The Vaccine and Immunotherapy Center, The Wistar Institute of Anatomy and Biology, Philadelphia, PA, 19104, USA.
Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN, 47405, USA.
Nat Commun. 2022 Oct 6;13(1):5886. doi: 10.1038/s41467-022-33309-6.
Monoclonal antibody therapy has played an important role against SARS-CoV-2. Strategies to deliver functional, antibody-based therapeutics with improved in vivo durability are needed to supplement current efforts and reach underserved populations. Here, we compare recombinant mAbs COV2-2196 and COV2-2130, which compromise clinical cocktail Tixagevimab/Cilgavimab, with optimized nucleic acid-launched forms. Functional profiling of in vivo-expressed, DNA-encoded monoclonal antibodies (DMAbs) demonstrated similar specificity, broad antiviral potency and equivalent protective efficacy in multiple animal challenge models of SARS-CoV-2 prophylaxis compared to protein delivery. In PK studies, DNA-delivery drove significant serum antibody titers that were better maintained compared to protein administration. Furthermore, cryo-EM studies performed on serum-derived DMAbs provide the first high-resolution visualization of in vivo-launched antibodies, revealing new interactions that may promote cooperative binding to trimeric antigen and broad activity against VoC including Omicron lineages. These data support the further study of DMAb technology in the development and delivery of valuable biologics.
单克隆抗体疗法在对抗 SARS-CoV-2 方面发挥了重要作用。需要采用能够提供功能性、基于抗体的治疗方法并提高其体内持久性的策略，以补充当前的努力并惠及服务不足的人群。在这里，我们比较了重组单克隆抗体 COV2-2196 和 COV2-2130，它们与临床鸡尾酒疗法 Tixagevimab/Cilgavimab 不同，采用了优化的核酸启动形式。体内表达的 DNA 编码单克隆抗体（DMAb）的功能分析表明，与蛋白质递送相比，在 SARS-CoV-2 预防的多种动物挑战模型中，它们具有相似的特异性、广泛的抗病毒效力和相当的保护效力。在 PK 研究中，DNA 递送可显著提高血清抗体滴度，且与蛋白质给药相比，其维持时间更长。此外，对血清衍生的 DMAb 进行的冷冻电镜研究首次提供了体内启动抗体的高分辨率可视化，揭示了可能促进与三聚体抗原协同结合以及对包括奥密克戎谱系在内的变体广泛活性的新相互作用。这些数据支持在有价值的生物制剂的开发和递送中进一步研究 DMAb 技术。
