Development of a mouse monoclonal antibody cocktail for post-exposure rabies prophylaxis in humans.
Development of a mouse monoclonal antibody cocktail for post-exposure rabies prophylaxis in humans.
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DOI：
10.1371/journal.pntd.0000542
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发表时间：
2009-11-03
影响因子：
3.8
通讯作者：
Kieny MP
中科院分区：
文献类型：
--
作者：
Müller T;Dietzschold B;Ertl H;Fooks AR;Freuling C;Fehlner-Gardiner C;Kliemt J;Meslin FX;Franka R;Rupprecht CE;Tordo N;Wanderler AI;Kieny MP
由于近年来对狂犬病暴露后预防（PEP）治疗的需求呈指数级增长，人和马狂犬病免疫球蛋白（HRIG和ERIG）的有限供应未能在犬狂犬病流行的国家提供PEP中所需的被动免疫成分。因此，用一种可能更便宜和有效的替代生物制剂替代HRIG和ERIG治疗人类狂犬病仍然是一个高度优先事项。在这项研究中，我们着手评估小鼠单克隆抗体（MoMAb）鸡尾酒，最终目标是以尽可能低的成本开发一种产品，可用于发展中国家作为PEP中RIG的替代品。基于严格的标准，如生物活性、中和效力、结合特异性、狂犬病毒中和谱和每种杂交瘤的历史，从可用的组中选择五种MoMAb，E559.9.14、1112-1、62-71-3、M727-5-1和M777-16-3。这些MoMAb中的四个识别狂犬病病毒（RABV）糖蛋白的抗原位点II中的表位，一个识别抗原位点III中的表位，如通过独特的MoMAb中和逃逸突变体的糖蛋白基因的核苷酸序列分析所确定的。MoMAb在良好实验室规范（GLP）条件下生产。使用能够靶向抗原位点II和III的非重叠表位的不同浓度的MoMAb制备独特的组合（混合物）。盲法体外功效研究表明，MoMab混合物可中和除属于系统群II和III的狂犬病毒外的广泛狂犬病毒。在体内，MoMAb混合物作为PEP的一个组成部分产生了与HRIG相当的保护作用。总之，MoMAb的所有三种新型组合显示出与HRIG具有相同的功效，因此可以被认为是用于PEP和预防人类狂犬病的潜在较便宜的替代生物制剂。据估计，在非洲和亚洲，每年有55，000人死于地方性犬狂犬病，但狂犬病在大多数这些国家仍然是一种被忽视的疾病。超过99%的人类狂犬病病例是由狗咬伤引起的感染引起的。在绝大多数人类接触狂犬病的情况下，患者需要接触后预防（PEP），其中包括被动免疫（狂犬病免疫球蛋白，RIG）和主动免疫（狂犬病疫苗）。近年来，需要PEP的受害者人数呈指数级增长，在犬狂犬病流行的国家，人和马RIG（HRIG和ERIG）的供应不足。来源于小鼠（Mo）的狂犬病病毒中和单克隆抗体（MAb）已被确定为HRIG和ERIG的有前途的替代品。我们已经开发并评估了体外和体内独特的小鼠单克隆抗体（MoMAb）鸡尾酒，这是非常有效的。三种新的组合显示具有与HRIG相同或上级的疗效，因此可以被认为是预防人类狂犬病发展的被动预防性使用的潜在较便宜的替代方案，特别是在发展中国家最需要的地方。
As the demand for rabies post-exposure prophylaxis (PEP) treatments has increased exponentially in recent years, the limited supply of human and equine rabies immunoglobulin (HRIG and ERIG) has failed to provide the required passive immune component in PEP in countries where canine rabies is endemic. Replacement of HRIG and ERIG with a potentially cheaper and efficacious alternative biological for treatment of rabies in humans, therefore, remains a high priority. In this study, we set out to assess a mouse monoclonal antibody (MoMAb) cocktail with the ultimate goal to develop a product at the lowest possible cost that can be used in developing countries as a replacement for RIG in PEP. Five MoMAbs, E559.9.14, 1112-1, 62-71-3, M727-5-1, and M777-16-3, were selected from available panels based on stringent criteria, such as biological activity, neutralizing potency, binding specificity, spectrum of neutralization of lyssaviruses, and history of each hybridoma. Four of these MoMAbs recognize epitopes in antigenic site II and one recognizes an epitope in antigenic site III on the rabies virus (RABV) glycoprotein, as determined by nucleotide sequence analysis of the glycoprotein gene of unique MoMAb neutralization-escape mutants. The MoMAbs were produced under Good Laboratory Practice (GLP) conditions. Unique combinations (cocktails) were prepared, using different concentrations of the MoMAbs that were capable of targeting non-overlapping epitopes of antigenic sites II and III. Blind in vitro efficacy studies showed the MoMab cocktails neutralized a broad spectrum of lyssaviruses except for lyssaviruses belonging to phylogroups II and III. In vivo, MoMAb cocktails resulted in protection as a component of PEP that was comparable to HRIG. In conclusion, all three novel combinations of MoMAbs were shown to have equal efficacy to HRIG and therefore could be considered a potentially less expensive alternative biological agent for use in PEP and prevention of rabies in humans. Human mortality from endemic canine rabies is estimated to be 55,000 deaths per year in Africa and Asia, yet rabies remains a neglected disease throughout most of these countries. More than 99% of human rabies cases are caused by infections resulting from a dog-bite injury. In the vast majority of human exposures to rabies, patients require post-exposure prophylaxis (PEP), which includes both passive (rabies immunoglobulin, RIG) and active immunization (rabies vaccine). The number of victims requiring PEP has increased exponentially in recent years, and human and equine RIG (HRIG and ERIG) were not sufficiently available in countries where canine rabies is endemic. Rabies virus-neutralizing monoclonal antibodies (MAbs) of mouse (Mo) origin have been identified as promising alternatives to HRIG and ERIG. We have developed and assessed both in vitro and in vivo unique mouse monoclonal antibody (MoMAb) cocktails, which are highly efficacious. Three novel combinations were shown to have an equal or superior efficacy to HRIG and therefore could be considered a potentially less expensive alternative for passive prophylactic use to prevent the development of rabies in humans, particularly where needed most in developing countries.
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