252Y/S254T/T256E（YTE）被引入到MEDI-524的Fc部分。虽然这些取代不影响MEDI-524结合其同源抗原和抑制RSV复制的能力，但它们导致其在pH 6.0时与食蟹猴和人FcRn的结合增加了10倍。在这两种情况下，MEDI-524-YTE在pH 7.4时都能有效地从FcRn中释放出来。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了近4倍。这是迄今为止在灵长类动物中描述的IgG半衰期最大的改善。我们首次证明，这些持续的血清水平导致肺部生物利用度提高了4倍。重要的是，我们还证实我们的非人灵长类动物模型与人类相关。最后，我们报告YTE三重取代提供了一种调节针对人整合素α(v)β3的人源化IgG1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IgG1的血清半衰期、组织分布和活性。
