Development of safe and effective immunotherapeutics for treatment of opioid abuse and overdose
开发安全有效的免疫疗法来治疗阿片类药物滥用和过量
基本信息
- 批准号:10010998
- 负责人:
- 金额:$ 22.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:Active ImmunizationAddressAffinityAnimal ModelAntibodiesAntibody TherapyAntibody titer measurementBacteriophagesBindingBiological AssayBiomedical EngineeringBloodBlood - brain barrier anatomyBlood CirculationBrainCause of DeathCessation of lifeClinicalClinical TrialsContractsCountryCustomCyclic GMPDevelopmentDisabled PersonsDiseaseDoseDrug KineticsDrug usageEmergency SituationEngineeringEnzyme-Linked Immunosorbent AssayEpidemicFDA approvedFc ReceptorFentanylFormulationFutureGenerationsGoalsGuidelinesHaptensHeroinHydrocodoneImmobilizationImmunoglobulin GImmunotherapeutic agentImmunotherapyIn VitroIndividualKineticsLibrariesMedicalMethodologyMethodsModalityMonitorMonoclonal AntibodiesNanotechnologyOpiate AddictionOpioidOpioid replacement therapyOverdoseOxycodonePassive ImmunotherapyPathway interactionsPatientsPenetrationPeripheralPhage DisplayPharmaceutical PreparationsPhaseRelapseReportingResistanceRodentSafetySmall Business Innovation Research GrantSolubilitySpecificitySystemTestingTherapeuticTherapeutic antibodiesTissuesToxicologyUnited StatesVaccinesVariantaddictionaqueousbasechemical conjugatecombatcost effectivedensitydrug of abuseeffective interventionexperimental studyfentanyl abuseimprovedin vivomagnetic beadsmanufacturing processmethamphetamine abusemethamphetamine usenanobodiesnanoparticlenovelnovel therapeuticsopioid abuseopioid epidemicopioid overdoseopioid userpre-clinicalpreclinical evaluationprescription opioidpreventreceptorside effectsuccesssynthetic biologysynthetic opioid
项目摘要
Project Summary
The abuse of opioids, which include heroin and synthetic opioids (e.g., fentanyl), is a growing
problem in the United States that is partly responsible for the recently declared National Emergency for
Opioid crisis. Between 2006 and 2015, the number of heroin-related deaths increased over 600% where
heroin laced synthetic opioids (e.g., the “killer opioids”) is responsible most of the deaths from abuse of
opioids. Although FDA-approved medications to treat opioid addiction are available, the utilization rate for
these medications is limited from side effects, tight prescription guidelines, and restricted availability. The
ongoing rise in opioid abuse creates a dire need for new therapy that offers long-lasting, safe, and cost-
effective interventions for overdoses and relapses but avoid side effects associated with current addiction
medications. Immunopharmacotherapy using drug-specific antibodies (i.e., immunoantagonists) to block
opioid drug activity and prevent the target opioids entering the brain are promising treatment approach
that have less side-effect than the traditional drug-based opioid replacement treatment. In this SBIR project,
we propose to develop a new class of immunotherapeutics-the nanobodies (e.g. the single domain
antibodies, sdAbs) that have high specificities and affinities to heroin, fentanyl for the treatment of “killer
opioids” overdose and abuse. We expect the opioid-specific nanobodies will be better
immunotherapeutics than traditional immunoglobulin G-based drug antibodies because nanobodies are
extremely robust, highly resistant to denaturation, have superior tissue penetration, and have ability to cross
blood brain barrier. Our goal is to achieve long-lasting and high titer antibodies to opioid drugs of abuse.
The phase I project will focus on in vitro methodologies for the generation of specific nanobodies with high
affinities to “killer opioids” from phage-display nanobody library. In the Phase I project, we will make
derivatives of opioid drugs such that they can be chemically conjugated at high density on magnetic
beads, and isolate high affinity nanobodies specific to heroin and fentanyl. Furthermore, we will engineer
and express individual single domain antibody to produce bivalent (multivalent) nanobody or multi-
nanobody-conjugated nanoparticles as new therapeutic modalities targeting two or more opioids
simultaneously. These nanobodies will improve upon current drug-specific antibody paradigms by
increasing multivalency and allowing pharmacokinetic customization, while avoiding interactions with
endogenous antibody receptor pathways. Successful completion of Phase I project will generate novel
opioid-specific nanobodies and provide a framework for the development of immunotherapeutics against
other drugs of abuse. In future Phase II, we will perform the pre-clinical in vitro and in vivo rodent
pharmacokinetic study of individual nanobodies and multivalent nanobody for therapeutic neutralizations of
the killer opioids.
项目概要
阿片类药物(包括海洛因和合成阿片类药物(例如芬太尼))的滥用日益严重
美国的问题是最近宣布的国家紧急状态的部分原因
阿片类药物危机。 2006年至2015年间,海洛因相关死亡人数增加了600%以上,其中
含有海洛因的合成阿片类药物(例如“杀手阿片类药物”)是滥用海洛因造成的大部分死亡的原因。
阿片类药物。尽管 FDA 批准的药物可以治疗阿片类药物成瘾,但其使用率
这些药物由于副作用、严格的处方指南和供应有限而受到限制。这
阿片类药物滥用的持续增加迫切需要提供持久、安全且成本低廉的新疗法
对过量和复发进行有效干预,但避免与当前成瘾相关的副作用
药物。使用药物特异性抗体(即免疫拮抗剂)来阻断的免疫药物疗法
阿片类药物活性和阻止目标阿片类药物进入大脑是有前途的治疗方法
与传统的基于药物的阿片类药物替代治疗相比,副作用更少。在这个 SBIR 项目中,
我们建议开发一类新的免疫治疗药物——纳米抗体(例如单域
抗体(sdAbs)对海洛因、芬太尼具有高度特异性和亲和力,用于治疗“杀手”
阿片类药物过量和滥用。我们预计阿片类药物特异性纳米抗体会更好
与传统的基于免疫球蛋白 G 的药物抗体相比,纳米抗体具有更好的免疫治疗效果
极其坚固,高度抗变性,具有卓越的组织渗透性,并且能够穿过
血脑屏障。我们的目标是获得针对滥用阿片类药物的持久且高效价的抗体。
第一阶段项目将重点关注体外方法学,用于生成具有高通量的特定纳米抗体。
与噬菌体展示纳米抗体库中的“杀手阿片类药物”的亲和力。在第一期项目中,我们将
阿片类药物的衍生物,使其可以在磁性上以高密度化学结合
珠子,并分离出针对海洛因和芬太尼的高亲和力纳米抗体。此外,我们将设计
并表达单个单域抗体以产生二价(多价)纳米抗体或多价
纳米抗体缀合的纳米颗粒作为针对两种或多种阿片类药物的新治疗方式
同时地。这些纳米抗体将通过以下方式改进当前的药物特异性抗体范例
增加多价并允许药代动力学定制,同时避免与
内源性抗体受体途径。一期工程的顺利完成将产生新的
阿片类药物特异性纳米抗体,并为开发针对阿片类药物的免疫疗法提供了框架
其他滥用药物。在未来的第二阶段,我们将进行临床前的体外和啮齿动物体内实验
用于治疗中和的单个纳米抗体和多价纳米抗体的药代动力学研究
杀手阿片类药物。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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XICHUN ZHOU其他文献
XICHUN ZHOU的其他文献
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{{ truncateString('XICHUN ZHOU', 18)}}的其他基金
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