Abstract：
The game between therapeutic monoclonal antibodies (mAbs) and continuously emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has favored the virus, as most therapeutic mAbs have been evaded. Addressing this challenge, we systematically explored a reproducible bispecific antibody (bsAb)-dependent synergistic effect in this study. It could effectively restore the neutralizing activity of the bsAb when any of its single mAbs is escaped by variants. This synergy is primarily attributed to the binding angle of receptor-binding domain (RBD)-5, facilitating inter-spike cross-linking and promoting cryptic epitope exposure that classical antibody cocktails cannot achieve. Furthermore, RBD-5 with RBD-2, RBD-6, and RBD-7, alongside RBD-8, also exhibit significantly enhanced effects. This study not only shifts the paradigm in understanding antibody interactions but paves the way for developing more effective therapeutic antibodies against rapidly mutating SARS-CoV-2, with Dia-19 already showing promise against emerging variants like BA.2.86, EG.5.1, and JN.1.
摘要：
治疗性单克隆抗体（mAb）与不断出现的严重急性呼吸道综合症冠状病毒2（SARS-CoV-2）变体之间的博弈有利于该病毒，因为大多数治疗性单克隆抗体都被逃避了。应对这一挑战，在这项研究中，我们系统地探索了可重复的双特异性抗体（bsAb）依赖性协同作用。当其单个mAb中的任何一个被变体逃脱时,它可以有效地恢复bsAb的中和活性。这种协同作用主要归因于受体结合结构域（RBD）-5的结合角度，促进了刺间交联并促进了经典抗体混合物无法实现的隐蔽表位暴露。此外，RBD-5与RBD-2、RBD-6和RBD-7以及RBD-8也表现出显著增强的效果。这项研究不仅改变了理解抗体相互作用的范式，而且为开发针对快速突变的SARS-CoV-2的更有效的治疗性抗体铺平了道路，Dia-19已经显示出针对BA.2.86，EG.1等新兴变体的希望。和JN.1。
