Isolation and structural analysis of peptide mimotopes for the disialoganglioside GD2, a neuroblastoma tumor antigen
Isolation and structural analysis of peptide mimotopes for the disialoganglioside GD2, a neuroblastoma tumor antigen
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DOI：
10.1016/j.molimm.2004.07.011
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发表时间：
2005-02-01
影响因子：
3.6
通讯作者：
Jensen-Jarolim, E
中科院分区：
文献类型：
--
作者：
Föster-Waldl, E;Riemer, AB;Jensen-Jarolim, E
二唾液酸神经节苷脂GalAcbeta 1 -4（NeuAcalpha 2 - 8 NeuAcalpha 2 -3）Galbeta 1 -4Glcbetal-1Cer（GD 2）在各种肿瘤中表达。包括神经母细胞瘤，并被定义为相关的Turner抗原。单克隆抗GD 2抗体14.18广泛用于神经母细胞瘤的诊断目的，其小鼠/人嵌合形式（第14.18章）目前已进入II期临床试验的被动免疫治疗方案。本研究旨在产生GD 2的14.18表位的结构模拟物。因此，我们使用ch14.18抗体从十聚体噬菌体展示文库中选择免疫反应性GD 2肽模拟表位。总之，13个GD 2肽模拟物可以通过生物淘选来确定，并且它们的特异性通过ch14.18抗体的排他性识别来证明。此外。它们作为GD 2模拟物的性质和它们的模拟程度通过与天然抗原的竞争来证实。当使用三维计算机建模系统（BALLView）进行GD 2表位和所选模拟表位的比较可视化时。我们证明了GD 2分子和模拟表位在GD 2特异性抗体的抗原结合袋中的配合。此外，计算机模拟认为GD 2模拟表位的最佳亲和力。因此，我们提供的证据表明，GD 2肽模拟表位的生成是成功的，当使用神经母细胞瘤抗体ch14.18进行选择，这种方法可能会提供一种工具，开发针对这种恶性儿科肿瘤的疫苗接种策略。(C)2004爱思唯尔有限公司保留所有权利。
The disialoganglioside GalAcbeta1-4(NeuAcalpha2-8NeuAcalpha2-3)Galbeta1-4Glcbetal-1Cer (GD2) is expressed on various tumors. including neuroblastoma, and was defined as a relevant turner antigen. The monoclonal anti-GD2 antibody 14.18 is widely used for diagnostic purposes in neuroblastoma, and in its mouse/human chimeric form (ch14.18) now enters passive immunotherapeutic regimens in phase II clinical trials. This study aimed to generate structural mimics of the 14.18 epitope of GD2. Therefore, we used the ch14.18 antibody for selecting immunoreactive GD2 peptide mimotopes from a decamer phage display library. In all, 13 GD2 peptide mimics could be determined by biopanning and their specificity was demonstrated by exclusive recognition by the ch14.18 antibody. Furthermore. their nature of being GD2 mimics and their degree of mimicry was confirmed by competition with the natural antigen. When performing a comparative visualization of the GD2 epitope and selected mimotopes using a three-dimensional computer modeling system (BALLView). we demonstrated fitting, of the GD2 molecule and the mimotopes in the antigen-binding pouch of a GD2 specific antibody. Moreover, the computer modeling argued for optimal affinity of the GD2 mimotopes.We thus provide evidence that the generation of GD2 peptide mimotopes is successful when using the neuroblastoma antibody ch14.18 for selection, and that this approach might offer a tool to develop a vaccination strategy against this malignant pediatric tumor. (C) 2004 Elsevier Ltd. All rights reserved.