TREATMENT OF LUNG FIBROSIS : IND PHARMACOLOGY AND TOXICOLOGY
肺纤维化的治疗:IND 药理学和毒理学
基本信息
- 批准号:10026462
- 负责人:
- 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
- 起止时间:2019-08-01 至 2021-03-31
- 项目状态:已结题
- 来源:
- 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
项目摘要
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).
不同来源的肺肌成纤维细胞(LMF)的激活是肺纤维化发生的原因
在 IPF 中,重要的是,LMF 通过细胞凋亡清除可以预防肺纤维化和肺损伤的发展,
并可能允许从肺纤维化的逆转中恢复抑制或逆转肌成纤维细胞活化和
巨噬细胞激活(治疗细胞靶点)可能对于肺纤维化的治疗至关重要
IPF。既可以预防肺纤维化和炎症的进展,也可以预防肺的消退。
正如我们在临床前研究中所记录的那样,尽管存在持续的肺损伤,但纤维化被认为是重要的
IPF 患者的临床目标最后,阻断肺纤维化的进展可能会降低肺纤维化的发生率。
我们研究的基础是开发一种新型的“人性化”技术。
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。
我们以逐步的方式进行分析,以选择最安全、最有效的“人源化”肽
(包括激活的原代人肺肌成纤维细胞的凋亡测定;无细胞 caspase 8 激活
肺损伤/纤维形成模型;CYP-450 抑制研究;
和初步毒理学测定)。我们已经开发出新型高效的抗纤维化药物。
动物模型中的肽,没有证据表明在最先进的人类 CD-4+ T 细胞和 B- 细胞中具有免疫原性
细胞测定,并且在人肺微粒体系统和人血浆中具有出色的稳定性。
肽在水中具有优异的治疗溶解度,这些特性应有助于通过给药。
每周皮下注射一次(约 50-200 μL),在临床前 PK 期间具有出色的生物利用度
根据 PEG-30kDa-肽在血浆中的稳态释放来判断的研究,实现了
Xfibra 将维持吸入途径作为替代制剂。
所提出的化合物显着抑制培养物中人肺肌成纤维细胞的活化。
在初步毒理学研究中,该化合物对小鼠没有毒性,至少在 100-
我们没有发现肝、肺或心脏毒性或 CYP-450 抑制的证据。
该 SBIR 的目标是完成 FDA 授权的 IND 支持研究。
FDA 同意现有的 IPF 药物非常昂贵,而且对大多数患者效果不佳。
Xfibra 将继续进行 XFB-19 的 IND 研究(Pre-IND # 131245)。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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MARTINA BUCK其他文献
MARTINA BUCK的其他文献
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{{ truncateString('MARTINA BUCK', 18)}}的其他基金
TREATMENT OF LIVER INJURY AND FIBROSIS: SAFETY PHARMACOLOGY AND TOXICOLOGY
肝损伤和纤维化的治疗:安全药理学和毒理学
- 批准号:
10095347 - 财政年份:2019
- 资助金额:
$ 132.7万 - 项目类别:
Targeting C/EBP-beta Phosphorylation for the Treatment of Lung Fibrosis
靶向 C/EBP-β 磷酸化治疗肺纤维化
- 批准号:
8904981 - 财政年份:2015
- 资助金额:
$ 132.7万 - 项目类别:
C/EBP-beta PEPTIDES FOR THE TREATMENT OF LUNG INJURY AND FIBROSIS
用于治疗肺损伤和纤维化的 C/EBP-β 肽
- 批准号:
8779048 - 财政年份:2014
- 资助金额:
$ 132.7万 - 项目类别:
C/EBP-beta PEPTIDES FOR THE TREATMENT OF LIVER INJURY AND FIBROSIS
用于治疗肝损伤和纤维化的 C/EBP-β 肽
- 批准号:
8592994 - 财政年份:2013
- 资助金额:
$ 132.7万 - 项目类别:
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