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

抽象的。这个UG3/UH3项目将开发针对芬太尼和芬太尼类化合物的疫苗 减少非法阿片类药物使用和致命过量发生率的战略。建议的活动将包括销售 疫苗的选择和优化，GMP疫苗的制造，以及支持IND的GLP毒理学研究。 美国因海洛因、假冒处方药和 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。作为对现有药物的补充策略，我们将开发疫苗 针对芬太尼和芬太尼类化合物，以减少其滥用风险和致命性。我们的团队已经 开发了针对海洛因和羟考酮的疫苗，可诱导有效减少阿片类药物的抗体 分布到大脑，阿片类药物诱导的行为，阿片类药物诱导的呼吸抑制。疫苗 有效和选择性地靶向预期阿片类药物，但不干扰内源性阿片类药物，也不干扰 批准的药物疗法。阿片类疫苗提供了一种持久、安全和成本效益高的干预措施 补充药物辅助治疗(MAT)。疫苗可能会减少阿片类药物使用者的过量使用 并保护那些面临意外风险的专业人员(例如，执法人员、机场安检人员、邮递员) 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，该疫苗由 芬太尼为基础的半抗原(F0)与锁孔帽状血蓝蛋白载体蛋白偶联并吸附 加入明矾佐剂。F0-KLH免疫可减少芬太尼在脑内的分布，并选择性地 减轻芬太尼诱导的大鼠抗伤害作用和呼吸抑制。我们将进一步优化领先优势 F0-KLH通过检测替代载体蛋白。同时，我们将开发其他结合疫苗，其中包含一种 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 交错地跨越UG3/UH3阶段，我们预计第一个领先的F0载体结合疫苗将 准备好在第三年年底提交IND申请。AIM1专注于含铅F0的疫苗的优化 新的FN半抗原结合到工业标准载体蛋白上，包括两个大肠杆菌表达的载体 从我们的行业合作伙伴FinaBiosolution获得。铅被确定为在诱导抗体方面的有效性 将减少芬太尼(或芬太尼类似物)在大脑中的分布，并减少抗伤害、呼吸 对大鼠的抑郁和致命性。AIM1还描述了额外的免疫方案和疫苗 芬太尼自身给药大鼠模型的疗效。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配方中联合使用 同时瞄准芬太尼及其类似物。AIM3专注于GMP疫苗的制造和评估 它们通过CMO和CRO合作伙伴在GLP临床前毒理学研究中的安全性。AIM3随后将提交IND 至少一种针对芬太尼和/或其类似物的疫苗配方。

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.