Development of Kv1.3 Monoclonal Antibodies Targeting TEM Cells for Treating Autoimmune Disorders
开发针对 TEM 细胞的 Kv1.3 单克隆抗体用于治疗自身免疫性疾病
基本信息
- 批准号:10374043
- 负责人:
- 金额:$ 58.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-05 至 2024-09-30
- 项目状态:已结题
- 来源:
- 关键词:AbbreviationsAddressAffectAffinityAmericanAnimal ModelAntibodiesAutoimmuneAutoimmune DiseasesBindingBiological AssayBiological MarkersBiosensorCardiacCell LineCellsChronicClinicalClinical TreatmentClinical TrialsComplexDataDelayed HypersensitivityDevelopmentDiseaseDrug KineticsDrug or chemical Tissue DistributionEffector CellElectrophysiology (science)EngineeringEnvironmentEpitopesExperimental Autoimmune EncephalomyelitisFamily memberFormulationFutureGoalsHealth Care CostsHumanImmuneInflammatoryInterferon Type IIInterleukin-2Ion ChannelIon Channel GatingKineticsLeadLipidsLupusMapsMediatingMembraneMembrane PotentialsMemoryModelingMonoclonal AntibodiesMutagenesisNeuronsPharmaceutical PreparationsPharmacologic SubstancePhaseProbabilityProteinsProteomePsoriasisPsoriatic ArthritisPublic HealthRattusResearchRheumatoid ArthritisRiskSafetySalesShotgunsSmall Business Innovation Research GrantSpecificityStructureT memory cellT-LymphocyteTechnologyTestingTherapeutic Monoclonal AntibodiesTimeLineantibody engineeringbiopharmaceutical industryblood-brain barrier crossingcandidate selectioncell typechronic inflammatory diseasecross reactivitydifferential expressionefficacy testinggraft vs host diseasehuman diseaseimmunogenicityimprovedin vivoinhibitorlead candidateoverexpressionpeptide drugphase 1 studyphase 2 studypreclinical studyside effectsmall moleculesubcutaneoussuccessterminally differentiated effector memory (TEM) T cellstherapeutic developmenttherapeutic targettherapy developmentvoltage
项目摘要
ABSTRACT
T cell-mediated autoimmune and chronic inflammatory diseases affect 23 million Americans,
corresponding to ~$100B/year in direct healthcare costs. Pharmaceutical advances have enabled
the development of treatments for these diseases, but existing drugs have severe immune-
compromising side effects because they broadly target all T cell activity. The voltage-gated ion
channel Kv1.3 is a validated therapeutic target for autoimmune diseases. Kv1.3 is differentially
expressed on disease-relevant T cell types (activated effector memory TEM cells), making it a
more selective (and safer) target. Small molecule and peptide-based drugs against Kv1.3 have
shown efficacy in nearly every human ex vivo and rat model of autoimmune disease, as well as
human clinical trials. However, existing molecules show poor pharmacokinetics and cross-
reactivity with other Kv family members. Drugs that can overcome these issues, such as MAbs,
are predicted to be highly effective in treating autoimmune disorders with fewer side effects.
However, inhibitory MAbs against ion channels such as Kv1.3 are extremely challenging to
isolate because ion channels form complex transmembrane structures, are toxic when over-
expressed, and are difficult to purify away from their native lipid environment. Here we propose
to develop Kv1.3 MAbs to treat autoimmune and chronic inflammatory disorders.
摘要
T细胞介导的自身免疫性和慢性炎症性疾病影响着2300万美国人,
相当于每年约1000亿美元的直接医疗保健成本。制药技术的进步
这些疾病的治疗方法的发展,但现有的药物有严重的免疫-
因为它们广泛靶向所有T细胞活性。电压门控离子
通道Kv1.3是自身免疫性疾病的有效治疗靶点。Kv1.3是不同的
在疾病相关的T细胞类型(激活的效应记忆TEM细胞)上表达,使其成为
选择性更强(也更安全)的目标。针对Kv1.3的小分子和肽类药物
在几乎每一种人离体和大鼠自身免疫性疾病模型中显示出有效性,
人体临床试验。然而,现有的分子显示出差的药代动力学和交叉-
与其他Kv家族成员的反应。可以克服这些问题的药物,如单克隆抗体,
被预测在治疗自身免疫性疾病方面非常有效,副作用更少。
然而,针对诸如Kv1.3的离子通道的抑制性MAb对于
隔离是因为离子通道形成复杂跨膜结构,当过度时是有毒的,
表达,并且难以从其天然脂质环境中纯化。在这里我们建议
开发Kv1.3单克隆抗体以治疗自身免疫性和慢性炎症性疾病。
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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JOSEPH Benjamin RUCKER其他文献
JOSEPH Benjamin RUCKER的其他文献
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{{ truncateString('JOSEPH Benjamin RUCKER', 18)}}的其他基金
Development of Claudin MAbs for Treating Solid Tumors
用于治疗实体瘤的 Claudin MAb 的开发
- 批准号:
10482193 - 财政年份:2022
- 资助金额:
$ 58.95万 - 项目类别:
Development of Claudin MAbs for Treating Solid Tumors
用于治疗实体瘤的 Claudin MAb 的开发
- 批准号:
10631161 - 财政年份:2022
- 资助金额:
$ 58.95万 - 项目类别:
Development of Nav1.7 Monoclonal Antibodies for Treating Pain
开发用于治疗疼痛的 Nav1.7 单克隆抗体
- 批准号:
10318547 - 财政年份:2021
- 资助金额:
$ 58.95万 - 项目类别:
Development of High-expressing Ion Channels for Research and Therapeutic Applicat
用于研究和治疗应用的高表达离子通道的开发
- 批准号:
8775955 - 财政年份:2014
- 资助金额:
$ 58.95万 - 项目类别:
Development of High-expressing Ion Channels for Research and Therapeutic Applicat
用于研究和治疗应用的高表达离子通道的开发
- 批准号:
8920157 - 财政年份:2014
- 资助金额:
$ 58.95万 - 项目类别:
Development of Kv1.3 Monoclonal Antibodies Targeting TEM Cells for Treating Autoimmune Disorders
开发针对 TEM 细胞的 Kv1.3 单克隆抗体用于治疗自身免疫性疾病
- 批准号:
9906631 - 财政年份:2014
- 资助金额:
$ 58.95万 - 项目类别:
Isolation of Monoclonal Antibodies against Membrane Proteins
膜蛋白单克隆抗体的分离
- 批准号:
8057198 - 财政年份:2011
- 资助金额:
$ 58.95万 - 项目类别:
Development of P2X3 Ion Channel MAbs for the Treatment of Pain
开发用于治疗疼痛的 P2X3 离子通道单克隆抗体
- 批准号:
9130898 - 财政年份:2011
- 资助金额:
$ 58.95万 - 项目类别:
Isolation of Monoclonal Antibodies against Membrane Proteins
膜蛋白单克隆抗体的分离
- 批准号:
8215713 - 财政年份:2011
- 资助金额:
$ 58.95万 - 项目类别:
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