DNA-delivered antibody cocktail exhibits improved pharmacokinetics and confers prophylactic protection against SARS-CoV-2.
DNA-delivered antibody cocktail exhibits improved pharmacokinetics and confers prophylactic protection against SARS-CoV-2.
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DOI：
10.1038/s41467-022-33309-6
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发表时间：
2022-10-06
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
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作者：
单克隆抗体治疗在抗SARS-CoV-2方面发挥了重要作用。需要提供具有改善的体内耐久性的功能性、基于抗体的治疗剂的策略来补充当前的努力并达到服务不足的人群。在这里，我们比较了重组单抗COV 2 -2196和COV 2 -2130，其折衷了临床混合物Tixagevimab/Cilgavimab与优化的核酸发射形式。体内表达的DNA编码的单克隆抗体（DMAbs）的功能分析表明，与蛋白质递送相比，在SARS-CoV-2预防的多个动物攻击模型中具有相似的特异性、广泛的抗病毒效力和等效的保护效力。在PK研究中，DNA递送驱动显著的血清抗体滴度，与蛋白质给药相比，血清抗体滴度得到更好的维持。此外，对血清来源的DMAb进行的冷冻EM研究提供了体内发射抗体的第一个高分辨率可视化，揭示了可能促进与三聚体抗原的合作结合和对VoC（包括Omicron谱系）的广泛活性的新相互作用。这些数据支持进一步研究DMAb技术在开发和提供有价值的生物制剂。在此，Parzych等人描述了一种DNA递送的SARS-CoV-2 mAb混合物的开发，该混合物显示协同RBD结合，在多种小动物模型中赋予针对关注变体的广泛中和活性和预防功效。
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. Here, Parzych et al describe the development of a DNA-delivered SARS-CoV-2 mAb cocktail displaying synergistic RBD binding that confers broad neutralizing activity against variants of concern and prophylactic efficacy in multiple small animal models.
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影响因子：
48
作者：
Barad BA;Echols N;Wang RY;Cheng Y;DiMaio F;Adams PD;Fraser JS
通讯作者：
Fraser JS
两种抗体鸡尾酒中和中和的遗传和结构基础。
影响因子：
28.3
作者：
Dong J;Zost SJ;Greaney AJ;Starr TN;Dingens AS;Chen EC;Chen RE;Case JB;Sutton RE;Gilchuk P;Rodriguez J;Armstrong E;Gainza C;Nargi RS;Binshtein E;Xie X;Zhang X;Shi PY;Logue J;Weston S;McGrath ME;Frieman MB;Brady T;Tuffy KM;Bright H;Loo YM;McTamney PM;Esser MT;Carnahan RH;Diamond MS;Bloom JD;Crowe JE Jr
通讯作者：
Crowe JE Jr
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
7.7
作者：
Bai, Xiao-chen;Rajendra, Eeson;Scheres, Sjors H. W.
通讯作者：
Scheres, Sjors H. W.
DOI：
10.1107/s0907444909042073
发表时间：
2010-01
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Chen VB;Arendall WB 3rd;Headd JJ;Keedy DA;Immormino RM;Kapral GJ;Murray LW;Richardson JS;Richardson DC
通讯作者：
Richardson DC