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TREATMENT OF LUNG FIBROSIS : IND PHARMACOLOGY AND TOXICOLOGY

TREATMENT OF LUNG FIBROSIS : IND PHARMACOLOGY AND TOXICOLOGY
肺纤维化的治疗:IND 药理学和毒理学
批准号:
10026462
负责人:
MARTINA BUCK
金额:
$132.7万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-08-01 至 2021-03-31
关键词:
Adverse effectsAmericanAnimal ModelAnimalsApoptosisAreaB-LymphocytesBindingBiological AssayBiological AvailabilityBleomycinCASP8 geneCardiotoxicityCause of DeathCellsCellular AssayChronicCicatrixClinicalComplexDataDepositionDevelopmentDisease ProgressionDoseDrug KineticsDrug usageEpithelialEpithelial CellsEpitheliumEventExtracellular MatrixFDA approvedFeedbackFibrosisFinancial HardshipFormulationFundingGoalsHealthHumanImmune responseIn VitroInflammationInhalationInjuryIsoenzymesKnowledgeLibrariesLiverLungLung InflammationLung TransplantationMacrophage ActivationMedicalMedical ResearchMesenchymalModelingMolecularMolecular TargetMusMyofibroblastNeuraxisOrganPathogenesisPathway interactionsPatientsPeptidesPharmaceutical PreparationsPharmacologyPharmacology and ToxicologyPhasePhenotypePhosphorylationPhosphorylation SitePhosphotransferasesPirfenidonePlasmaProcessProliferatingProteinsPulmonary FibrosisPulmonary Surfactant-Associated Protein CRecoveryResearchRespiratory physiologyReverse Transcriptase Polymerase Chain ReactionRouteSafetySkinSmall Business Innovation Research GrantSolubilitySubcutaneous InjectionsSystemT-LymphocyteTherapeuticTissuesToxicologyValidationWateralveolar epitheliumanalogcell injurycellular targetingclinical candidatecostdesignfibrogenesisidiopathic pulmonary fibrosisimmunogenicityimprovedin vivoinnovationlung developmentlung injurymeetingsmortalitynoveloutcome forecastpeptide drugpneumocytepre-clinicalpreclinical developmentpreclinical studypreventprogramsrespiratorysubcutaneoustreatment durationwound healing

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中文摘要
翻译
不同来源的肺肌成纤维细胞(LMF)活化与肺纤维化的发生 在IPF中,通过细胞凋亡清除LMF可能阻止肺纤维化和肺损伤的发展, 并有可能从肺纤维化的逆转中恢复。抑制或逆转肌成纤维细胞的激活和 巨噬细胞活化(治疗性细胞靶点)可能是治疗肺纤维化的关键。 IPF。既可防止肺纤维化和炎症的进展,也可防止肺的退化。 尽管持续肺损伤,但纤维化,正如我们在临床前研究中所记录的那样,被认为是重要的。 特发性肺纤维化患者的临床指标。最后,阻止肺纤维化的进展可能会减少 对肺移植的需求。我们研究的基础是一部《人性化》小说的发展 治疗性多肽。我们使用模拟合成创建了一个库,以防止人类治疗的潜在陷阱。 我们已经以一步一步的方式进行了试验,以选择最安全和最有效的人源化多肽 (包括原代激活的人肺肌成纤维细胞的凋亡检测;无细胞的caspase8激活 检测;肺损伤/纤维化模型;药代动力学;生物测定;CYP-450抑制研究;心脏毒性 化验;和初步毒理学化验)。我们已经开发出了新型高效的抗纤维化药物 在动物模型中,没有证据表明最先进的人类CD-4+T细胞和B-T细胞具有免疫原性 细胞分析,并在人肺微粒体系统和人血浆中具有极高的稳定性。这个 治疗多肽在水中具有良好的溶解性。这些功能应该有助于通过以下方式进行管理 临床前PK期间每周皮下注射一次(~50-200μL)具有良好的生物利用度 从聚乙二醇30 kDa多肽在血浆中的稳态释放情况来看,研究实现了 治疗性肺浓度。Xfibra将维持吸入路线作为治疗 发展。该化合物能显著抑制体外培养的人肺成纤维细胞的活性。 在小鼠体内。在初步的毒理学研究中,这种化合物对小鼠没有毒性,至少100- 加倍治疗剂量。我们没有发现CYP-450对肝脏、肺或心脏有毒性或抑制作用的证据 同工酶。这项SBIR的目的是完成FDA授权的、支持IND的研究。这个 可用的IPF药物非常昂贵,而且对大多数患者不是很有效。FDA同意 XFIBRA继续进行XFB-19的IND-Enabling研究(IND#131245之前)。
英文摘要
