IND-enabling program for a long-acting anti-methamphetamine monoclonal antibody for treating methamphetamine use disorder
用于治疗甲基苯丙胺使用障碍的长效抗甲基苯丙胺单克隆抗体的 IND 项目
基本信息
- 批准号:10706499
- 负责人:
- 金额:$ 433.63万
- 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:2022-09-30 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AdherenceAffinityAmendmentAnimalsAntibodiesBehavior TherapyBehavioralBindingBiological AssayBrainCell LineChronicClinicalClinical ProtocolsClinical ResearchClinical TrialsCognitiveDataDevelopmentDiagnosisDoseDrug KineticsFDA approvedFab ImmunoglobulinsFrequenciesGoalsGrantHalf-LifeHealthHealth Care CostsHealthcareHomeHumanImmunoglobulin GIn VitroInfusion proceduresLengthMethamphetamineMethamphetamine overdoseMethamphetamine use disorderModelingModificationMonoclonal AntibodiesMotor ActivityMutationOutcomeParticipantPatient CarePatient-Focused OutcomesPatientsPersonsPharmaceutical PreparationsPopulationPreclinical TestingPreparationProductionRattusRecoveryRelapseResearchResearch DesignRiskRodentRunningSafetyStep TestsStimulantTestingTimeToxicokineticsToxicologyTreatment CostVaccinesVisitWorkWritingantagonistcandidate selectioncell bankclinic readyclinical developmentcompliance behaviorcontingency managementcostdesigndisabilityefficacy studyfirst-in-humanhealthy volunteerhumanized monoclonal antibodiesimmunogenicityimprovedlead candidatemanufacturemanufacturing processmedication compliancemeetingsmethamphetamine effectmethamphetamine usenonhuman primatephase 1 studypre-Investigational New Drug meetingprogramsresponsestable cell line
项目摘要
PROJECT ABSTRACT
Nearly 1 million people in the US were diagnosed with a methamphetamine (METH) use disorder (MUD) in 2017.
Once established, MUD can last a long time and is very difficult to treat. Yet there are still no FDA-approved
medications indicated specifically for MUD. Anti-METH antibodies have been tested preclinically in efficacy
models and have shown the ability to reduce METH’s stimulant effects in rodents. In humans, these same
antibodies alter METH PK by reducing volume of distribution and likely decreasing distribution to the brain.
Current antibodies would be dosed once a month; longer-acting agents would increase compliance due to less
frequent dosing. The goal of this application is to identify a follow-on anti-METH monoclonal antibody with an
extended half-life and conduct IND-enabling development and toxicology studies so that at the end of the project
it is ready for a first-in-human clinical trial. In addition to increased compliance, the benefits of a long-acting
antibody for treating MUD may include lower cost of treatment and overall better clinical outcomes. The identified
antibody will also be fully humanized, which may lower the risk of antigenicity upon chronic dosing.
The project will be accomplished through four Specific Aims. Aim 1 is to select the final lead candidate long-
acting antibody. A panel of seven previously humanized METH-binding regions will be produced as Fabs and
tested in a METH-stimulated locomotor model in rats. The best will be paired with two IgG constant domains that
have selected mutations to extend their half-life. The two IgG will be compared in the same efficacy model, along
with in vitro characterization, and the final candidate selected.
In Aim 2, a clonal cell line and scalable manufacturing process will be developed for the final candidate IgG. A
Master Cell Bank will be generated from the cell line and used for manufacture of clinical batches. A 50L run will
produce material for development work and testing, then a 250L batch will be made to provide antibody for
toxicology testing in Aim 3. Finally, a 500L GMP batch will be manufactured for first-in-human clinical studies.
IND-enabling toxicology studies in rats will be conducted under Aim 3. A single-dose study will test IV doses up
to 1.5 g/kg. A multiple-dose study will test doses up to 1 g/kg given every other week for six months. Antibody
toxicokinetics and immunogenicity will be determined along with typical toxicology outcomes.
Aim 4 consists of the development of the regulatory submissions and other preparations for initial clinical trials.
A pre-IND meeting will be held with FDA following the completion of Aim 1, then a clinical protocol will be fully
developed based on the discussion. As the program develops, the entire IND including quality, nonclinical, and
FDA-specific modules will be written and submitted at the end.
The expected outcome of this project is a clinic-ready humanized monoclonal antibody to treat MUD that only
has to be dosed once every 2-3 months. Such a candidate would deliver improved patient outcomes with lower
treatment burden and higher adherence.
项目摘要
2017年,美国有近100万人被诊断患有甲基苯丙胺(METH)使用障碍(MUD)。
一旦确诊,MUD可以持续很长时间,并且很难治疗。
专门针对MUD的药物。抗METH抗体已在临床前进行了有效性测试
模型,并已显示出减少METH的刺激作用在啮齿动物的能力。在人类中,这些相同的
抗体通过减少分布体积和可能减少向脑的分布来改变METH PK。
目前的抗体将每月给药一次;长效药物将增加依从性,因为
频繁给药。本申请的目的是鉴定具有以下特性的后续抗METH单克隆抗体:
延长半衰期,并进行IND开发和毒理学研究,以便在项目结束时
它已经准备好进行首次人体临床试验。除了增加依从性外,
治疗MUD的抗体可能包括更低的治疗成本和总体更好的临床结果。所识别的
抗体也将是完全人源化的,这可以降低长期给药时抗原性的风险。
该项目将通过四个具体目标来实现。目标1是选择最终的领先候选人长-
作用抗体一组七个先前人源化的MET结合区将作为Fab产生,
在大鼠的MET刺激运动模型中测试。最好的将与两个IgG恒定结构域配对,
选择突变来延长半衰期。将在相同的疗效模型中比较两种IgG,沿着
进行体外表征,并选择最终候选物。
在目标2中,将为最终候选IgG开发克隆细胞系和可扩展的生产工艺。一
主细胞库将由细胞系生成,并用于生产临床批次。50 L运行将
生产用于开发工作和检测的材料,然后生产250 L批次,为
目标3中的毒理学测试。最后,将生产500 L GMP批次用于首次人体临床研究。
将根据目标3在大鼠中进行IND使能毒理学研究。单次给药研究将测试IV剂量
至1.5g/kg。多次给药研究将测试每隔一周给予高达1 g/kg的剂量,持续6个月。抗体
将沿着典型的毒理学结果确定毒代动力学和免疫原性。
目标4包括为初始临床试验开发监管申报和其他准备工作。
在完成目标1后,将与FDA举行IND前会议,然后将全面制定临床方案。
根据讨论制定。随着项目的发展,整个IND包括质量、非临床和
FDA特定模块将在最后编写并提交。
该项目的预期成果是临床准备的人源化单克隆抗体,用于治疗MUD,
必须每2-3个月给药一次。这样的候选人将以更低的成本提供改善的患者结果。
治疗负担和更高的依从性。
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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{{ truncateString('Misty Ward Stevens', 18)}}的其他基金
IND-enabling program for a long-acting anti-methamphetamine monoclonal antibody for treating methamphetamine use disorder
用于治疗甲基苯丙胺使用障碍的长效抗甲基苯丙胺单克隆抗体的 IND 项目
- 批准号:
10476678 - 财政年份:2022
- 资助金额:
$ 433.63万 - 项目类别:
Optimization and testing of anti-methamphetamine antibody therapy to support pivotal clinical trials and commercialization
抗甲基苯丙胺抗体疗法的优化和测试以支持关键的临床试验和商业化
- 批准号:
10361540 - 财政年份:2020
- 资助金额:
$ 433.63万 - 项目类别:
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