Advancing humanized monoclonal antibody for counteracting fentanyl toxicity towards clinical development.
Advancing humanized monoclonal antibody for counteracting fentanyl toxicity towards clinical development.
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DOI：
10.1080/21645515.2022.2122507
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发表时间：
2022-11-30
影响因子：
4.8
通讯作者：
中科院分区：
文献类型：
--
作者：
需要创新疗法来补充目前的治疗方法，以遏制与合成阿片类药物相关的致命过量的日益增长的发病率。对芬太尼及其类似物具有特异性的鼠和嵌合单克隆抗体（mAb）已在啮齿动物模型中证明了预防和逆转药物诱导毒性的临床前疗效。然而，单克隆抗体为基础的治疗需要广泛的工程以及在体外和体内表征推进到首次在人体临床试验。在此，基于对芬太尼的亲和力和抵消芬太尼在小鼠中的药理学作用的功效，选择新型鼠抗芬太尼mAb用于开发。旨在消除预测翻译后修饰的突变的人源化和评估产生了两种人源化mAb，它们可有效预防芬太尼诱导的大鼠药理作用。这些人源化的单克隆抗体显示出良好的生物物理特性方面的聚集和疏水性的色谱法为基础的测定，和热稳定性的动态扫描荧光法。这些结果共同支持本文开发的人源化抗芬太尼mAb保证用于治疗芬太尼毒性的进一步临床开发。
Innovative therapies to complement current treatments are needed to curb the growing incidence of fatal overdoses related to synthetic opioids. Murine and chimeric monoclonal antibodies (mAb) specific for fentanyl and its analogs have demonstrated pre-clinical efficacy in preventing and reversing drug-induced toxicity in rodent models. However, mAb-based therapeutics require extensive engineering as well as in vitro and in vivo characterization to advance to first-in-human clinical trials. Here, novel murine anti-fentanyl mAbs were selected for development based on affinity for fentanyl, and efficacy in counteracting the pharmacological effects of fentanyl in mice. Humanization and evaluation of mutations designed to eliminate predicted post-translational modifications resulted in two humanized mAbs that were effective at preventing fentanyl-induced pharmacological effects in rats. These humanized mAbs showed favorable biophysical properties with respect to aggregation and hydrophobicity by chromatography-based assays, and thermostability by dynamic scanning fluorimetry. These results collectively support that the humanized anti-fentanyl mAbs developed herein warrant further clinical development for treatment of fentanyl toxicity.
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影响因子：
2.9
作者：
Cacia, J;Keck, R;Frenz, J
通讯作者：
Frenz, J
DOI：
10.1016/j.bbrc.2007.02.042
发表时间：
2007-04-13
影响因子：
3.1
作者：
Garber, Ellen;Demarest, Stephen J.
通讯作者：
Demarest, Stephen J.
影响因子：
5.3
作者：
Bailly, Marc;Mieczkowski, Carl;Fayadat-Dilman, Laurence
通讯作者：
Fayadat-Dilman, Laurence
影响因子：
--
作者：
Crouse, Bethany;Wu, Mariah M.;Pravetoni, Marco
通讯作者：
Pravetoni, Marco
影响因子：
5.3
作者：
Estep, Patricia;Caffry, Isabelle;Xu, Yingda
通讯作者：
Xu, Yingda