Aggregation-Prone Motifs in Human Immunoglobulin G
Aggregation-Prone Motifs in Human Immunoglobulin G
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DOI：
10.1016/j.jmb.2009.06.028
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发表时间：
2009-08-14
影响因子：
5.6
通讯作者：
Trout, Bernhardt L.
中科院分区：
文献类型：
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作者：
Chennamsetty, Naresh;Helk, Bernhard;Trout, Bernhardt L.
许多不同 IgG 亚类（IgG1、IgG2 和 IgG4）的治疗性抗体用于治疗各种癌症、类风湿性关节炎和其他炎症和传染病。根据疾病治疗的需要，这些抗体在高浓度下长期储存。不幸的是，这些抗体在这些储存条件下聚集，导致抗体活性降低并引起对引起免疫反应的担忧。因此，非常需要鉴定不同类别抗体中的易聚集区域。我们使用基于分子模拟的 SAP（空间聚集倾向）技术来确定 IgG1 类抗体恒定区中的聚集倾向基序。在这些易于聚集的基序区域上进行的突变导致抗体稳定性增强。鉴定出十四个易于聚集的基序，每个基序包含一到七个残基。虽然其中一些基序包含在一级序列中相邻的残基，但其他基序包含在一级序列中相距较远但在三级结构中靠近的残基。 IgG1 序列与其他亚类（IgG2、IgG3 和 IgG4）序列的比较表明，这些易于聚集的基序在所有 IgG 亚类中都得到了很大程度的保留。然而，其他更广泛类别的抗体（IgA1、IgD、IgE 和 IgM）在这些基序区域上有所不同。因此，所鉴定的易于聚集的基序对于所有 IgG 亚类来说都是常见的，但与非 IgG 类别的不同。此外，由于所鉴定的基序位于恒定区，因此它们适用于 IgG 类内的抗体，而与可变区无关。因此，所鉴定的基序区域可以在所有 IgG 上进行修饰，以产生稳定性增强的抗体。 (C) 2009 Elsevier Ltd. 保留所有权利。
Therapeutic antibodies of many different IgG subclasses (IgG1, IgG2 and IgG4) are used in the treatment of various cancers, rheumatoid arthritis and other inflammatory and infectious diseases. These antibodies are stored for long durations under high concentrations as required in the disease treatment. Unfortunately, these antibodies aggregate under these storage conditions, leading to a decrease in antibody activity and raising concerns about causing an immunological response. Thus, there is a tremendous need to identify the aggregation-prone regions in different classes of antibodies. We use the SAP (spatial-aggregation-propensity) technology based on molecular simulations to determine the aggregation-prone motifs in the constant regions of IgG1 classes of antibodies. Mutations engineered on these aggregation-prone motif regions led to antibodies of enhanced stability. Fourteen aggregation-prone motifs are identified, with each motif containing one to seven residues. While some of these motifs contain residues that are neighbors in primary sequence, others contain residues that are far apart in primary sequence but are close together in the tertiary structure. Comparison of the IgG1 sequence with those of other subclasses (IgG2, IgG3 and IgG4) showed that these aggregation-prone motifs are largely preserved among all IgG subclasses. Other broader classes of antibodies (IgA1, IgD, IgE and IgM), however, differed in these motif regions. The aggregation-prone motifs identified were therefore common to all IgG subclasses, but differ from those of non-IgG classes. Moreover, since the motifs identified are in the constant regions, they are applicable for an antibodies within the IgG class irrespective of the variable region. Thus, the motif regions identified could be modified on all IgGs to yield antibodies of enhanced stability. (C) 2009 Elsevier Ltd. All rights reserved.