Activation of lung myofibroblasts (LMF) of different origins is responsible for the development of lung fibrosis in in IPF and remarkably, LMF clearance by apoptosis may prevent development of lung fibrosis and lung injury, and possibly allow recovery from reversal of lung fibrosis. Inhibiting or reversing myofibroblast activation and macrophage activation (the therapeutic cellular targets) may be critical for the treatment of lung fibrosis in IPF. Both preventing progression of lung fibrosis and inflammation, as well as possibly, regression of lung fibrosis despite continued lung injury, as we documented in our pre-clinical studies, are considered important clinical targets for patients with IPF. Finally, blocking the progression of lung fibrosis may decrease the demand for lung transplants. The basis for our Research is the development of a novel ‘humanized’ therapeutic peptide. We created a library using analog synthesis to prevent potential pitfalls for human therapy. We have performed in a step-wise manner assays to select the safest and most efficient ‘humanized’ peptide (including apoptosis assays in activated primary human lung myofibroblasts; cell-free caspase 8 activation assays; lung injury/fibrogenesis model; pharmacokinetics; bioassay; CYP-450 inhibition studies; cardiotoxicity assays; and preliminary toxicology assays). We have developed novel and highly effective anti-fibrotic peptides in animal models, with no evidences of immunogenicity in state-of-the-art human CD-4+ T-cell and B- cell assays, and with exceptional stability in human lung microsomal systems and human plasma. The therapeutic peptide has excellent solubility in water. These features should facilitate administration by subcutaneous injection once per week (~ 50-200 μL) with excellent bioavailability during preclinical PK studies judging by the steady-state release in plasma of the peptide from the PEG-30kDa-Peptide, achieving therapeutic lung concentrations. Xfibra will maintain the inhalation route as an alternative formulation for development. The proposed compound markedly inhibits the activation of human lung myofibroblast in culture and in vivo in mice. This compound was not toxic to mice in the preliminary toxicology studies, at least at 100- fold the therapeutic dose. We found no evidence of liver, lung or cardiac toxicity or inhibition of CYP-450 isoenzymes. The Aims of this SBIR are to complete FDA-mandated, IND-enabling studies. The available IPF medications are very expensive, and not highly effective in most patients. The FDA agreed with Xfibra to proceed with IND-enabling studies for XFB-19 (Pre-IND # 131245).
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TREATMENT OF LIVER INJURY AND FIBROSIS: SAFETY PHARMACOLOGY AND TOXICOLOGY
  • 批准号:
    10095347
  • 项目类别:
  • 资助金额:
    $113.61万
  • 财政年份:
    2019
  • 负责人:
    MARTINA BUCK
  • 依托单位:
Targeting C/EBP-beta Phosphorylation for the Treatment of Lung Fibrosis
  • 批准号:
    8904981
  • 项目类别:
  • 资助金额:
    $31.61万
  • 财政年份:
    2015
  • 负责人:
    MARTINA BUCK
  • 依托单位:
C/EBP-beta PEPTIDES FOR THE TREATMENT OF LUNG INJURY AND FIBROSIS
  • 批准号:
    8779048
  • 项目类别:
  • 资助金额:
    $31.18万
  • 财政年份:
    2014
  • 负责人:
    MARTINA BUCK
  • 依托单位:
C/EBP-beta PEPTIDES FOR THE TREATMENT OF LIVER INJURY AND FIBROSIS
  • 批准号:
    8592994
  • 项目类别:
  • 资助金额:
    $30.69万
  • 财政年份:
    2013
  • 负责人:
    MARTINA BUCK
  • 依托单位:
海外基金