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首页> 外文期刊>Journal of Molecular Biology >Potent Neutralization of Staphylococcal Enterotoxin B In Vivo by Antibodies that Block Binding to the T-Cell Receptor
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Potent Neutralization of Staphylococcal Enterotoxin B In Vivo by Antibodies that Block Binding to the T-Cell Receptor

机译：通过抗体与T细胞受体的抗体抗体的体内葡萄球菌肠毒素B的有效中和

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摘要

To develop an antibody (Ab) therapeutic against staphylococcal enterotoxin B (SEB), a potential incapacitating bioterrorism agent and a major cause of food poisoning, we developed a "class T" anti-SEB neutralizing Ab (GC132) targeting an epitope on SEB distinct from that of previously developed "class M" Abs. A systematic engineering approach was applied to affinity-mature Ab GC132 to yield an optimized therapeutic candidate (GC132a) with sub-nanomolar binding affinity. Mapping of the binding interface by hydrogen-deuterium exchange coupled to mass spectrometry revealed that the class T epitope on SEB overlapped with the T-cell receptor binding site, whereas other evidence suggested that the class M epitope overlapped with the binding site for the major histocompatibility complex. In the IgG format, GC132a showed similar to 50-fold more potent toxin-neutralizing efficacy than the best class M Ab in vitro, and fully protected mice from lethal challenge in a toxic shock post-exposure model. We also engineered bispecific Abs (bsAbs) that bound tetravalently by utilizing two class M binding sites and two class T binding sites. The bsAbs displayed enhanced toxin neutralization efficacy compared with the respective monospecific Ab subunits as well as a mixture of the two, indicating that enhanced efficacy was due to heterotypic tetravalent binding to two non-overlapping epitopes on SEB. Together, these results suggest that class T anti-SEB Ab GC132a is an excellent candidate for clinical development and for bsAb engineering. (C) 2019 Elsevier Ltd. All rights reserved.
机译：为了开发抗葡萄球菌肠毒素B（SEB）的抗体（AB），潜在的生物畸形剂和食物中毒的主要原因，我们开发了一种“T”抗SEB中和AB（GC132）靶向SEB截然不同的表位从先前开发的“m级”abs。将系统的工程方法应用于亲和成熟的AB GC132，得到具有亚载亚摩尔结合亲和力的优化治疗候选（GC132A）。通过氢 - 氘交换的结合界面的映射耦合到质谱表明，SEB的类T表位与T细胞受体结合位点重叠，而其他证据表明，M表位重叠与粘结位点具有主要的组织相容性复杂的。在IgG格式中，GC132A显示出与最佳类M AB在体外最佳的毒素中和毒素中和效力类似于50倍，并且在毒性冲击后的致死攻击中的完全受保护的小鼠。我们还通过利用两类M级结合位点和两类T级结合位点设计了双特异性ABS（BSAB）。与各自的单特异性AB亚基以及两者的混合物相比，BSAB显示出增强的毒素中和功效，表明增强的疗效是由于异型四价结合到SEB上的两个非重叠表位引起的。这些结果表明，T类抗SEB AB GC132A是临床开发和BSAB工程的优秀候选者。 （c）2019 Elsevier Ltd.保留所有权利。

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