Increased serum clearance of oligomannose species present on a human IgG1 molecule.
Increased serum clearance of oligomannose species present on a human IgG1 molecule.
复制标题
人IgG1分子上存在的寡聚物种的血清清除率增加。
作者：
Alessandri L;Ouellette D;Acquah A;Rieser M;Leblond D;Saltarelli M;Radziejewski C;Fujimori T;Correia I
在临床前或临床药代动力学（PK）研究中，不同的实验小组已经研究了Fc聚糖对IgG分子清除的作用，这些实验中富集了特定的聚糖或研究了给药后的全谱聚糖。这些研究的总体结论并不一致，这可能是由于抗体结构或实验设计的差异。在本研究中，从人类PK研究中获得的血清样本中分析了一个具有良好特征的重组单克隆IgG1分子（mAb-1）。利用与Sepharose珠交联的配体从血清中回收mAb-1。使用各种方法仔细评估所有同种异构体的总体纯度和回收率。然后酶解多糖，用2-氨基苯甲酰胺标记，用正相高效液相色谱分析。从血清中回收mAb-1的试验和随后的聚糖分析严格合格，定量下限为15 μg/mL，因此可以在临床PK研究的第14天进行分析。对8种聚糖进行监测，并将其分为两组：(1)低聚糖型结构（M5、M6和M7）和(2)聚焦双天线低聚糖（FBO）结构（NGA2F、NA1F、NA2F、NA1F- glcnac和NGA2F- glcnac）。我们观察到低甘露糖种类的清除率（40%）比FBOs快得多，并得出结论，高甘露糖种类应仔细监测和控制，因为它们可能影响治疗药的PK；因此，它们应该被视为一个重要的质量属性。这些观察只有通过应用严格的分析方法才能实现，我们认为在比较创新分子和生物类似物分子时需要使用这些分析方法。
The role of Fc glycans on clearance of IgG molecule has been examined by various groups in experiments where specific glycans have been enriched or the entire spectrum of glycans was studied after administration in pre-clinical or clinical pharmacokinetic (PK) studies. The overall conclusions from these studies are inconsistent, which may result from differences in antibody structure or experimental design. In the present study a well-characterized recombinant monoclonal IgG1 molecule (mAb-1) was analyzed from serum samples obtained from a human PK study. mAb-1 was recovered from serum using its ligand cross-linked to Sepharose beads. The overall purity and recovery of all isoforms were carefully evaluated using a variety of methods. Glycans were then enzymatically cleaved, labeled using 2-aminobenzamide and analyzed by normal phase high performance liquid chromatography. The assays for recovering mAb-1 from serum and subsequent glycan analysis were rigorously qualified at a lower limit of quantitation of 15 μg/mL, thus permitting analysis to day 14 of the clinical PK study. Eight glycans were monitored and classified into two groups: (1) the oligomannose type structures (M5, M6 and M7) and (2) fucosylated biantennary oligosaccharides (FBO) structures (NGA2F, NA1F, NA2F, NA1F-GlcNAc and NGA2F-GlcNAc). We observed that the oligomannose species were cleared at a much faster rate (40%) than FBOs and conclude that high mannose species should be carefully monitored and controlled as they may affect PK of the therapeutic; they should thus be considered an important quality attribute. These observations were only possible through the application of rigorous analytical methods that we believe will need to be employed when comparing innovator and biosimilar molecules.
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DOI：
10.1016/s0021-9673(00)96972-3
发表时间：
1990-01-19
期刊：
JOURNAL OF CHROMATOGRAPHY
影响因子：
--
作者：
ALPERT, AJ
通讯作者：
ALPERT, AJ
CH2相关碳水化合物结构改变的影响对嵌合小鼠 - 人类免疫球蛋白G1的功能特性和体内命运的影响。
DOI：
10.1084/jem.180.3.1087
发表时间：
1994-09-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Wright A;Morrison SL
通讯作者：
Morrison SL
影响因子：
120.1
作者：
Jiang, Xu-Rong;Song, An;Schenerman, Mark
通讯作者：
Schenerman, Mark
影响因子：
4.3
作者：
Jones, Andrew J. S.;Papac, Damon I.;Battersby, John E.
通讯作者：
Battersby, John E.
影响因子：
3.6
作者：
Boyd, PN;Lines, AC;Patel, AK
通讯作者：
Patel, AK