Denise Guerra, Laura Radić, Mitch Brinkkemper, Meliawati Poniman, Lara van der Maas, Jonathan L Torres, Andrew B Ward, Kwinten Sliepen, Janke Schinkel, Rogier W Sanders, Marit J van Gils, Tim Beaumont
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引用次数: 0
摘要
单克隆中和抗体(mAbs)被认为是预防高危人群感染 SARS-CoV-2 的重要手段,也是应对未来由沙巴病毒引发的疾病的策略之一。然而,迄今为止分离出的大多数 mAbs 只能中和少数几种沙巴克病毒株。因此,人们对双特异性抗体(bsAbs)的兴趣与日俱增,这种抗体可以同时针对不同的尖峰表位,从而提高中和广度并防止病毒逃逸。在这里,我们利用高效可控的 Fab 臂交换协议生成了 30 种新型宽反应性 bsAbs,并对其进行了表征。我们特别结合了迄今为止描述过的一些针对受体结合域(RBD)上保守表位的广谱 mAbs。与亲代 mAbs 和鸡尾酒相比,几种 bsAbs 对不同支系的沙巴病毒(包括最近的 SARS-CoV-2 变体)具有更强的交叉结合能力和中和能力。包括 mAb COVA2-02 在内的 BsAbs 是最有效和最广泛的组合之一。因此,我们对 COVA2-02 的未知表位进行了研究,结果表明这种 mAb 靶向的是 RBD 基部的一个独特的保守区域,这在设计下一代 bsAb 构建物时可能很有意义,有助于更好地防范大流行病。
Broadening sarbecovirus neutralization with bispecific antibodies combining distinct conserved targets on the receptor binding domain.
Monoclonal neutralizing antibodies (mAbs) are considered an important prophylactic against SARS-CoV-2 infection in at-risk populations and a strategy to counteract future sarbecovirus-induced disease. However, most mAbs isolated so far neutralize only a few sarbecovirus strains. Therefore, there is a growing interest in bispecific antibodies (bsAbs) which can simultaneously target different spike epitopes and thereby increase neutralizing breadth and prevent viral escape. Here, we generate and characterize a panel of 30 novel broadly reactive bsAbs using an efficient controlled Fab-arm exchange protocol. We specifically combine some of the broadest mAbs described so far, which target conserved epitopes on the receptor binding domain (RBD). Several bsAbs show superior cross-binding and neutralization compared to the parental mAbs and cocktails against sarbecoviruses from diverse clades, including recent SARS-CoV-2 variants. BsAbs which include mAb COVA2-02 are among the most potent and broad combinations. As a result, we study the unknown epitope of COVA2-02 and show that this mAb targets a distinct conserved region at the base of the RBD, which could be of interest when designing next-generation bsAb constructs to contribute to a better pandemic preparedness.
期刊介绍:
(formerly Human Vaccines; issn 1554-8619)
Vaccine research and development is extending its reach beyond the prevention of bacterial or viral diseases. There are experimental vaccines for immunotherapeutic purposes and for applications outside of infectious diseases, in diverse fields such as cancer, autoimmunity, allergy, Alzheimer’s and addiction. Many of these vaccines and immunotherapeutics should become available in the next two decades, with consequent benefit for human health. Continued advancement in this field will benefit from a forum that can (A) help to promote interest by keeping investigators updated, and (B) enable an exchange of ideas regarding the latest progress in the many topics pertaining to vaccines and immunotherapeutics.
Human Vaccines & Immunotherapeutics provides such a forum. It is published monthly in a format that is accessible to a wide international audience in the academic, industrial and public sectors.