Antibody-based countermeasures against fentanyl and its analogues
基于抗体的芬太尼及其类似物对策
基本信息
- 批准号:10598994
- 负责人:
- 金额:$ 77.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdjuvantAdministrative SupplementAffinityAlfentanilAntibodiesAntigensB-Cell Antigen ReceptorB-LymphocytesBehaviorBenchmarkingBindingBiological AssayBradycardiaBrainBuprenorphineCanadaChemical WarfareChemicalsCloningContractorDevelopmentDrug KineticsEuropeExposure toFDA approvedFab ImmunoglobulinsFamilyFentanylFormulationFutureGenerationsGoalsHalf-LifeHeroinHospitalizationHumanHybridomasImmunizationImmunizeImmunoglobulin FragmentsIn VitroIndustryIndustry StandardIntellectual PropertyLeadLengthLymphocyteMacaca mulattaMagnetismMethadoneMilitary PersonnelModelingModificationMonoclonal AntibodiesMusNaloxoneNaltrexoneNorth AmericaOpioidOpioid AntagonistOpioid ReceptorOxycodonePassive ImmunizationPharmaceutical PreparationsPoisoningPolymersProcessPublic HealthRattusRiskRisk AssessmentSeriesSiteSufentanilSystemTechnologyTestingToxic effectTransgenic MiceUnited StatesVaccinesVentilatory DepressionX-Ray Crystallographyanalogantagonistbasebiocompatible polymerbiodegradable polymerbiophysical propertiescarfentanilchemical threatcommercializationefficacy testingendogenous opioidshumanized monoclonal antibodieshumanized mouseimprovedin vivolead optimizationmass casualtymedical countermeasuremeetingsmouse modelnext generationnonhuman primateopioid overdosepolyclonal antibodypolymerizationpreclinical developmentresearch clinical testingscale upscreening
项目摘要
ABSTRACT. This project will develop monoclonal antibodies (mAb) against toxicity and lethality from accidental
or deliberate exposure to fentanyl, carfentanil, acetylfentanil, and alfentanil. The US has seen dramatic increases
in fatal opioid poisoning due to the widespread availability of fentanyl and fentanyl-like analogs. Because of the
risk for accidental or deliberate mass casualty incidents, the fentanyl chemical family is listed in the DHS
Chemical Threat Risk Assessment list. As a complementary adjuvant strategy to current medications for rescue
of opioid poisoning (e.g., the opioid receptor antagonist naloxone), our team is developing mAb against fentanyl
and its potent analogs to reduce toxicity and lethality in both civilian and defense applications. Our team has
shown that antibody-based strategies effectively reduce opioid distribution to the brain as well as opioid-induced
respiratory depression and bradycardia in mice and rats. Antibodies selectively target the intended opioid, but
do not interfere with endogenous opioids nor with naloxone or other approved medications. Our team has
identified lead first-generation mouse anti-fentanyl mAbs using an antigen-based enrichment strategy to isolate
opioid-specific B cell lymphocytes from immunized mice to generate hybridomas, and mouse/human chimeric
mAb for expression in a suitable mammalian system. The proposed U01 project will further optimize these leads
through an iterative developmental plan. AIM1 focuses on optimization of humanized mAb against fentanyl,
carfentanil, acetylfentanyl, and alfentanil by integrating humanization of lead mouse mAb and immunization of
humanized or transgenic mice. The lead mAb will be used as a benchmark for selection of next-generation
candidates. Leads will be identified for their affinity and selectivity in vitro, and for in vivo efficacy in reducing
antinociception, respiratory depression and lethality in rats. The humanization process will be guided by
biophysical characterization of mAb binding to fentanyl and its analogs by X-ray crystallography. AIM2 focuses
on optimization of lead mAb (Fab or F(ab)2 fragments as alternative options) via polymer-based modifications to
improve half-life and volume of distribution, and increase efficacy against fentanyl and its analogs. AIM3 will test
efficacy of leads co-administered as a multicomponent mAb formulation in combination with opioid antagonists
to provide enhanced protection against respiratory depression and lethality in rats challenged with fentanyl and
its derivatives. To provide proof of scalability, AIM4 tests the efficacy of the lead humanized mAb in a non-human
primate model of opioid-induced respiratory depression. Leads from previous aims will be synthesized at a larger
scale at a contractor site. Finally, AIM5 focuses on drafting a regulatory path toward late-stage development and
commercialization.
