Breadth of neutralization and synergy of clinically relevant human monoclonal antibodies against HCV genotypes 1a, 1b, 2a, 2b, 2c, and 3a.
Breadth of neutralization and synergy of clinically relevant human monoclonal antibodies against HCV genotypes 1a, 1b, 2a, 2b, 2c, and 3a.
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DOI：
10.1002/hep.27298
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发表时间：
2014-11
期刊：
影响因子：
13.5
通讯作者：
Bukh, Jens
中科院分区：
文献类型：
--
作者：
Carlsen, Thomas H. R.;Pedersen, Jannie;Prentoe, Jannick C.;Giang, Erick;Keck, Zhen-Yong;Mikkelsen, Lotte S.;Law, Mansun;Foung, Steven K. H.;Bukh, Jens
具有中和能力的人单克隆抗体（HMAb）构成针对丙型肝炎病毒（HCV）的潜在的基于免疫的治疗或预防。然而，缺乏细胞培养衍生的HCV（HCV-HCV）携带真实的包膜蛋白（E1/E2）阻碍了跨基因型，亚型和分离株的中和研究。我们研究了10种具有治疗潜力的HMAb对一组16种表达来自基因型1a的患者来源的Core-NS 2的基于JFH 1的HCV-RNA的中和宽度。（菌株H77、TN和DH 6）、1b（J 4、DH 1和DH 5）、2a（J6、JFH 1和T9）、2b（J8、DH 8和DH 10）、2c（S83）和3a（S52、DBN和DH 11）。用于体外中和分析的病毒贮备液含有真实的E1/E2，但在E2中获得N417 S置换的全长JFH 1除外。在Huh7.5细胞中通过剂量-反应中和试验测定每种HMAb对HCV-panel的50%抑制浓度（IC 50），抗体浓度范围为0.0012 - 100 μg/ml。有趣的是，针对不同HC 50的IC 50值在HMAb之间表现出很大的变化，并且只有三种HMAb（HC-1AM、HC 84.24和AR 4A）中和了所有16种HC 50重组体。此外，给定HMAb的IC 50值随HCV 6毒株的不同而变化很大，这支持使用不同的病毒组。在合作分析中，HMAb HC84.24、AR 3A，尤其是HC84.26，当单独与AR 4A组合时，对大多数HC 4A表现出协同作用。结论：通过对10种临床相关HMAb针对来自基因型1a、1b、2a、2b、2c和3a的16种基于JFH 1的核心-NS 2重组体的中和分析，我们鉴定了至少3种具有有效和广泛中和潜力的HMAb。当汇集最有效的HMAb时获得的中和协同作用可能对开发治疗和控制HCV的新策略具有重要意义。
Human monoclonal antibodies (HMAbs) with neutralizing capabilities constitute potential immune-based treatments or prophylaxis against hepatitis C virus (HCV). However, lack of cell culture-derived HCV (HCVcc) harboring authentic envelope proteins (E1/E2) has hindered neutralization investigations across genotypes, subtypes, and isolates. We investigated the breadth of neutralization of 10 HMAbs with therapeutic potential against a panel of 16 JFH1-based HCVcc expressing patient-derived Core-NS2 from genotypes 1a (strains H77, TN, and DH6), 1b (J4, DH1, and DH5), 2a (J6, JFH1, and T9), 2b (J8, DH8, and DH10), 2c (S83), and 3a (S52, DBN, and DH11). Virus stocks used for in vitro neutralization analysis contained authentic E1/E2, with the exception of full-length JFH1 that acquired the N417S substitution in E2. The 50% inhibition concentration (IC50) for each HMAb against the HCVcc panel was determined by dose-response neutralization assays in Huh7.5 cells with antibody concentrations ranging from 0.0012 to 100 μg/ml. Interestingly, IC50-values against the different HCVcc’s exhibited large variations among the HMAbs, and only three HMAbs (HC-1AM, HC84.24, and AR4A) neutralized all 16 HCVcc recombinants. Furthermore, the IC50-values for a given HMAb varied greatly with the HCVcc strain, which supports the use of a diverse virus panel. In cooperation analyses, HMAbs HC84.24, AR3A, and, especially HC84.26, demonstrated synergistic effects towards the majority of the HCVcc’s when combined individually with AR4A. Conclusion: Through a neutralization analysis of 10 clinically relevant HMAbs against 16 JFH1-based Core-NS2 recombinants from genotypes 1a, 1b, 2a, 2b, 2c, and 3a, we identified at least 3 HMAbs with potent and broad neutralization potential. The neutralization synergism obtained when pooling the most potent HMAbs could have significant implications for developing novel strategies to treat and control HCV.
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影响因子：
64.8
作者：
Dorner, Marcus;Horwitz, Joshua A.;Robbins, Justin B.;Barry, Walter T.;Feng, Qian;Mu, Kathy;Jones, Christopher T.;Schoggins, John W.;Catanese, Maria Teresa;Burton, Dennis R.;Law, Mansun;Rice, Charles M.;Ploss, Alexander
通讯作者：
Ploss, Alexander
影响因子：
6.7
作者：
Morin TJ;Broering TJ;Leav BA;Blair BM;Rowley KJ;Boucher EN;Wang Y;Cheslock PS;Knauber M;Olsen DB;Ludmerer SW;Szabo G;Finberg RW;Purcell RH;Lanford RE;Ambrosino DM;Molrine DC;Babcock GJ
通讯作者：
Babcock GJ
DOI：
10.1073/pnas.0504877103
发表时间：
2006-05-09
影响因子：
11.1
作者：
Pietschmann, Thomas;Kaul, Artur;Bartenschlager, Ralf
通讯作者：
Bartenschlager, Ralf
影响因子：
13.5
作者：
Meuleman, Philip;Bukh, Jens;Leroux-Roels, Geert
通讯作者：
Leroux-Roels, Geert
影响因子：
29.4
作者：
Li, Yi-Ping;Ramirez, Santseharay;Bukh, Jens
通讯作者：
Bukh, Jens