A Single Tri-Epitopic Antibody Virtually Recapitulates the Potency of a Combination of Three Monoclonal Antibodies in Neutralization of Botulinum Neurotoxin Serotype A.
A Single Tri-Epitopic Antibody Virtually Recapitulates the Potency of a Combination of Three Monoclonal Antibodies in Neutralization of Botulinum Neurotoxin Serotype A.
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DOI：
10.3390/toxins10020084
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发表时间：
2018-02-15
期刊：
影响因子：
4.2
通讯作者：
Marks JD
中科院分区：
文献类型：
--
作者：
Lou J;Wen W;Conrad F;Meng Q;Dong J;Sun Z;Garcia-Rodriguez C;Farr-Jones S;Cheng LW;Henderson TD;Brown JL;Smith TJ;Smith LA;Cormier A;Marks JD
肉毒杆菌中毒的治疗标准，马抗毒素，是一种具有相关安全性问题和短血清半衰期的外源蛋白，这排除了其作为预防性抗毒素的用途，并使其成为一种不太理想的治疗剂。由于这些限制，优选重组单克隆抗体（mAb）产品。已经显示，结合非重叠表位的三种mAb的组合导致高度有效的肉毒杆菌神经毒素（BoNT）中和。最近，BoNT/A的三重人抗体组合在小鼠模型中显示出有效的毒素中和作用，当在I期临床试验中测试时没有严重的不良事件。然而，三重抗体治疗剂提出了独特的开发和制造挑战。因此，为了简化BoNT抗毒素的开发，我们试图在具有长血清半衰期的单个IgG基分子中实现多种mAb组合的效力。设计、生产和测试含有三种亲本BoNT/A mAb中每一种的结合位点的单一三表位基于IgG 1的mAb（TeAb），产生了与组合几乎相等效力的抗体。这里采用的方法可以应用于设计和创建其他多价抗体，这些抗体可以用于各种应用，包括毒素消除。
The standard of treatment for botulism, equine antitoxin, is a foreign protein with associated safety issues and a short serum half-life which excludes its use as a prophylactic antitoxin and makes it a less-than-optimal therapeutic. Due to these limitations, a recombinant monoclonal antibody (mAb) product is preferable. It has been shown that combining three mAbs that bind non-overlapping epitopes leads to highly potent botulinum neurotoxin (BoNT) neutralization. Recently, a triple human antibody combination for BoNT/A has demonstrated potent toxin neutralization in mouse models with no serious adverse events when tested in a Phase I clinical trial. However, a triple antibody therapeutic poses unique development and manufacturing challenges. Thus, potentially to streamline development of BoNT antitoxins, we sought to achieve the potency of multiple mAb combinations in a single IgG-based molecule that has a long serum half-life. The design, production, and testing of a single tri-epitopic IgG1-based mAb (TeAb) containing the binding sites of each of the three parental BoNT/A mAbs yielded an antibody of nearly equal potency to the combination. The approach taken here could be applied to the design and creation of other multivalent antibodies that could be used for a variety of applications, including toxin elimination.
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影响因子：
3.7
作者：
Fan Y;Geren IN;Dong J;Lou J;Wen W;Conrad F;Smith TJ;Smith LA;Ho M;Pires-Alves M;Wilson BA;Marks JD
通讯作者：
Marks JD
影响因子：
11.8
作者：
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通讯作者：
Khalil, Wajahat
影响因子：
3.7
作者：
Fan, Yongfeng;Garcia-Rodriguez, Consuelo;Marks, James D.
通讯作者：
Marks, James D.
影响因子：
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作者：
Fan, Yongfeng;Barash, Jason R.;Arnon, Stephen S.
通讯作者：
Arnon, Stephen S.
影响因子：
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作者：
Kaech, Stefanie;Banker, Gary
通讯作者：
Banker, Gary