抽象的。该项目将开发抗意外致死性和毒性的单抗(MAb)。
或故意接触芬太尼、卡芬太尼、乙酰芬太尼和阿芬太尼。美国经历了急剧的增长
由于芬太尼和芬太尼类似物的广泛使用,导致致命的阿片类药物中毒。因为
意外或故意大规模伤亡事件的风险,芬太尼化学家族被列入国土安全部
化学品威胁风险评估清单。作为当前抢救药物的补充辅助策略
对于阿片中毒(如阿片受体拮抗剂纳洛酮),我们的团队正在开发针对芬太尼的mAb
以及其有效的类似物,以降低民用和国防应用中的毒性和致命性。我们队有
表明基于抗体的策略有效地减少了阿片类药物在大脑中的分布以及阿片类药物的诱导
小鼠和大鼠的呼吸抑制和心动过缓。抗体选择性地针对预期的阿片类药物,但
不要干扰内源性阿片类药物,也不要干扰纳洛酮或其他经批准的药物。我们队有
用基于抗原的浓缩策略鉴定Lead第一代小鼠抗芬太尼单抗
免疫小鼠产生杂交瘤的阿片类特异性B细胞和人/鼠嵌合体
用于在合适的哺乳动物系统中表达的单抗。建议的U01项目将进一步优化这些线索
通过一个迭代的发展计划。AIM1致力于人源化抗芬太尼单抗的优化,
卡芬太尼、乙酰芬太尼和阿芬太尼
人源化或转基因小鼠。主导单抗将被用作下一代选择的基准
候选人。将在体外确定铅的亲和力和选择性,并在体内确定其降低
大鼠的抗伤害性、呼吸抑制和致死性。人性化进程将由
单抗与芬太尼及其类似物结合的X射线结晶学生物物理表征AIM2焦点
关于通过聚合物修饰来优化铅单抗(Fab或F(Ab)2片段作为替代选项)
改善半衰期和分布体积,并提高对芬太尼及其类似物的疗效。AIM3将测试
多组分单抗制剂与阿片类拮抗剂联合给药的疗效
加强对芬太尼和芬太尼激发的大鼠呼吸抑制和致死的保护
它的衍生产品。为了提供可伸缩性的证据,AIM4测试了先导人源化mAb在非人类体内的效果
阿片类药物所致呼吸抑制的灵长类动物模型。来自以前目标的线索将在更大的
承包商现场的规模。最后,AIM5侧重于起草一条通往后期开发和
商业化。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Pharmacology and pharmacokinetics of fentanyl toxicity reversal by anti-fentanyl monoclonal antibodies in combination with naloxone.
