Restricted V gene usage and VH/VL pairing of mouse humoral response against the N-terminal immunodominant epitope of the amyloid β peptide.
Restricted V gene usage and VH/VL pairing of mouse humoral response against the N-terminal immunodominant epitope of the amyloid β peptide.
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DOI：
10.1016/j.molimm.2010.09.012
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发表时间：
2010-11
影响因子：
3.6
通讯作者：
Dolezal O
中科院分区：
文献类型：
--
作者：
Robert R;Lefranc MP;Ghochikyan A;Agadjanyan MG;Cribbs DH;Van Nostrand WE;Wark KL;Dolezal O
在过去的十年中，基于在转基因小鼠中成功的实验和临床试验，抗体作为治疗阿尔茨海默病（AD）的治疗策略的潜力一直在增长。尽管使用主动免疫方法在人类中存在不期望的副作用，但免疫疗法仍然是AD最有希望的治疗方法之一。在这项研究中，我们分析了12个独立分离的抗淀粉样β肽（Aβ或A β）N-末端免疫显性表位的单克隆抗体的V基因。令人惊讶的是，我们在这些抗体的VH/VL配对中发现了高且不寻常的限制水平。此外，这些抗体主要在其重链互补决定区3（HCDR 3）方面存在差异，并且抗体中与Aβ接触的残基已经存在于生殖系V基因中。基于这些观察结果和/或抗体与Aβ的共晶体结构，本研究的目的是更好地理解抗体V结构域、HCDR 3区、关键接触残基（H58）和种系编码残基在Aβ识别中的作用。为此，我们设计并生产了一系列重组Fab构建体。通过表面等离子体共振技术对所有Fab进行了Aβ1-16、Aβ1-42高分子量和Aβ1-42低分子量可溶性寡聚体的检测和比较。尽管所有Fab均识别Aβ1-16肽和Aβ1-42高分子量可溶性寡聚体，但它们不结合Aβ1-42低分子量可溶性寡聚体。此外，我们证明：（1）抗体中H58位的芳香族残基在Aβ的识别中是必不可少的;（2）基于种系V基因的Fab以低亲和力与Aβ单体结合。这些发现可能对设计更有效的抗Aβ治疗抗体具有重要意义。
Over the last decade, the potential of antibodies as therapeutic strategies to treat Alzheimer’s disease (AD) has been growing, based on successful experimental and clinical trials in transgenic mice. Despite, undesirable side effects in humans using an active immunization approach, immunotherapy still remains one of the most promising treatments for AD. In this study, we analyzed the V genes of twelve independently isolated monoclonal antibodies raised against the N-terminal immunodominant epitope of the amyloid β peptide (Aβ or A beta). Surprisingly, we found a high and unusual level of restriction in the VH/VL pairing of these antibodies. Moreover, these antibodies mostly differ in their heavy chain complementary determining region 3 (HCDR3) and the residues in the antibodies which contact Aβ are already present in the germline V-genes. Based on these observations and or co-crystal structures of antibodies with Aβ, the aim of the current study was to better understand the role of antibody V-domains, HCDR3 regions, key contact residue (H58) and germline encoded residues in Aβ recognition. For that purpose, we designed and produced a range of recombinant Fab constructs. All the Fabs were tested and compared by surface plasmon resonance on Aβ1–16, Aβ1–42 high molecular weight and Aβ1–42 low molecular weight soluble oligomers. Although all the Fabs recognized the Aβ1–16 peptide and the Aβ1–42 high molecular weight soluble oligomers, they did not bind the Aβ1–42 low molecular weight soluble oligomers. Furthermore, we demonstrated that: (1) an aromatic residue at position H58 in the antibody is essential in the recognition of Aβ and (2) Fabs based on germline V-genes bind to Aβ monomers with a low affinity. These findings may have important implications in designing more effective therapeutic antibodies against Aβ.
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影响因子：
64.8
作者：
Janus, C;Pearson, J;Westaway, D
通讯作者：
Westaway, D
影响因子：
14.9
作者：
Ehrenmann F;Kaas Q;Lefranc MP
通讯作者：
Lefranc MP
DOI：
10.1073/pnas.95.11.6448
发表时间：
1998-05-26
影响因子：
11.1
作者：
Lambert, MP;Barlow, AK;Klein, WL
通讯作者：
Klein, WL
DOI：
10.1073/pnas.0705888104
发表时间：
2007-10-02
影响因子：
11.1
作者：
Gardberg, Anna S.;Dice, Lezlee T.;Dealwis, Chris
通讯作者：
Dealwis, Chris
影响因子：
2.9
作者：
Chromy, BA;Nowak, RJ;Klein, WL
通讯作者：
Klein, WL