Labrijn Aran F, Buijsse Antonio Ortiz, van den Bremer Ewald T J, Verwilligen Annemiek Y W, Bleeker Wim K, Thorpe Susan J, Killestein Joep, Polman Chris H, Aalberse Rob C, Schuurman Janine, van de Winkel Jan G J, Parren Paul W H I
Genmab, Utrecht, The Netherlands.
Nat Biotechnol. 2009 Aug;27(8):767-71. doi: 10.1038/nbt.1553. Epub 2009 Jul 20.
Two humanized IgG4 antibodies, natalizumab and gemtuzumab, are approved for human use, and several others, like TGN1412, are or have been in clinical development. Although IgG4 antibodies can dynamically exchange half-molecules, Fab-arm exchange with therapeutic antibodies has not been demonstrated in humans. Here, we show that natalizumab exchanges Fab arms with endogenous human IgG4 in natalizumab-treated individuals. Gemtuzumab, in contrast, contains an IgG4 core-hinge mutation that blocks Fab-arm exchange to undetectable levels both in vitro and in a mouse model. The ability of IgG4 therapeutics to recombine with endogenous IgG4 may affect their pharmacokinetics and pharmacodynamics. Although pharmacokinetic modeling lessens concerns about undesired cross-linking under normal conditions, unpredictability remains and mutations that completely prevent Fab-arm exchange in vivo should be considered when designing therapeutic IgG4 antibodies.
两种人源化IgG4抗体，那他珠单抗和吉妥珠单抗，已被批准用于人类，还有其他几种，如TGN1412，正在或已经处于临床开发阶段。尽管IgG4抗体可以动态交换半分子，但治疗性抗体的Fab臂交换在人类中尚未得到证实。在此，我们表明那他珠单抗在接受那他珠单抗治疗的个体中与内源性人IgG4进行Fab臂交换。相比之下，吉妥珠单抗含有一个IgG4核心铰链突变，在体外和小鼠模型中均可将Fab臂交换阻断至无法检测的水平。IgG4治疗药物与内源性IgG4重组的能力可能会影响其药代动力学和药效学。尽管药代动力学建模减轻了对正常情况下不期望的交联的担忧，但不可预测性仍然存在，在设计治疗性IgG4抗体时应考虑完全阻止体内Fab臂交换的突变。
