Molecular basis of recognition of human osteopontin by 23C3, a potential therapeutic antibody for treatment of rheumatoid arthritis
Molecular basis of recognition of human osteopontin by 23C3, a potential therapeutic antibody for treatment of rheumatoid arthritis
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23C3 识别人骨桥蛋白的分子基础，23C3 是治疗类风湿性关节炎的潜在治疗抗体
DOI：
10.1016/j.jmb.2008.07.075
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发表时间：
2008-10-17
影响因子：
5.6
通讯作者：
Ding, Jianping
中科院分区：
文献类型：
--
作者：
Du, Jiamu;Hou, Sheng;Ding, Jianping
骨桥蛋白在类风湿关节炎（RA）的发展和延续中起着重要作用。针对骨桥蛋白的抗体已显示出治疗这种疾病的良好效果。我们之前报道了一种新的抗RA单克隆抗体，即23C3，并证明它能够缓解小鼠胶原诱导关节炎模型中的RA症状，恢复关节组织中细胞因子的产生，并减少t细胞对II型胶原的召回反应。本文描述了23C3复合物及其表位肽的晶体结构。对其复杂结构的分析揭示了23C3识别骨桥蛋白的分子机制。该肽折叠成两个串联的β -旋，并且该肽的两个关键残基被鉴定为对23C3识别至关重要：TrpP43深嵌在由AlaL34、TyrL36、LeuL46、TyrL49、PheL91和MetH102组成的疏水囊中，因此与23C3具有广泛的疏水相互作用，而AspP47与抗体的ArgH50、ArgH52、SerH53和AsnH56残基具有亲水性相互作用网络。除了互补决定区环外，230的框架区L2还显示与表位肽相互作用，这在抗体-抗原相互作用中并不常见，因此可以在23C3的工程中利用。这些结果不仅为进一步改进23C3的嵌合或人源化等治疗应用提供了有价值的信息，而且揭示了该骨桥蛋白特异性表位的特征，可能有助于开发新的抗RA抗体药物。(C) 2008 Elsevier Ltd版权所有。
Osteopontin plays an important role in the development and perpetuation of rheumatoid arthritis (RA). Antibodies targeting osteopontin have shown promising therapeutic benefits against this disease. We have previously reported a novel anti-RA monoclonal antibody, namely, 23C3, and shown it capable of alleviating the symptoms of RA in a murine collagen-induced arthritis model, restoring the cytokine production profile in joint tissues, and reducing T-cell recall responses to collagen type II. We describe here the crystal structure of 23C3 in complex with its epitope peptide. Analyses of the complex structure reveal the molecular mechanism of osteopontin recognition by 23C3. The peptide folds into two tandem beta-turns, and two key residues of the peptide are identified to be critical for the recognition by 23C3: TrpP43 is deeply embedded into a hydrophobic pocket formed by AlaL34, TyrL36, LeuL46, TyrL49, PheL91, and MetH102 and therefore has extensive hydrophobic interactions with 23C3, while AspP47 has a network of hydrophilic interactions with residues ArgH50, ArgH52, SerH53, and AsnH56 of the antibody. Besides the complementarity-determining region loops, the framework region L2 of 230 is also shown to interact with the epitope peptide, which is not common in the antibody-antigen interactions and thus could be exploited in the engineering of 23C3. These results not only provide valuable information for further improvement of 23C3 such as chimerization or humanization for its therapeutic application, but also reveal the features of this specific epitope of osteopontin that may be useful for the development of new antibody drugs against RA. (C) 2008 Elsevier Ltd. All rights reserved.