Development of a monoclonal antibody to reverse overdose from fentanyl and its analogs: from manufacturing to clinical trials

摘要。该项目寻求资金以完成生产和IND支持药代动力学， 候选人源化单克隆抗体的I期临床试验的有效性和安全性/毒理学临床前研究 抗芬太尼单克隆抗体（mAb）治疗和逆转与芬太尼及其强效类似物过量相关的毒性。 致命的药物过量的发生率急剧增加，由于扩散和广泛的 芬太尼及其类似物的供应，经常在街头毒品混合物中发现。致命的药物过量 2020年超过92，000人。目前的药物并不总是足以预防或逆转芬太尼过量 及其类似物。作为当前药物的补充策略，我们的团队开发了人源化mAb， 芬太尼及其类似物铅单抗可有效预防和逆转药物诱导的呼吸道疾病 暴露于芬太尼和卡芬太尼的啮齿动物的抑郁和心动过缓。抗药物mAb选择性螯合 从流通中清除目标药物由于其对靶标的选择性，我们的mAb不会干扰 内源性配体，FDA批准的用于治疗阿片类药物使用障碍（OUD）和过量的药物，以及 其他关键药物。抗芬太尼mAb可与OUD的标准护理治疗共同给药 和/或过量，并且可以提供比阿片受体拮抗剂更持久的临床益处。翻译 单克隆抗体将使OUD患者和其他因意外或其他原因而处于致命过量高风险的个体受益。 故意暴露于芬太尼和芬太尼类似物UG 3/UH 3项目提出了一个里程碑驱动的 具有预定的进行/不进行标准的迭代开发计划，以推进针对芬太尼的mAb， 它的类似物到诊所。AIM 1专注于与以下公司合作生产主要候选mAb的GMP CDMO合作伙伴AIM 2专注于关键动物模型中的IND使能效力和有效性研究。AIM3 重点关注先导mAb的GLP毒理学和安全性。AIM 4专注于I期临床试验，以首次测试 mAb的安全性、药代动力学和免疫原性，以及mAb在健康人中对芬太尼的有效性 科目该项目的完成将提供临床数据，以支持未来II-III期试验中的mAb检测。

ABSTRACT. This project seeks funding to complete manufacturing and IND-supporting pharmacokinetic, efficacy, and safety/toxicology preclinical studies for a Phase I clinical trial of a candidate humanized monoclonal antibody (mAb) to treat and reverse toxicity associated with overdose involving fentanyl and its potent analogs. The incidence of fatal drug overdoses has dramatically increased due to the proliferation and widespread availability of fentanyl and its analogs, often found in street drug mixtures. Fatal drug overdoses totaled more than 92,000 in 2020. Current medications are not always sufficient to prevent or reverse overdose from fentanyl and its analogs. As a complementary strategy to current medications, our team has developed humanized mAbs against fentanyl and its analogs. Lead mAbs are effective in preventing and reversing drug-induced respiratory depression and bradycardia in rodents exposed to fentanyl and carfentanil. Anti-drug mAbs selectively sequester the target drug from circulation. Due to their selectivity for the target(s), our mAbs do not interfere with endogenous ligands, FDA-approved medications for treating opioid use disorders (OUD) and overdose, and other critical medications. Anti-fentanyl mAbs can be co-administered with standard of care treatments for OUD and/or overdose, and may offer longer-lasting clinical benefits over opioid receptor antagonists. Translation of mAbs will benefit those with an OUD and other individuals at high-risk of fatal overdoses from accidental or deliberate exposure to fentanyl and fentanyl analogs. This UG3/UH3 project proposes a milestone-driven iterative developmental plan with predetermined go/no go criteria to advance a mAb against fentanyl and its analogs to the clinic. AIM1 focuses on the GMP manufacturing of a lead candidate mAb in collaboration with a partner CDMO. AIM2 focuses on IND-enabling potency and efficacy studies in key animal models. AIM3 focuses on the GLP toxicology and safety of the lead mAb. AIM4 focuses on Phase I clinical trials to first test mAb safety, pharmacokinetics, and immunogenicity, and then mAb efficacy against fentanyl in healthy human subjects. Completion of this project will provide clinical data to support mAb testing in future Phase II-III trials.