Development of Clinical-Stage Human Monoclonal Antibodies That Treat Advanced Ebola Virus Disease in Nonhuman Primates.
Development of Clinical-Stage Human Monoclonal Antibodies That Treat Advanced Ebola Virus Disease in Nonhuman Primates.
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DOI：
10.1093/infdis/jiy285
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发表时间：
2018-11-22
期刊：
影响因子：
--
通讯作者：
Kyratsous CA
中科院分区：
文献类型：
--
作者：
Pascal KE;Dudgeon D;Trefry JC;Anantpadma M;Sakurai Y;Murin CD;Turner HL;Fairhurst J;Torres M;Rafique A;Yan Y;Badithe A;Yu K;Potocky T;Bixler SL;Chance TB;Pratt WD;Rossi FD;Shamblin JD;Wollen SE;Zelko JM;Carrion R Jr;Worwa G;Staples HM;Burakov D;Babb R;Chen G;Martin J;Huang TT;Erlandson K;Willis MS;Armstrong K;Dreier TM;Ward AB;Davey RA;Pitt MLM;Lipsich L;Mason P;Olson W;Stahl N;Kyratsous CA
对于大多数类别的药物，治疗新发感染的治疗剂的快速开发受到鉴定具有所需功效、安全性和药代动力学特征的化合物所需的时间表的挑战。全人单克隆抗体（mAb）提供了一种有吸引力的方法来克服许多这些障碍，以快速生产治疗新出现的疾病。在这项研究中，我们部署了一个平台来生成，测试和开发针对扎伊尔埃博拉病毒的完全人源抗体。我们通过免疫VelocImmune小鼠获得了特异性抗埃博拉病毒（EBOV）抗体，该小鼠在其体液反应中使用人免疫球蛋白可变区。在分离的抗体克隆中，选择3个在中和EBOV和触发FcγRIIIa方面最好。结合研究和负染色电子显微镜显示，3种选定的抗体结合非重叠表位，包括一个潜在的新的保护性表位不被其他基于抗体的治疗靶向。当组合时，单剂量的3种抗体的混合物保护非人灵长类动物（NHP）免受EBOV疾病，即使在疾病症状明显之后。这种抗体混合物提供了互补的作用机制，结合了新的特异性，并在NHP中显示出高水平的抗致死性EBOV疾病的免疫后保护。目前正在正常健康志愿者中进行测试，为未来埃博拉疫情的潜在用途做准备。
For most classes of drugs, rapid development of therapeutics to treat emerging infections is challenged by the timelines needed to identify compounds with the desired efficacy, safety, and pharmacokinetic profiles. Fully human monoclonal antibodies (mAbs) provide an attractive method to overcome many of these hurdles to rapidly produce therapeutics for emerging diseases. In this study, we deployed a platform to generate, test, and develop fully human antibodies to Zaire ebolavirus. We obtained specific anti-Ebola virus (EBOV) antibodies by immunizing VelocImmune mice that use human immunoglobulin variable regions in their humoral responses. Of the antibody clones isolated, 3 were selected as best at neutralizing EBOV and triggering FcγRIIIa. Binding studies and negative-stain electron microscopy revealed that the 3 selected antibodies bind to non-overlapping epitopes, including a potentially new protective epitope not targeted by other antibody-based treatments. When combined, a single dose of a cocktail of the 3 antibodies protected nonhuman primates (NHPs) from EBOV disease even after disease symptoms were apparent. This antibody cocktail provides complementary mechanisms of actions, incorporates novel specificities, and demonstrates high-level postexposure protection from lethal EBOV disease in NHPs. It is now undergoing testing in normal healthy volunteers in preparation for potential use in future Ebola epidemics.
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影响因子：
17.1
作者：
Qiu, Xiangguo;Audet, Jonathan;Kobinger, Gary P.
通讯作者：
Kobinger, Gary P.
DOI：
10.1073/pnas.1324022111
发表时间：
2014-04-08
影响因子：
11.1
作者：
Murphy, Andrew J.;Macdonald, Lynn E.;Yancopoulos, George D.
通讯作者：
Yancopoulos, George D.
影响因子：
3
作者：
Pettersen, EF;Goddard, TD;Ferrin, TE
通讯作者：
Ferrin, TE
影响因子：
20.3
作者：
Peipp, Matthias;van Bueren, Jeroen J. Lammerts;Valerius, Thomas
通讯作者：
Valerius, Thomas
影响因子：
158.5
作者：
Baize, Sylvain;Pannetier, Delphine;Guenther, Stephan
通讯作者：
Guenther, Stephan