Immunotherapy to Counteract Lethal Doses of Carfentanil

抵消致死剂量卡芬太尼的免疫疗法

• 批准号: 9563769
• 负责人: Kim Janda
• 金额: $ 52.07万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 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 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9563769
• 关键词: Acute; Affect; Affinity; Analgesics; Animals; Antibodies; Antibody Affinity; Antibody Therapy; Attenuated; B-Lymphocytes; Behavioral; Binding; Biodistribution; Biological Assay; Blood; Brain; Catabolism; Catalytic Antibodies; Cell Separation; Cessation of life; Characteristics; Chemical Warfare Agents; China; Clinical Trials; Clone Cells; Cocaine; Code; Conjugate Vaccines; Coupled; Dangerousness; Designer Drugs; Development; Dose; Drug Controls; Drug Kinetics; Drug abuse; Epitopes; Exhibits; Exposure to; Family; Fentanyl; Genes; Growth; Half-Life; Haptens; Health Personnel; Hematologic Agents; Heroin; Human; Immersion Investigative Technique; Immunize; Immunoconjugates; Immunoglobulin G; Immunotherapeutic agent; Immunotherapy; Infusion procedures; Kinetics; Lead; Lethal Dose 50; Location; Macaca mulatta; Mass Spectrum Analysis; Metabolism; Methamphetamine; Methods; Modality; Modeling; Monitor; Monoclonal Antibodies; Monoclonal Antibody Therapy; Morphine; Mouse Strains; Mus; Naloxone; Nicotine; Opioid; Opioid user; Overdose; Oxycodone; Passive Immunization; Performance; Pharmaceutical Preparations; Pharmacodynamics; Physiological Processes; Preparation; Process; Production; Property; Proteins; Psychotropic Drugs; Rat Strains; Resolution; Rodent; Russia; Sampling; Schedule; Scheme; Secure; Series; Site; Specificity; Surface Plasmon Resonance; Tail; Test Result; Testing; Tetanus Toxoid; Therapeutic; Therapeutic Monoclonal Antibodies; Therapeutic Uses; Time; Toxic effect; Transgenic Organisms; Translating; Vaccination; Vaccines; acute toxicity; addiction; aerosolized; analog; behavior test; carfentanil; chemical threat; cohort; combat; cost efficient; depressive symptoms; design; drug synthesis; first responder; fluorophore; humanized antibody; humanized monoclonal antibodies; improved; medical countermeasure; mortality; mortality risk; mu receptors; nonhuman primate; opioid abuse; opioid overdose; overexpression; preservation; prevent; prophylactic; remifentanil; respiratory; response; stem; synthetic opioid; therapeutic lead compound

