Discovery of a Prefusion Respiratory Syncytial Virus F-Specific Monoclonal Antibody That Provides Greater In Vivo Protection than the Murine Precursor of Palivizumab
Discovery of a Prefusion Respiratory Syncytial Virus F-Specific Monoclonal Antibody That Provides Greater In Vivo Protection than the Murine Precursor of Palivizumab
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发现一种融合前呼吸道合胞病毒 F 特异性单克隆抗体，比帕利珠单抗的小鼠前体提供更强的体内保护
DOI：
10.1128/jvi.00176-17
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发表时间：
2017-05
影响因子：
5.4
通讯作者：
Xia Ning-Shao
中科院分区：
文献类型：
--
作者：
Zhao Min;Zheng Zi-Zheng;Chen Man;Modjarrad Kayvon;Zhang Wei;Zhan Lu-Ting;Cao Jian-Li;Sun Yong-Peng;McLellan Jason S.;Graham Barney S.;Xia Ning-Shao
帕利珠单抗是一种人源化鼠单克隆抗体，可识别呼吸道合胞病毒（RSV）F糖蛋白融合前（pre-F）和融合后（post-F）构象上的抗原位点II，是唯一批准用于治疗RSV感染的预防剂。然而，其相对较低的中和效力和高成本限制了其在严重疾病高风险的有限婴儿群体中的使用。以前，我们分离出一种高效的中和抗体，5C 4，它特异性地识别前F蛋白三聚体顶端的抗原位点。我们在体外和体内比较了5C 4和帕利珠单抗的鼠前体抗体1129的效力和保护功效。两种抗体均在相同的鼠骨架上合成为IgG 1或IgG 2a亚类，并评价其与多种F蛋白构象的结合、RSV感染和繁殖的体外抑制以及小鼠中的保护效力。尽管1129和5C 4具有相似的前F蛋白结合亲和力，但5C 4的体外中和活性比1129高近50倍。在BALB/c小鼠中，5C 4在上呼吸道和下呼吸道中使RSV的峰值滴度降低了1，000倍以上。这些数据表明，对抗原位点II特异性的抗体在预防RSV感染方面比对抗原位点II特异性的抗体更有效。我们的数据还表明，位点特异性抗体可用于预防或治疗RSV感染，并支持使用前F蛋白作为疫苗抗原。目前还没有疫苗可用于预防RSV感染。许可抗体帕利珠单抗（可识别前F和后F蛋白上的位点II）的使用仅限于预防重度RSV疾病高风险的新生儿。在一般人群中使用被动免疫或在持续感染的免疫功能低下的人中使用治疗的建议是有限的，因为成本是由补偿其相对较低的中和效力所需的高剂量决定的。先前改善位点II特异性抗体的体外效力的努力没有转化为显著的体内剂量节省。我们分离了一种前F蛋白特异性、高效中和抗体（5C 4），该抗体可识别抗原位点，并将其效力与同种型和前F蛋白结合亲和力匹配的帕利珠单抗（抗体1129）的鼠前体进行了比较。我们的研究结果表明，表位特异性是抗体中和效力的重要决定因素，并且定义中和机制具有鉴定用于预防和治疗RSV感染的改进产品的潜力。
ABSTRACT Palivizumab, a humanized murine monoclonal antibody that recognizes antigenic site II on both the prefusion (pre-F) and postfusion (post-F) conformations of the respiratory syncytial virus (RSV) F glycoprotein, is the only prophylactic agent approved for use for the treatment of RSV infection. However, its relatively low neutralizing potency and high cost have limited its use to a restricted population of infants at high risk of severe disease. Previously, we isolated a high-potency neutralizing antibody, 5C4, that specifically recognizes antigenic site Ø at the apex of the pre-F protein trimer. We compared in vitro and in vivo the potency and protective efficacy of 5C4 and the murine precursor of palivizumab, antibody 1129. Both antibodies were synthesized on identical murine backbones as either an IgG1 or IgG2a subclass and evaluated for binding to multiple F protein conformations, in vitro inhibition of RSV infection and propagation, and protective efficacy in mice. Although 1129 and 5C4 had similar pre-F protein binding affinities, the 5C4 neutralizing activity was nearly 50-fold greater than that of 1129 in vitro. In BALB/c mice, 5C4 reduced the peak titers of RSV 1,000-fold more than 1129 did in both the upper and lower respiratory tracts. These data indicate that antibodies specific for antigenic site Ø are more efficacious at preventing RSV infection than antibodies specific for antigenic site II. Our data also suggest that site Ø-specific antibodies may be useful for the prevention or treatment of RSV infection and support the use of the pre-F protein as a vaccine antigen. IMPORTANCE There is no vaccine yet available to prevent RSV infection. The use of the licensed antibody palivizumab, which recognizes site II on both the pre-F and post-F proteins, is restricted to prophylaxis in neonates at high risk of severe RSV disease. Recommendations for using passive immunization in the general population or for therapy in immunocompromised persons with persistent infection is limited because of cost, determined from the high doses needed to compensate for its relatively low neutralizing potency. Prior efforts to improve the in vitro potency of site II-specific antibodies did not translate to significant in vivo dose sparing. We isolated a pre-F protein-specific, high-potency neutralizing antibody (5C4) that recognizes antigenic site Ø and compared its efficacy to that of the murine precursor of palivizumab (antibody 1129) matched for isotype and pre-F protein binding affinities. Our findings demonstrate that epitope specificity is an important determinant of antibody neutralizing potency, and defining the mechanisms of neutralization has the potential to identify improved products for the prevention and treatment of RSV infection.
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影响因子：
3.6
作者：
GRAHAM, BS;DAVIS, TH;GRUBER, WC
通讯作者：
GRUBER, WC
影响因子：
3.7
作者：
Hotard AL;Shaikh FY;Lee S;Yan D;Teng MN;Plemper RK;Crowe JE Jr;Moore ML
通讯作者：
Moore ML
DOI：
10.1126/science.1234914
发表时间：
2013-05-31
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
McLellan JS;Chen M;Leung S;Graepel KW;Du X;Yang Y;Zhou T;Baxa U;Yasuda E;Beaumont T;Kumar A;Modjarrad K;Zheng Z;Zhao M;Xia N;Kwong PD;Graham BS
通讯作者：
Graham BS
影响因子：
2.2
作者：
Chen, M.;Chang, J. S.;Nason, M.;Rangel, D.;Gall, J. G.;Graham, B. S.;Ledgerwood, J. E.
通讯作者：
Ledgerwood, J. E.
影响因子：
12.7
作者：
GRAHAM, BS;PERKINS, MD;KARZON, DT
通讯作者：
KARZON, DT