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.

摘要。UG 3/UH 3项目将开发针对芬太尼和芬太尼样化合物的疫苗， 减少非法类阿片使用和致命过量发生率的战略。拟议的活动将包括 疫苗选择和优化、GMP疫苗生产以及IND启动GLP毒理学研究。 在美国，由于海洛因、假冒处方药和 可卡因掺杂芬太尼或类似芬太尼的物质。目前的药物可能不足以解决 阿片类药物过量流行病作为目前药物治疗的补充策略，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命性。我们的团队已经 开发了针对海洛因和羟考酮的疫苗， 阿片样物质对大脑的分布、阿片样物质诱导的行为和阿片样物质诱导的呼吸抑制的影响。疫苗 有效地和选择性地靶向预期的阿片样物质，但不干扰内源性阿片样物质， 批准的药物治疗。阿片类疫苗提供了一种持久、安全和具有成本效益的干预措施 药物辅助治疗（MAT）。疫苗可以减少阿片类药物使用者的过量服用， 以及保护那些从事职业的人（例如，执法人员、机场保安人员、邮政工作人员） 暴露于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， 芬太尼基半抗原（F0）与钥孔血蓝蛋白（KLH）载体蛋白偶联，并吸附 加到明矾佐剂上。用F0-KLH免疫减少芬太尼向大脑的分布，并且选择性地 减少芬太尼诱导的大鼠抗伤害感受和呼吸抑制。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 靶向卡芬太尼、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 在UG 3/UH 3阶段交错，我们预计第一个领先的F0载体结合疫苗将在 在第三年年底前准备好IND申请。AIM 1侧重于优化含有先导F0的疫苗 以及与工业标准载体蛋白缀合的新的Fn半抗原，包括两个E.大肠杆菌表达载体 从我们的行业合作伙伴FinaBiosolutions获得。鉴定了先导化合物诱导抗体的功效， 将减少芬太尼（或芬太尼类似物）向大脑的分布， 抑郁症和致死性。AIM 1还具有额外免疫方案和疫苗的特征 芬太尼自我给药大鼠模型中的功效。作为应急计划，AIM 2测试AIM 1是否导致 含有F0和Fn半抗原的疫苗制剂可以在多组分疫苗制剂中共同施用， 同时靶向芬太尼及其类似物。AIM 3专注于GMP疫苗的生产和评估 通过CMO和CRO合作伙伴在GLP临床前毒理学研究中评估其安全性。AIM 3将提交IND 用于针对芬太尼和/或其类似物的至少一种疫苗制剂。