Novel treatments for Autoimmune Disease
自身免疫性疾病的新疗法
基本信息
- 批准号:10758915
- 负责人:
- 金额:$ 30.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-06-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AcantholysisAddressAdhesionsAdrenal Cortex HormonesAdultAdverse effectsAdverse eventAffectAftercareAntibodiesAntibody TherapyAntigensApplications GrantsAutoantibodiesAutoimmuneAutoimmune DiseasesB-LymphocytesBacteriaBindingBiological AssayBullaCell Surface ReceptorsChimeric ProteinsChronicClinicClinicalClinical ManagementCombined Modality TherapyDeglutitionDesmosomesDevelopmentDisadvantagedDiseaseDoseEndothelial CellsEngineeringExcisionFundingGamma globulinGeneral PopulationGenerationsGoalsHypertensionIgG autoantibodiesImmune ToleranceImmunoglobulin GImmunosuppressionImmunosuppressive AgentsInfectionInfectious AgentInflammatoryInfusion proceduresIntravenousKupffer CellsLaboratoriesLeadLesionLiverLysosomesMediatingMucous MembraneNamesOsteoporosisPainPathogenicityPatientsPemphigusPemphigus VulgarisPhasePlasmapheresisProceduresProcessPropertyQuality of lifeReactionReagentRelapseResearchResearch DesignRoleSamplingSerumSkinSpecificitySteroidsSurfaceTechnologyTexasTherapeuticTissuesTranslatingUniversitiesVirusWorkcommercializationdesigndesmoglein 1desmoglein IIIexperimental analysisimprovedin vivoinfection riskkeratinocytemortalitymortality riskmouse modelmycophenolate mofetilnew technologynovelnovel strategiesnovel therapeuticsoligodendrocyte-myelin glycoproteinpreventrelapse patientsrituximabside effectskin lesiontargeted deliverytargeted treatmenttherapy developmentward
项目摘要
PROJECT SUMMARY/ABSTRACT
The overall goal of this project is to develop a novel therapeutic for the treatment of pemphigus.
Pemphigus involves blistering of the skin or mucosal surfaces and can lead to difficulty in
swallowing, very painful lesions, and a ~2-3 fold increased risk of mortality. About 90-95% of
pemphigus cases can be accounted for by pemphigus vulgaris (PV) or pemphigus foliaceus (PF).
Autoantibodies of the IgG class that are specific for desmogleins 1 and 3 (Dsg1 and Dsg3) disrupt
the desmosomal-mediated adhesion of keratinocytes and are the causative agents of disease.
PV can present as a mucosal-dominant form involving Dsg3-specific autoantibodies, or a form
with both Dsg1- and Dsg3-specific autoantibodies that affects skin and mucosal surfaces. PF is
a skin-dominant disease, involving only Dsg1-specific autoantibodies.
Current treatments for pemphigus, such as the combination of corticosteroids and the B cell-
depleting antibody, rituximab, have associated adverse effects such as osteoporosis and
hypertension. In addition, the onset of action of rituximab takes several months since this
therapeutic agent targets B cells, rather than the autoantibodies themselves. The combination of
rituximab with tapered corticosteroids is also accompanied by a significant relapse rate (25-60%)
and increased infection risk due to the immunosuppressive effects of B cell depletion. Other
therapeutic approaches for pemphigus include the use of intravenous gammaglobulin,
plasmapheresis or immunoadsorption, and can lead to undesirable side effects. Consequently,
there is an unmet need to develop therapies for pemphigus that have rapid onset and high
specificity for the autoantibodies.
This application seeks to address the need for new and improved therapies for pemphigus by
generating engineered, antibody-based reagents that specifically and rapidly deplete Dsg-specific
antibodies. Importantly, these depleting agents are highly selective and do not affect the levels of
other antibodies that have a protective role against infection. This first-in-class, novel technology
has been named Seldeg technology (for selective degradation).
The Specific aims of the study are:
1. To design and express Seldegs to target Dsg-specific antibodies.
2. To analyze the stability and binding activity of the Seldegs.
The proposed approach could be transformative for the management of pemphigus, and also
has relevance to the use of Seldeg-based strategies for multiple other clinical settings where
pathogenic antibodies cause disease.
项目摘要/摘要
该项目的总体目标是开发一种治疗天疱疮的新疗法。
天疱疮涉及皮肤或粘膜表面起泡,可导致
吞咽,非常痛苦的皮损,以及~2-3倍的死亡风险。约90%-95%的
天疱疮病例可由寻常型天疱疮(PV)或叶型天疱疮(PF)引起。
针对Desmoglein 1和3(DSG1和Dsg3)的Ig G类自身抗体破坏
桥粒介导的角质形成细胞的黏附是疾病的致病因素。
PV可以表现为粘膜占优势的形式,涉及Dsg3特异性自身抗体,或一种形式
具有DSG1和Dsg3特异性自身抗体,影响皮肤和粘膜表面。PF是
一种皮肤显性疾病,仅涉及DSG1特异性自身抗体。
目前天疱疮的治疗方法,如皮质类固醇和B细胞的联合治疗-
耗竭抗体,利妥昔单抗,有相关的不良反应,如骨质疏松和
高血压。此外,利妥昔单抗的起效时间为几个月后
治疗剂针对的是B细胞,而不是自身抗体本身。这两种技术的结合
使用锥形皮质类固醇的利妥昔单抗还伴有显著的复发率(25%-60%)。
由于B细胞耗尽的免疫抑制作用,感染风险增加。其他
治疗天疱疮的方法包括静脉注射丙种球蛋白,
血浆置换或免疫吸附,并可能导致不良副作用。因此,
有一种尚未得到满足的需求,即开发起病快、高发的天疱疮疗法。
自身抗体的特异性。
本申请旨在通过以下方式解决天疱疮新的和改进的治疗方法的需求
产生以抗体为基础的工程化试剂,特异性地快速耗尽DSG特异性
抗体。重要的是,这些耗竭剂具有很高的选择性,不会影响
对感染有保护作用的其他抗体。这项一流的、新颖的技术
已被命名为Seldeg Technology(用于选择性降解)。
这项研究的具体目的是:
1.设计并表达针对DSG特异性抗体的Seldegs。
2.分析Seldegs的稳定性和结合活性。
建议的方法可能会对天疱疮的管理产生变革,而且
与在多种其他临床环境中使用基于Seldeg的策略相关
致病抗体导致疾病。
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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Sunil Kannanganat Sidharthan其他文献
Sunil Kannanganat Sidharthan的其他文献
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{{ truncateString('Sunil Kannanganat Sidharthan', 18)}}的其他基金
Novel approaches for the treatment of autoimmune disease
治疗自身免疫性疾病的新方法
- 批准号:
10601899 - 财政年份:2023
- 资助金额:
$ 30.54万 - 项目类别:
Depleting autoantibodies for the treatment of autoimmunity
消耗自身抗体来治疗自身免疫
- 批准号:
10698700 - 财政年份:2022
- 资助金额:
$ 30.54万 - 项目类别:
Targeting autoreactive antibodies for the therapy of MOG antibody-associated disease
靶向自身反应性抗体治疗 MOG 抗体相关疾病
- 批准号:
10250601 - 财政年份:2021
- 资助金额:
$ 30.54万 - 项目类别:
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