Vaccines for fentanyl and its derivatives: A strategy to reduce illicit use and overdose

芬太尼及其衍生物疫苗：减少非法使用和过量服用的策略

• 批准号: 10523190
• 负责人: Marco Pravetoni
• 金额: $ 400.38万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10523190
• 关键词: Address; Adjuvant; Agonist; Antibodies; Antibody Affinity; Antibody Response; B-Lymphocytes; Behavior; Benchmarking; Bradycardia; Brain; Buprenorphine; Canada; Carrier Proteins; Categories; Chemicals; Clinical Trials; Cocaine; Conjugate Vaccines; Conjugated Carrier; Contracts; Data; Development; Drug Prescriptions; Epidemic; Escherichia coli; Europe; Exposure to; Family; Fentanyl; Follow-Up Studies; Formulation; Funding; Guidelines; Haptens; Heroin; Human Resources; Immunization; Immunize; Incidence; Individual; Industry Standard; Keyhole Limpet Hemocyanin; Law Enforcement; Lead; Licensing; Maintenance; Manufacturer Name; Methadone; Modeling; Mus; Naloxone; Naltrexone; Occupational Exposure; Occupations; Opioid; Overdose; Overdose reduction; Oxycodone; Pharmaceutical Preparations; Pharmacotherapy; Phase; Positioning Attribute; Public Health; Rattus; Recombinants; Regimen; Risk; Safety; Security; Self Administration; Series; Site; TLR9 gene; Testing; Toxicology; United States; Vaccines; Ventilatory Depression; abuse liability; aluminum sulfate; analog; antagonist; base; carfentanil; clinical toxicology; cost effective; cost effective intervention; cross reacting material 197; cross reactivity; drug distribution; efficacy testing; endogenous opioids; fentanyl overdose; high risk; illicit opioid; in vivo; industry partner; lead optimization; medication-assisted treatment; opioid overdose; opioid use; opioid user; pre-clinical; preclinical development; prescription opioid; remifentanil; research clinical testing; response; tetanus toxin fragment C; vaccine development; vaccine efficacy; vaccine evaluation; vaccine formulation; vaccine trial

ABSTRACT. This UG3/UH3 project will develop vaccines against fentanyl and fentanyl-like compounds as a strategy to reduce illicit opioid use and the incidence of fatal overdoses. Proposed activities will include lead vaccine selection and optimization, manufacturing of GMP vaccines, and IND-enabling GLP toxicology studies. The US has seen dramatic increases in fatal overdoses due to heroin, counterfeit prescription drugs, and cocaine adulterated with fentanyl or fentanyl-like analogs. Current medications may not be sufficient to address the opioid overdose epidemic. As a complementary strategy to current medications, we will develop vaccines against fentanyl and fentanyl-like compounds to reduce their abuse liability and lethality. Our team has already developed vaccines against heroin and oxycodone that induce antibodies effective in reducing opioid distribution to the brain, opioid-induced behaviors, and opioid-induced respiratory depression. Vaccines effectively and selectively target the intended opioid but do not interfere with endogenous opioids nor with approved pharmacotherapies. Opioid vaccines offer a long-lasting, safe and cost-effective intervention complementary to medication assisted treatment (MAT). Vaccines may reduce overdoses in opioid users as well as protect those in professions (e.g., law enforcement, airport security, postal workers) at risk of accidental exposure to fentanyl and fentanyl analogs. Our team has identified a candidate fentanyl vaccine consisting of a fentanyl-based hapten (F0) conjugated to the keyhole limpet hemocyanin (KLH) carrier protein, and adsorbed onto alum adjuvant. Immunization with F0-KLH reduces fentanyl distribution to the brain, and selectively reduces fentanyl-induced antinociception and respiratory depression in rats. We will further optimize the lead F0-KLH by testing alternative carrier proteins. In parallel we will develop other conjugate vaccines containing a new series of haptens (Fn) to target carfentanil, remifentanil, and other fentanyl analogs. Development will be staggered across UG3/UH3 phases, and we expect that the first lead F0-carrier conjugate vaccine will be ready for IND filing by the end of Year 3. AIM1 focuses on optimization of vaccines containing the lead F0 and new Fn haptens conjugated to industry-standard carrier proteins, including two E. coli-expressed carriers obtained from our industry partner FinaBiosolutions. Leads are identified for efficacy in inducing antibodies that will reduce fentanyl (or fentanyl analog) distribution to the brain as well as reducing antinociception, respiratory depression and lethality in rats. AIM1 also characterizes additional immunization regimens and vaccine efficacy in fentanyl self-administration rat models. As a contingency plan, AIM2 tests whether AIM1 leads containing F0 and Fn haptens can be co-administered in a multicomponent vaccine formulation to simultaneously target fentanyl and its analogs. AIM3 focuses on manufacturing of GMP vaccines and evaluate their safety in GLP pre-clinical toxicology studies through CMO and CRO partners. AIM3 will then file an IND for at least one vaccine formulation against fentanyl and/or its analogs.

