Toxicokinetics of a humanized anti-cocaine monoclonal antibody in male and female rats and lack of cross-reactivity.
Toxicokinetics of a humanized anti-cocaine monoclonal antibody in male and female rats and lack of cross-reactivity.
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DOI：
10.1080/21645515.2023.2274222
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发表时间：
2023-12-15
影响因子：
4.8
通讯作者：
Norman, Andrew B.
中科院分区：
文献类型：
--
作者：
Webster, Rose P.;Marckel, Jordan A.;Norman, Andrew B.
一种人源化单克隆抗体h2E2被设计用于结合可卡因，具有高亲和力、特异性和长半衰期（在大鼠中~7天），用于治疗可卡因使用障碍。我们在此报告了在良好实验室规范（GLP）方案下，在40至1200mg /kg的剂量范围内，用雄性和雌性大鼠进行了h2E2的药代动力学（PK）研究。在雄性和雌性大鼠血浆中测量的最大浓度（Cmax）随给药剂量成比例变化。在所有剂量下，雄性和雌性大鼠的终末消除半衰期（t1/2β）无显著差异。重要的是，本研究报告了一种人源化单克隆抗体在从未测试过的剂量下的药代动力学。h2E2对可卡因具有高亲和力，而对可卡因代谢物（除可卡因外）、内源性单胺和甲基苯丙胺具有低亲和力或无亲和力。这证明了它的特异性和潜在的缺乏与生理和内分泌系统的相互作用。对大鼠单剂量毒性研究临床症状的回顾显示，单次静脉注射剂量为40至1200mg /kg对中枢神经系统、呼吸系统或心血管系统没有影响。本研究预测该单克隆抗体在人体内可能是安全有效的。
A humanized monoclonal antibody h2E2 designed to bind cocaine with high affinity, specificity, and a long half-life (~7 d in rats) is being developed as a treatment for cocaine use disorder. We report here a pharmacokinetic (PK) study of h2E2 using male and female rats conducted under a Good Laboratory Practice (GLP) protocol over a dose range of 40 to 1200 mg/kg. The maximum concentration measured in rat plasma (Cmax) varied proportionately to the dose administered in both male and female rats. The terminal elimination half-lives (t1/2β) were not significantly different in male and female rats at all doses tested. Importantly, this study reports pharmacokinetics for a humanized monoclonal antibody at a dose never tested before. h2E2 has a high affinity for cocaine, whereas low or no affinity was demonstrated for cocaine metabolites (all except cocaethylene), endogenous monoamines, and methamphetamine. This demonstrates its specificity and a potential lack of interactions with physiological and endocrine systems. A review of the clinical signs in single-dose toxicity studies in rats revealed no effects on the central nervous, respiratory, or cardiovascular systems following single intravenous doses of 40 to 1200 mg/kg. This study predicts that this monoclonal antibody may be safe and effective in humans.
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影响因子：
3.4
作者：
Wang Y;Zheng C;Zhuang C;Fu Q;Qin J;Zhang B;Bian Y;Qi N;Zhu J
通讯作者：
Zhu J
影响因子：
10.6
作者：
Haney, Margaret;Gunderson, Erik W.;Jiang, Huiping;Collins, Eric D.;Foltin, Richard W.
通讯作者：
Foltin, Richard W.
影响因子：
2.6
作者：
通讯作者：
--
影响因子：
4.8
作者：
Kirley TL;Norman AB
通讯作者：
Norman AB
影响因子：
--
作者：
Martell, Bridget A.;Orson, Frank M.;Poling, James;Mitchell, Ellen;Rossen, Roger D.;Gardner, Tracie;Kosten, Thomas R.
通讯作者：
Kosten, Thomas R.