抗芬太尼单克隆抗体与纳洛酮联合逆转芬太尼毒性的药理学和药代动力学。
- DOI:
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:Baehr,CarlyA;Pravetoni,Marco
- 通讯作者:Pravetoni,Marco
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Marco Pravetoni其他文献
Marco Pravetoni的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Marco Pravetoni', 18)}}的其他基金
Antibody-based countermeasures against fentanyl and its analogues
基于抗体的芬太尼及其类似物对策
- 批准号:
10227130 - 财政年份:2020
- 资助金额:
$ 77.44万 - 项目类别:
Antibody-based countermeasures against fentanyl and its analogues
基于抗体的芬太尼及其类似物对策
- 批准号:
10015669 - 财政年份:2020
- 资助金额:
$ 77.44万 - 项目类别:
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 - 财政年份:2019
- 资助金额:
$ 77.44万 - 项目类别:
Novel nanovaccines against opioid use disorders
针对阿片类药物使用障碍的新型纳米疫苗
- 批准号:
9796252 - 财政年份:2019
- 资助金额:
$ 77.44万 - 项目类别:
Enhancing efficacy of vaccines for substance abuse through polymer-assisted delivery of immunomodulators
通过聚合物辅助免疫调节剂的递送来增强药物滥用疫苗的功效
- 批准号:
9117235 - 财政年份:2016
- 资助金额:
$ 77.44万 - 项目类别:
Early antigen-specific B cell responses as markers of oxycodone vaccine efficacy
早期抗原特异性 B 细胞反应作为羟考酮疫苗功效的标志
- 批准号:
8484815 - 财政年份:2012
- 资助金额:
$ 77.44万 - 项目类别:
Early antigen-specific B cell responses as markers of oxycodone vaccine efficacy
早期抗原特异性 B 细胞反应作为羟考酮疫苗功效的标志
- 批准号:
8402476 - 财政年份:2012
- 资助金额:
$ 77.44万 - 项目类别:
相似海外基金
Metachronous synergistic effects of preoperative viral therapy and postoperative adjuvant immunotherapy via long-term antitumor immunity
术前病毒治疗和术后辅助免疫治疗通过长期抗肿瘤免疫产生异时协同效应
- 批准号:
23K08213 - 财政年份:2023
- 资助金额:
$ 77.44万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Improving the therapeutic immunity of cancer vaccine with multi-adjuvant polymeric nanoparticles
多佐剂聚合物纳米粒子提高癌症疫苗的治疗免疫力
- 批准号:
2881726 - 财政年份:2023
- 资助金额:
$ 77.44万 - 项目类别:
Studentship
Evaluation of the Sensitivity to Endocrine Therapy (SET ER/PR) Assay to predict benefit from extended duration of adjuvant endocrine therapy in the NSABP B-42 trial
NSABP B-42 试验中内分泌治疗敏感性 (SET ER/PR) 测定的评估,用于预测延长辅助内分泌治疗持续时间的益处
- 批准号:
10722146 - 财政年份:2023
- 资助金额:
$ 77.44万 - 项目类别:
Countering sympathetic vasoconstriction during skeletal muscle exercise as an adjuvant therapy for DMD
骨骼肌运动期间对抗交感血管收缩作为 DMD 的辅助治疗
- 批准号:
10735090 - 财政年份:2023
- 资助金额:
$ 77.44万 - 项目类别:
AUGMENTING THE QUALITY AND DURATION OF THE IMMUNE RESPONSE WITH A NOVEL TLR2 AGONIST-ALUMINUM COMBINATION ADJUVANT
使用新型 TLR2 激动剂-铝组合佐剂增强免疫反应的质量和持续时间
- 批准号:
10933287 - 财政年份:2023
- 资助金额:
$ 77.44万 - 项目类别:
DEVELOPMENT OF SAS A SYNTHETIC AS01-LIKE ADJUVANT SYSTEM FOR INFLUENZA VACCINES
流感疫苗类 AS01 合成佐剂系统 SAS 的开发
- 批准号:
10935776 - 财政年份:2023
- 资助金额:
$ 77.44万 - 项目类别:
DEVELOPMENT OF SMALL-MOLECULE DUAL ADJUVANT SYSTEM FOR INFLUENZA VIRUS VACCINE
流感病毒疫苗小分子双佐剂体系的研制
- 批准号:
10935796 - 财政年份:2023
- 资助金额:
$ 77.44万 - 项目类别:
A GLYCOLIPID ADJUVANT 7DW8-5 FOR MALARIA VACCINES
用于疟疾疫苗的糖脂佐剂 7DW8-5
- 批准号:
10935775 - 财政年份:2023
- 资助金额:
$ 77.44万 - 项目类别:
Adjuvant strategies for universal and multiseasonal influenza vaccine candidates in the context of pre-existing immunity
在已有免疫力的情况下通用和多季节流感候选疫苗的辅助策略
- 批准号:
10649041 - 财政年份:2023
- 资助金额:
$ 77.44万 - 项目类别:
Adjuvant Photodynamic Therapy to Reduce Bacterial Bioburden in High-Energy Contaminated Open Fractures
辅助光动力疗法可减少高能污染开放性骨折中的细菌生物负载
- 批准号:
10735964 - 财政年份:2023
- 资助金额:
$ 77.44万 - 项目类别: