TREATMENT OF LUNG FIBROSIS : IND PHARMACOLOGY AND TOXICOLOGY
TREATMENT OF LUNG FIBROSIS : IND PHARMACOLOGY AND TOXICOLOGY
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
中文摘要
不同来源的肺肌成纤维细胞(LMF)的激活是导致肺纤维化发生的原因。
在IPF中,通过细胞凋亡清除LMF可显著防止肺纤维化和肺损伤的发展,
并且可能允许从肺纤维化逆转中恢复。抑制或逆转肌成纤维细胞活化,
巨噬细胞活化(治疗性细胞靶点)可能对治疗肺纤维化至关重要,
IPF。既防止肺纤维化和炎症的进展,也可能防止肺纤维化和炎症的消退。
我们在临床前研究中证实,尽管持续肺损伤,纤维化仍被认为是重要的
IPF患者的临床目标。最后,阻断肺纤维化的进展可能会减少肺纤维化的发生。
肺移植的需求。我们研究的基础是开发一种新的“人性化”的
治疗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。
我们已经以逐步的方式进行了测定,以选择最安全和最有效的“人源化”肽
(包括在活化的原代人肺肌成纤维细胞中的凋亡测定;无细胞半胱天冬酶8活化
测定;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
试验;和初步毒理学试验)。我们已经开发出新型高效的抗纤维化
在动物模型中,没有证据表明在最先进的人CD-4+ T细胞和B-
细胞测定,并在人肺微粒体系统和人血浆中具有优异的稳定性。的
治疗性肽在水中具有优异的溶解性。这些功能应便于管理,
每周一次皮下注射(约50-200 μL),在临床前PK期间具有良好的生物利用度
通过肽在血浆中从PEG-30 kDa-肽的稳态释放判断的研究,
治疗肺浓度。Xfibra将保持吸入途径作为替代制剂,
发展所提出的化合物显著抑制培养的人肺肌成纤维细胞的活化
以及在小鼠体内。在初步毒理学研究中,该化合物对小鼠没有毒性,至少在100- 200 μ g/ml时是如此。
治疗剂量的两倍我们没有发现肝脏、肺或心脏毒性的证据,
同工酶本SBIR的目的是完成FDA授权的IND启动研究。的
可用的IPF药物非常昂贵,并且对大多数患者不是非常有效。FDA同意
Xfibra继续进行XFB-19的IND使能研究(Pre-IND # 131245)。
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).
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
TREATMENT OF LIVER INJURY AND FIBROSIS: SAFETY PHARMACOLOGY AND TOXICOLOGY
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批准号:10095347
-
项目类别:
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资助金额:$113.61万
-
财政年份:2019
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负责人:MARTINA BUCK
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依托单位:
Targeting C/EBP-beta Phosphorylation for the Treatment of Lung Fibrosis
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批准号:8904981
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项目类别:
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资助金额:$31.61万
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财政年份:2015
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负责人:MARTINA BUCK
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依托单位:
C/EBP-beta PEPTIDES FOR THE TREATMENT OF LUNG INJURY AND FIBROSIS
-
批准号:8779048
-
项目类别:
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资助金额:$31.18万
-
财政年份:2014
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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:
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资助金额:$30.69万
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财政年份:2013
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负责人:MARTINA BUCK
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依托单位:
Hepatitis C: E2 Molecular Mechanisms
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批准号:7887884
-
项目类别:
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资助金额:$35.4万
-
财政年份:2010
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负责人:MARTINA BUCK
-
依托单位:
Hepatitis C: E2 Molecular Mechanisms
-
批准号:8322071
-
项目类别:
-
资助金额:$29.09万
-
财政年份:2010
-
负责人:MARTINA BUCK
-
依托单位:
Hepatitis C: E2 Molecular Mechanisms
-
批准号:8663241
-
项目类别:
-
资助金额:$29.09万
-
财政年份:2010
-
负责人:MARTINA BUCK
-
依托单位:
Hepatitis C: E2 Molecular Mechanisms
-
批准号:8497680
-
项目类别:
-
资助金额:$28.07万
-
财政年份:2010
-
负责人:MARTINA BUCK
-
依托单位:
Hepatitis C: E2 Molecular Mechanisms
-
批准号:8198487
-
项目类别:
-
资助金额:$3.96万
-
财政年份:2010
-
负责人:MARTINA BUCK
-
依托单位:
Hepatitis C: E2 Molecular Mechanisms
-
批准号:8071218
-
项目类别:
-
资助金额:$29.69万
-
财政年份:2010
-
负责人:MARTINA BUCK
-
依托单位:
C/EBP beta Peptides for the Treatment of Hepatic Fibrosis
-
批准号:7941877
-
项目类别:
-
资助金额:$40.91万
-
财政年份:2009
-
负责人:MARTINA BUCK
-
依托单位:
C/EBP beta Peptides for the Treatment of Hepatic Fibrosis
-
批准号:7832282
-
项目类别:
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资助金额:$46.75万
-
财政年份:2009
-
负责人:MARTINA BUCK
-
依托单位:
HEPATOCELLULAR CARCINOMA AND HEPATITIS C: E2 MOLECULAR MECHANISMS
-
批准号:7628592
-
项目类别:
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资助金额:$14.88万
-
财政年份:2008
-
负责人:MARTINA BUCK
-
依托单位:
HEPATOCELLULAR CARCINOMA AND HEPATITIS C: E2 MOLECULAR MECHANISMS
-
批准号:7470415
-
项目类别:
-
资助金额:$14.88万
-
财政年份:2008
-
负责人:MARTINA BUCK
-
依托单位:
INFECTION AND REPLICATION OF NATURALLY OCCURRING HEPATITIS C VIRUS
-
批准号:7722452
-
项目类别:
-
资助金额:$0.2万
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财政年份:2008
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负责人:MARTINA BUCK
-
依托单位:
HEPATOCELLULAR CARCINOMA AND HEPATITIS C: E2 MOLECULAR MECHANISMS
-
批准号:7933355
-
项目类别:
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资助金额:$4.54万
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财政年份:2008
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负责人:MARTINA BUCK
-
依托单位:
HEPATOCELLULAR CARCINOMA AND HEPATITIS C: E2 MOLECULAR MECHANISMS
-
批准号:7851359
-
项目类别:
-
资助金额:$14.88万
-
财政年份:2008
-
负责人:MARTINA BUCK
-
依托单位:
HEPATIC CARCINOGENESIS: MOLECULAR MECHANISMS
-
批准号:6663736
-
项目类别:
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资助金额:$11.67万
-
财政年份:2002
-
负责人:MARTINA BUCK
-
依托单位:
HEPATIC CARCINOGENESIS: MOLECULAR MECHANISMS
-
批准号:6530519
-
项目类别:
-
资助金额:$11.41万
-
财政年份:2002
-
负责人:MARTINA BUCK
-
依托单位:
HEPATIC CARCINOGENESIS: MOLECULAR MECHANISMS
-
批准号:6930419
-
项目类别:
-
资助金额:$14.88万
-
财政年份:2002
-
负责人:MARTINA BUCK
-
依托单位:
海外基金