Merck BioProcess Development, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Merck BioProcess Development, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA; Gilead Bioscience, Inc, 4049 Avenida de la Plata Oceanside, CA 92056, USA.
Curr Opin Biotechnol. 2014 Dec;30:225-9. doi: 10.1016/j.copbio.2014.09.001. Epub 2014 Sep 23.
Half molecule exchange is the process whereby two IgG4 molecules exchange a heavy chain-light chain unit to form a new IgG4 entity with specificity towards two different antigens. While this unique property of IgG4 molecules confers anti-inflammatory properties in nature, it is not a desirable feature for a therapeutic mAb. Engineering of the IgG4 hinge region making it resemble that of an IgG1 is sufficient to dramatically reduce half molecule exchange in vitro and in vivo. The S228P modification of the hinge confers pharmaceutical properties to IgG4 equivalent to those of standard IgG1, while retaining the inability to trigger ADCC and CDC. Application of the molecular precepts underlying half molecule exchange between IgG4 molecules to IgG1 scaffolds offers the possibility to produce bispecific antibodies in vitro.
半分子交换是指两个 IgG4 分子交换重链-轻链单位，形成对两个不同抗原具有特异性的新 IgG4 实体的过程。虽然这种 IgG4 分子的独特特性在自然界中赋予了抗炎特性，但对于治疗性单抗来说并不是一个理想的特性。对 IgG4 铰链区进行工程改造，使其类似于 IgG1，足以在体外和体内显著降低半分子交换。铰链区 S228P 的修饰赋予 IgG4 与标准 IgG1 相当的药物特性，同时保留了不能触发 ADCC 和 CDC 的能力。将 IgG4 分子之间半分子交换的分子原理应用于 IgG1 支架，为体外产生双特异性抗体提供了可能。
