Targeting the CCR6-CCL20 pathway for treatment of psoriatic joint and entheseal inflammation
靶向 CCR6-CCL20 通路治疗银屑病关节和附着点炎症
基本信息
- 批准号:10699251
- 负责人:
- 金额:$ 99.86万
- 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:2023-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAlkaline PhosphataseAlternative TherapiesAnimal ModelAnimalsAntibodiesAutoimmune DiseasesBiochemicalBiologicalBiological Response Modifier TherapyBiological SciencesBone InjuryCCL20 geneCCR6 geneCandidiasisCellsChronic DiseaseClinicalClinical TrialsConnective TissueCreatinineDNADataDermatitisDevelopmentDiagnosisDiseaseDisease modelDoseEngineeringEtanerceptFDA approvedFormulationFundingG-Protein-Coupled ReceptorsGenerationsGoalsHalf-LifeHepatotoxicityHomeostasisHumanHumiraIL17 geneImmuneImmune responseImmunosuppressionInfectionInflammationInflammatoryInjectionsInjuryJointsLeadLigandsLiverMalignant NeoplasmsMeasuresMediatingMetabolic Clearance RateMethodsModelingModificationMolecularMucous MembraneMusMycosesPathologyPathway interactionsPatientsPersonsPharmaceutical PreparationsPhasePhase I Clinical TrialsPreclinical TestingPredispositionProductionProteinsProtocols documentationPsoriasisPsoriatic ArthritisPublishingQuality ControlQuality of lifeRecombinant ProteinsReproducibilityRiskRodentSafetyScheduleSignal TransductionSigns and SymptomsSiteSkinSkin TissueSmall Business Innovation Research GrantSymptomsTendon structureTestingTherapeuticTherapeutic EffectTimeTissuesTreatment EfficacyTreatment ProtocolsTuberculosisUreaVariantWisconsinarthritis therapyarthropathiesautoinflammatory diseaseschemokineclinically relevantdimerdrug developmenteffective therapyexperimental studyfirst-in-humanhigh riskhuman diseasehuman modelimmune functionimmunoregulationimprovedin vivoinfection riskinfliximabinhibitorinnovationinterleukin-23joint inflammationmanufacturemedical schoolsmigrationmilligrammouse modelnephrotoxicitynovel therapeuticspre-clinicalpreclinical developmentpreclinical studypreservationpreventradiological imagingreceptorrecruitresearch and developmentside effectsuccesstherapeutic lead compoundtumor necrosis factor-alpha inhibitor
项目摘要
Project Summary/Abstract
The goal of this project is to develop and validate a novel therapeutic lead compound for the treatment of
psoriatic arthritis (PsA). Chemokines orchestrate the migration of inflammatory cells during normal immune
responses and are required for immune tissue development and homeostasis. When aberrant chemokine
function occurs, improper recruitment of immune cells can lead to a variety of inflammatory pathologies with
devastating effects on a patient’s quality of life. The chemokine CCL20 and its G protein-coupled receptor
CCR6 drive the development of psoriatic disease through the initiation and continuous recruitment of
inflammatory Th17-expressing cells into skin and connective tissue. Our published biochemical, cell-based and
in vivo studies prove that an engineered recombinant protein that mimics the dimeric version of the natural
CCL20 molecule completely reverses its normal pro-inflammatory functional profile. In a Phase I SBIR project,
the lead compound (CCL20LD) reduced the signs of established psoriatic dermatitis (PsD) in a preclinical
mouse model that faithfully recapitulates human psoriasis. Unexpectedly, CCL20LD treatment also alleviated
joint and tendon inflammation, demonstrating efficacy in a clinically relevant model of human psoriatic
arthritis. The same project also yielded a favorable preliminary safety profile with no indication of liver or
kidney toxicity and a validated manufacturing and quality control protocol. There is a significant need for new
treatments for psoriatic arthritis because current options carry the risk of immunosuppression and loss of
efficacy over time. This Direct-to-Phase II proposal builds on the completed Phase I milestones to complete
preclinical testing and optimization of CCL20LD and assemble the necessary efficacy, safety, and
manufacturing data for an IND application and clinical trials for psoriatic arthritis. XLock Biosciences, LLC (XL)
will manufacture the CCL20LD protein and direct the studies proposed in three specific aims. In Aim 1, XLock
will improve the in vivo stability of the first generation CCL20LD molecule with modifications known to extend
the circulating half-life of biologic drugs. In Aim 2 XL and its academic collaborators at UC Davis will establish
the therapeutic dose and schedule which produces the strongest anti-psoriatic effect in joint tissues in the
shortest time period. Lastly, in Aim 3, XL’s collaborators at the Medical College of Wisconsin will measure
CCL20LD’s immunomodulatory activity and its effect on rodent susceptibility to commensal fungal infection.
Altering CCR6 signaling through the engineering of its native ligand is an innovative paradigm shift in clinical
approaches for treating auto-inflammatory diseases. Development of engineered CCL20 variants as biological
therapeutics will have significant positive impact for psoriatic arthritis patients by reducing side effects and
providing a drug with extended therapeutic lifetimes. Moreover, the resultant method has the potential for
treating other Th17–mediated diseases.
