Identification of human monoclonal antibodies specific for human SOD1 recognizing distinct epitopes and forms of SOD1.
Identification of human monoclonal antibodies specific for human SOD1 recognizing distinct epitopes and forms of SOD1.
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DOI：
10.1371/journal.pone.0061210
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Babcock GJ
中科院分区：
文献类型：
--
作者：
Broering TJ;Wang H;Boatright NK;Wang Y;Baptista K;Shayan G;Garrity KA;Kayatekin C;Bosco DA;Matthews CR;Ambrosino DM;Xu Z;Babcock GJ
编码人类SOD1 （hSOD1）的基因突变可导致肌萎缩性侧索硬化症（ALS），但SOD1突变诱导ALS的机制尚不完全清楚。目前还没有治愈ALS的方法，也没有能显著减少症状或进展的治疗方法。为了开发工具来了解突变型sod1诱导的ALS中存在的蛋白质构象，并作为可能的免疫治疗，我们分离并鉴定了11种独特的针对hSOD1的人类单克隆抗体。其中，hSOD1上有5个明确的线性表位，这些表位在正确折叠的蛋白质中不存在，但在某种程度的错误折叠的蛋白质形式中存在。其他6种抗体识别存在于正确折叠蛋白中的构象依赖性表位，具有两种不同的识别谱：3种可以结合hSOD1二聚体或单体，另外3种仅针对hSOD1二聚体。当突变体hSOD1暴露于升高的温度和EDTA时，具有结合hSOD1单体能力的抗体能够防止疏水性增加，这表明抗体稳定了hSOD1的天然结构。在G93A突变体hSOD1转基因ALS小鼠模型中测试了两种抗体，但没有产生统计学意义上的总生存率增加。可能是在小鼠模型中选择用于测试的两种抗体对治疗无效，或者模型和/或给药途径不是产生治疗效果的最佳途径。因此，需要额外的测试来确定SOD1突变型ALS和散发性ALS的潜在治疗潜力。
Mutations in the gene encoding human SOD1 (hSOD1) can cause amyotrophic lateral sclerosis (ALS) yet the mechanism by which mutant SOD1 can induce ALS is not fully understood. There is currently no cure for ALS or treatment that significantly reduces symptoms or progression. To develop tools to understand the protein conformations present in mutant SOD1-induced ALS and as possible immunotherapy, we isolated and characterized eleven unique human monoclonal antibodies specific for hSOD1. Among these, five recognized distinct linear epitopes on hSOD1 that were not available in the properly-folded protein but were available on forms of protein with some degree of misfolding. The other six antibodies recognized conformation-dependent epitopes that were present in the properly-folded protein with two different recognition profiles: three could bind hSOD1 dimer or monomer and the other three were specific for hSOD1 dimer only. Antibodies with the capacity to bind hSOD1 monomer were able to prevent increased hydrophobicity when mutant hSOD1 was exposed to increased temperature and EDTA, suggesting that the antibodies stabilized the native structure of hSOD1. Two antibodies were tested in a G93A mutant hSOD1 transgenic mouse model of ALS but did not yield a statistically significant increase in overall survival. It may be that the two antibodies selected for testing in the mouse model were not effective for therapy or that the model and/or route of administration were not optimal to produce a therapeutic effect. Therefore, additional testing will be required to determine therapeutic potential for SOD1 mutant ALS and potentially some subset of sporadic ALS.
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影响因子：
12.7
作者：
Forsberg K;Andersen PM;Marklund SL;Brännström T
通讯作者：
Brännström T
影响因子：
3.1
作者：
Babcock, Gregory J.;Broering, Teresa J.;Thomas, William D., Jr.
通讯作者：
Thomas, William D., Jr.
影响因子：
12.7
作者：
Kerman, Aaron;Liu, Hsueh-Ning;Chakrabartty, Avijit
通讯作者：
Chakrabartty, Avijit
影响因子：
3.7
作者：
Forsberg K;Jonsson PA;Andersen PM;Bergemalm D;Graffmo KS;Hultdin M;Jacobsson J;Rosquist R;Marklund SL;Brännström T
通讯作者：
Brännström T
影响因子：
25
作者：
Bosco, Daryl A.;Morfini, Gerardo;Karabacak, N. Murat;Song, Yuyu;Gros-Louis, Francois;Pasinelli, Piera;Goolsby, Holly;Fontaine, Benjamin A.;Lemay, Nathan;McKenna-Yasek, Diane;Frosch, Matthew P.;Agar, Jeffrey N.;Julien, Jean-Pierre;Brady, Scott T.;Brown, Robert H., Jr.
通讯作者：
Brown, Robert H., Jr.