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

抽象的。该项目寻求资金以完成制造和IND支持的药代动力学， 候选人源化单抗I期临床试验的有效性和安全性/毒理学临床前研究 用于治疗和逆转涉及芬太尼及其有效类似物的过量毒性的抗体(MAb)。 由于毒品泛滥和泛滥，致命性药物过量的发生率急剧增加。 芬太尼及其类似物的可用性，通常在街头药物混合物中发现。致命的药物过量总数更多 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的过量使用 和它的类似物。作为对当前药物的补充策略，我们的团队开发了人性化的mAbs 对抗芬太尼及其类似物。铅单抗在预防和逆转药物所致呼吸道感染中的作用 暴露于芬太尼和卡芬太尼的啮齿动物的抑郁和心动过缓。抗药物单抗选择性隔离 流通中的靶向药物。由于它们对靶标(S)的选择性，我们的单抗不干扰 内源性配体，FDA批准的治疗阿片使用障碍(OUD)和过量用药的药物，以及 其他关键药物。抗芬太尼单抗可与标准护理治疗联合使用 和/或过量，并可能提供比阿片受体拮抗剂更持久的临床益处。翻译： 单抗将有益于患有尿毒症的人和其他因意外或 故意接触芬太尼和芬太尼类似物。这个UG3/UH3项目提出了一个里程碑驱动的 具有预定进行/不进行标准的迭代发展计划以推进抗芬太尼和 它类似于诊所。AIM1专注于与GMP合作生产主要候选单抗 合作伙伴CDMO。AIM2专注于在关键动物模型中进行的IND使能效力和功效研究。AIM3 重点介绍了前导单抗的GLP毒理学和安全性。AIM4专注于I期临床试验以进行第一次测试 抗芬太尼单抗在健康人中的安全性、药代动力学和免疫原性及其效力 研究对象。该项目的完成将提供临床数据，以支持未来II-III期试验中的单抗测试。

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.