Department of Pharmacology & Systems Physiology, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
Hum Vaccin Immunother. 2023 Dec 15;19(3):2274222. doi: 10.1080/21645515.2023.2274222. Epub 2023 Nov 8.
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 (C) varied proportionately to the dose administered in both male and female rats. The terminal elimination half-lives (t) 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.
一种人源化单克隆抗体 h2E2 被设计为高亲和力、特异性和长半衰期（~7d 在大鼠中）结合可卡因，作为可卡因使用障碍的治疗方法。我们在此报告一项在 GLP 协议下使用雄性和雌性大鼠进行的 h2E2 的药代动力学（PK）研究，剂量范围为 40 至 1200mg/kg。在雄性和雌性大鼠中，最大浓度（C）与给药剂量成比例变化。在所有测试剂量下，雄性和雌性大鼠的终末消除半衰期（t）均无显著差异。重要的是，这项研究报告了以前从未在人类中测试过的剂量的人源化单克隆抗体的药代动力学。h2E2 对可卡因具有高亲和力，而对可卡因代谢物（除了可卡因-1-乙基醚）、内源性单胺和甲基苯丙胺则表现出低亲和力或无亲和力。这证明了它的特异性和与生理和内分泌系统潜在缺乏相互作用的可能性。对大鼠单次毒性研究中的临床症状进行回顾，发现单次静脉内给予 40 至 1200mg/kg 后，中枢神经系统、呼吸系统或心血管系统没有任何影响。这项研究预测，这种单克隆抗体在人类中可能是安全有效的。