This proposal is in response to PAR-16-330: “Countermeasures Against Chemical Threats (CounterACT): Identification of Therapeutic Lead Compounds” and incorporates the development of monoclonal antibody (mAb) therapy as a solution for acute exposure to the potent synthetic opioid threat, carfentanil. Beginning in 1979, the illicit synthesis of drugs was elevated to an extraordinarily sophisticated level. A number of overdose victims' deaths were attributed to heroin, however, seized samples contained no heroin, rather the victims were inadvertently buying “China White” (i.e., α-methylfentanyl). The fentanyls are a large family of synthetic analgesics that possess all the properties of the opiates, except they are 100-10,000 times more potent than morphine. Reasons for fentanyl resurfacing are tied to a decline in heroin purity, a need to increase potency and cost-efficient preparation. Designer fentanyl's can be synthesized at a single location and because of their potency; a single gram could be formulated (cut) into many thousand, perhaps millions of doses. Preventing the distribution of such small amounts of a pure drug is exceedingly difficult. Thus, while drug control efforts will need to continue, so will efforts to treat synthetic psychoactive drug (SPD) abuse. One (SPD) analogue, carfentanil, is of particular concern because of its extreme potency (10,000 times that of morphine). It has no therapeutic use in humans, posing a significant mortality risk for opioid users. Another issue arises from the persistence of carfentanil in the body; the half-life of the drug exceeds naloxone, requiring multiple infusions of naloxone over time and careful monitoring or else results in re-narcotization. An aerosolized mixture of carfentanil and remifentanil was used as a chemical warfare agent in Russia, resulting in 170 civilian deaths in 2002. A promising therapeutic strategy for attenuating the effects of SPDs can be found in antibody vaccine hapten conjugate. Indeed this strategy has been successfully used against cocaine, nicotine and methamphetamine. Accordingly, we plan to investigate various antibody manifolds stemming from these hapten bioconjugates including catalytic antibodies; importantly each unique antibody manifold may prove more effective than naloxone due drug catabolism and a tunable half-life. We will take two approaches, active and passive vaccine strategies, to counter this dangerous drug, however, both will be grounded upon unique hapten design that will be critical in producing antibodies with tight binding and selective specificity. Antibodies from the latter will come via active vaccination in transgenic OmniRats, and will use a selection process wherein human antibodies will be secured through unique carfentanil-tagged fluorophore coupled with fluorescent-activated cell sorting and analysis. Finally, a metric will be needed to judge the value of both types of vaccines for treating carfentanil's physiological processes; we will look at protection against carfentanil- induced toxicity in both rodents and nonhuman primates. Humanized mAb's against carfentanil will provide a new and improved medical countermeasure to combat the acute toxicity of this chemical threat.

该提议是对16-330 par的回应：“针对化学威胁的对策 （抵消）：鉴定治疗性铅化合物”，并结合了 单克隆抗体（MAB）疗法作为急性暴露于潜在合成阿片类药物威胁的解决方案， carfentanil。从1979年开始，药物的非法综合被提升为非常精致的 等级。但是，许多滥用滥用的死亡归因于海洛因，但是，扣押的样本中没有 海洛因，而令人恐惧的东西是无意中购买的“中国白”（即α-甲基芬太尼）。芬太尼是 大型合成镇痛药具有操作的所有特性，除了100-10,000 倍于吗啡的潜力更多。芬太尼重铺的原因与海洛因纯度下降有关，需要 增加效力和成本效益的准备。设计师芬太尼可以在一个位置合成 并且由于他们的效力；可以将一克制定（切成）成千上万，也许是数百万 剂量。防止如此少量的纯药物的分布非常困难。那，而 药物控制工作将需要继续，因此将努力治疗合成精神药物（SPD）滥用。一 （SPD）类似物（Carfentanil 吗啡）。它在人类中没有治疗用途，对阿片类药物使用者带来了重大的死亡风险。其他 问题是由于体内卡芬太尼的持续存在而引起的。药物的半衰期超过纳洛酮，需要 随着时间的推移，纳洛酮多次输注和仔细的监测或导致重新纳入。一个 Carfentanil和Remifentanil的雾化混合物在俄罗斯被用作化学战剂 在2002年的170例平民死亡中。 发现在抗体疫苗抗原结合物中。确实，该策略已成功地用于可卡因， 尼古丁和甲基苯丙胺。根据，我们计划研究来自 这些抗催化抗体在内的Hapen hapten生物缀合物；重要的是，每种独特的抗体歧管可能 由于药物分解代谢和可调节的半衰期而言，证明比纳洛酮更有效。我们将采用两种方法， 但是，为了应对这种危险药物，主动和被动疫苗策略将基于 独特的触觉设计对于产生具有紧密结合和选择性特异性的抗体至关重要。 后来的抗体将通过转基因综合体中的主动疫苗接种，并将使用选择 其中将通过独特的carfentanil标记的荧光团和连接的人类抗体固定的过程 荧光激活的细胞分选和分析。最后，需要一个指标来判断两种类型的价值 用于治疗Carfentanil物理过程的疫苗；我们将研究防止Carfentanil- 引起啮齿动物和非人类隐私的毒性。人性化的mab反对carfentanil将提供 与这种化学威胁的急性毒性作斗争的新医疗对策。