抽象的。该 UG3/UH3 项目将开发针对芬太尼和芬太尼类化合物的疫苗作为 减少非法阿片类药物使用和致命过量用药发生率的战略。拟议的活动将包括铅 疫苗选择和优化、GMP 疫苗生产以及支持 IND 的 GLP 毒理学研究。 美国因海洛因、假冒处方药和毒品而致死的过量用药急剧增加 掺有芬太尼或芬太尼类似物的可卡因。目前的药物可能不足以解决 阿片类药物过量流行。作为当前药物的补充策略，我们将开发疫苗 针对芬太尼和芬太尼类化合物，以减少其滥用倾向和致死率。我们的团队已经 开发了针对海洛因和羟考酮的疫苗，可诱导有效减少阿片类药物的抗体 大脑分布、阿片类药物引起的行为和阿片类药物引起的呼吸抑制。疫苗 有效和选择性地靶向预期的阿片类药物，但不干扰内源性阿片类药物，也不干扰 批准的药物疗法。阿片类疫苗提供持久、安全且具有成本效益的干预措施 药物辅助治疗 (MAT) 的补充。疫苗可以减少阿片类药物使用者的过量服用，因为 以及保护那些面临意外风险的职业人员（例如执法人员、机场保安、邮政工作人员） 接触芬太尼和芬太尼类似物。我们的团队已经确定了一种候选芬太尼疫苗，其中包含 基于芬太尼的半抗原 (F0) 与匙孔血蓝蛋白 (KLH) 载体蛋白缀合并吸附 到明矾佐剂上。 F0-KLH 免疫减少了芬太尼向大脑的分布，并选择性地 减少芬太尼引起的大鼠镇痛和呼吸抑制。我们将进一步优化领先优势 F0-KLH 通过测试替代载体蛋白。与此同时，我们将开发其他含有以下成分的结合疫苗： 针对卡芬太尼、瑞芬太尼和其他芬太尼类似物的新系列半抗原 (Fn)。发展将是 UG3/UH3 阶段交错进行，我们预计第一个先导 F0 载体结合疫苗将是 准备在第 3 年年底提交 IND 申请。AIM1 重点关注含有先导 F0 的疫苗的优化 以及与行业标准载体蛋白缀合的新型 Fn 半抗原，包括两种大肠杆菌表达的载体 从我们的行业合作伙伴 FinaBiosolutions 处获得。确定先导物在诱导抗体方面的功效 将减少芬太尼（或芬太尼类似物）向大脑的分布，并减少镇痛、呼吸 大鼠的抑郁和致死率。 AIM1 还具有其他免疫方案和疫苗的特征 芬太尼自我给药大鼠模型的功效。作为应急计划，AIM2 测试 AIM1 是否领先 含有 F0 和 Fn 半抗原的疫苗可以在多组分疫苗制剂中共同施用， 同时针对芬太尼及其类似物。 AIM3专注于GMP疫苗的生产并评估 通过 CMO 和 CRO 合作伙伴进行 GLP 临床前毒理学研究，了解其安全性。 AIM3 随后将提交 IND 用于至少一种针对芬太尼和/或其类似物的疫苗制剂。