项目摘要/摘要
该项目的目标是开发和验证一种新的治疗糖尿病的先导化合物。
银屑病关节炎(PSA)。趋化因子在正常免疫过程中协调炎症细胞的迁移
这是免疫组织发育和动态平衡所必需的。当异常趋化因子
功能发生时,免疫细胞的不当募集可导致多种炎性病理
对病人的生活质量产生毁灭性的影响。趋化因子CCL20及其G蛋白偶联受体
CCR6通过启动和持续招募的方式推动银屑病的发展
皮肤和结缔组织中表达Th17的炎性细胞。我们出版的生物化学,基于细胞和
体内研究证明,一种模仿天然二聚体的工程化重组蛋白
CCL20分子完全逆转其正常的促炎功能。在第一阶段SBIR项目中,
先导化合物(CCL20LD)减少了临床前已建立的银屑病皮炎(PSD)的迹象
真实再现人类牛皮癣的小鼠模型。出乎意料的是,CCL20LD治疗也缓解了
关节和肌腱炎症,在临床相关的人类银屑病模型中显示疗效
关节炎。同一项目也产生了良好的初步安全概况,没有肝脏或
肾脏毒性和有效的制造和质量控制方案。有很大需求需要新的
银屑病关节炎的治疗,因为目前的选择带有免疫抑制和丧失
随着时间的推移而产生效果。这个直接到第二阶段的提案建立在完成的第一阶段里程碑的基础上
CCL20LD的临床前测试和优化,并组装必要的有效性、安全性和
IND应用程序和牛皮癣关节炎临床试验的制造数据。XLock Biosciences,LLC(XL)
将生产CCL20LD蛋白,并指导提出的三个特定目标的研究。在目标1中,XLock
将通过已知的扩展修饰来提高第一代CCL20LD分子的体内稳定性
生物药物的循环半衰期。在Aim 2 XL和它在加州大学戴维斯分校的学术合作者将建立
在关节组织中产生最强抗银屑病效果的治疗剂量和方案
最短的时间段。最后,在Aim 3中,XL在威斯康星医学院的合作者将测量
CCL20LD的免疫调节活性及其对啮齿动物对共生真菌感染易感性的影响
通过改造天然配体改变CCR6信号是临床上的一种创新范式转变
治疗自发性炎症性疾病的方法。工程化CCL20生物突变体的研究进展
治疗将通过减少副作用和治疗对银屑病关节炎患者产生显著的积极影响
提供一种延长治疗寿命的药物。此外,所得到的方法具有潜在的
治疗其他Th17介导的疾病。
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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William R Clarke其他文献
353 STUDIES OF THE QUALITY OF BLOOD PRESSURE MEASUREMENTS: THE MUSCATINE STUDY
353 项血压测量质量的研究:马斯卡廷研究
- DOI:
10.1203/00006450-197804001-00358 - 发表时间:
1978-04-01 - 期刊:
- 影响因子:3.100
- 作者:
William R Clarke;Ronald M Lauer - 通讯作者:
Ronald M Lauer
ELEVATION OF PULMONARY PDE5-SPECIFIC ACTIVITY IN AN EXPERIMENTAL FETAL OVINE PERINATAL PULMONARY HYPERTENSION MODEL. † 1990
实验性胎儿绵羊围产期肺动脉高压模型中肺 PDE5 比活性的升高。†1990
- DOI:
10.1203/00006450-199604001-02014 - 发表时间:
1996-04-01 - 期刊:
- 影响因子:3.100
- 作者:
Kimberly A Hanson;Steven H Abman;William R Clarke - 通讯作者:
William R Clarke
Blood Coagulation Changes Following Hypoxemia in the Near-Term Fetal Lamb
近足月胎羊低氧血症后的凝血变化
- DOI:
10.1203/00006450-198209000-00006 - 发表时间:
1982-09-01 - 期刊:
- 影响因子:3.100
- 作者:
C Thomas Kisker;Jean E Robillard;William R Clarke - 通讯作者:
William R Clarke
562 BLOOD PRESSURE AND SODIUM SENSITIVITY IN CHILDREN THE MUSCATINE STUDY
562 穆斯卡廷研究中儿童的血压和钠敏感性
- DOI:
10.1203/00006450-198504000-00592 - 发表时间:
1985-04-01 - 期刊:
- 影响因子:3.100
- 作者:
Larry T Mahoney;Julie Lee;William R Clarke;Ronald M Lauer - 通讯作者:
Ronald M Lauer
77 SOCIAL FACTORS RELATED TO CIGARETTE SMOKING IN CHIL-DREN: THE MUSCATINE STUDY
- DOI:
10.1203/00006450-198104001-00086 - 发表时间:
1981-04-01 - 期刊:
- 影响因子:3.100
- 作者:
James L Massey;Ronald L Akers;William R Clarke;Ronald H Lauer - 通讯作者:
Ronald H Lauer
William R Clarke的其他文献
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