High-mannose glycans on the Fc region of therapeutic IgG antibodies increase serum clearance in humans
High-mannose glycans on the Fc region of therapeutic IgG antibodies increase serum clearance in humans
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DOI：
10.1093/glycob/cwr027
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发表时间：
2011-07-01
期刊：
影响因子：
4.3
通讯作者：
Flynn, Gregory C.
中科院分区：
文献类型：
--
作者：
Goetze, Andrew M.;Liu, Y. Diana;Flynn, Gregory C.
与免疫球蛋白G（IgG）Fc区C（H）2结构域连接的聚糖结构对于特异性效应子功能至关重要，但其在调节清除中的作用尚不清楚。清除对于治疗性单克隆抗体（Mab）是明显重要的，因为它直接影响疗效。在此，我们研究了Fc聚糖结构对人体中4种治疗性人IgG（1种IgG1和3种IgG2）清除率的影响。从人药代动力学研究的血清样品中亲和纯化治疗性IgG，并采用高分辨率质谱法通过肽图谱测定聚糖谱随时间的变化。高甘露糖5（M5）聚糖的相对水平随循环时间的变化而降低，而其他聚糖保持不变。这些结果表明，含有Fc高甘露糖聚糖的治疗性IgG在人体中比其他聚糖形式更快地清除。计算了其对药代动力学曲线下面积的定量影响，结果表明，对于所研究的四种分子中的三种分子，其影响相对较小，但根据给药方案和高甘露糖聚糖的相对水平，这也可能产生显著影响。治疗性单克隆抗体的高甘露糖含量应被视为重要的产品质量属性，可能影响治疗性抗体的药代动力学特性。
Glycan structures attached to the C(H)2 domain of the Fc region of immunoglobulin G (IgG) are essential for specific effector functions but their role in modulating clearance is less clear. Clearance is of obvious importance for therapeutic monoclonal antibodies (Mabs) as it directly impacts efficacy. Here, we study the impact of Fc glycan structure on the clearance of four therapeutic human IgGs (one IgG1 and three IgG2s) in humans. The therapeutic IgGs were affinity purified from serum samples from human pharmacokinetic studies, and changes to the glycan profile over time were determined by peptide mapping employing high-resolution mass spectrometry. Relative levels of high-mannose 5 (M5) glycan decreased as a function of circulation time, whereas other glycans remained constant. These results demonstrate that therapeutic IgGs containing Fc high-mannose glycans are cleared more rapidly in humans than other glycan forms. The quantitative effect of this on pharmacokinetic area under the curve was calculated and shown to be relatively minor for three of the four molecules studied, but, depending on the dosing regimen and the relative level of the high-mannose glycan, this can also have significant impact. High-mannose content of therapeutic Mabs should be considered an important product quality attribute which may affect pharmacokinetic properties of therapeutic antibodies.