Identification of the antigenic epitopes in Staphylococcal enterotoxins A and E and design of a superantigen for human cancer therapy
Identification of the antigenic epitopes in Staphylococcal enterotoxins A and E and design of a superantigen for human cancer therapy
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DOI：
10.1016/j.jmb.2003.09.009
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发表时间：
2003-11-07
影响因子：
5.6
通讯作者：
Forsberg, G
中科院分区：
文献类型：
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作者：
Erlandsson, E;Andersson, K;Forsberg, G
单克隆抗体具有癌症治疗的潜力，可以通过将其与效应分子如超抗原连接来进一步改善。超抗原的肿瘤靶向导致针对肿瘤组织的强大T细胞攻击。在临床前和使用超抗原葡萄球菌肠毒素A（SEA）的患者中观察到了令人鼓舞的结果。为了进一步改进这一概念，我们降低了对超抗原抗体的反应性，这种抗体存在于所有个体中。使用表位作图，在SEA和SEE中的抗体结合位点被发现围绕它们的MHC II类结合位点。这些表位被遗传去除，并在迭代工程程序中产生大量的合成超抗原。与表达MHC II类的细胞相比，诸如与抗SEA的结合降低以及诱导杀死肿瘤细胞的更高选择性的性质依次得到改善。赖氨酸残基79、81、83和84都是主要抗原表位的一部分，Gln 204、Lys 74、Asp 75和Asn 78对于肿瘤细胞的最佳杀伤是重要的，而Asp 45影响与MHC II类的结合。通过进一步工程化优化生产特性，并设计了新型合成超抗原SEA/E-120。它被大约15%的人抗SEA抗体识别，并且具有比SEA更有效的肿瘤细胞杀伤特性。SEA/E-120可能具有低毒性，因为其介导杀死表达MHC II类细胞的能力降低。在大肠杆菌中以约35 mg/l的浓度作为Fab融合蛋白产生。(C)2003爱思唯尔有限公司。保留所有权利。
Monoclonal antibodies have a potential for cancer therapy that may be further improved by linking them to effector molecules such as superantigens. Tumor targeting of a superantigen leads to a powerful T cell attack against the tumour tissue. Encouraging results have been observed preclinically and in patients using the superantigen staphylococcal enterotoxin A, SEA. To further improve the concept, we have reduced the reactivity to antibodies against superantigens, which is found in all individuals. Using epitope mapping, antibody binding sites in SEA and SEE were found around their MHC class II binding sites. These epitopes were removed genetically and a large number of synthetic superantigens were produced in an iterative engineering procedure. Properties such as decreased binding to anti-SEA as well as higher selectivity to induce killing of tumour cells compared to MHC class II expressing cells, were sequentially improved. The lysine residues 79, 81, 83 and 84 are all part of major antigenic epitopes, Gln204, Lys74, Asp75 and Asn78 are important for optimal killing of tumour cells while Asp45 affects binding to MHC class II. The production properties were optimised by further engineering and a novel synthetic superantigen, SEA/E-120, was designed. It is recognised by approximately 15% of human anti-SEA antibodies and have more potent tumour cell killing properties than SEA. SEA/E-120 is likely to have a low toxicity due to its reduced capacity to mediate killing of MHC class II expressing cells. It is produced as a Fab fusion protein at approximately 35 mg/l in Escherichia coli. (C) 2003 Elsevier Ltd. All rights reserved.