eCIRP-Neutralizing mAb for Acute Lung Injury in Sepsis
eCIRP 中和单克隆抗体治疗脓毒症急性肺损伤
基本信息
- 批准号:10632117
- 负责人:
- 金额:$ 12.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-06-01 至 2023-11-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAcute Lung InjuryAcute Respiratory Distress SyndromeAdultAlveolarAlveolar MacrophagesAmericanAnimalsAntiinflammatory EffectArea Under CurveAttenuatedBilirubinBlood Cell CountBlood specimenBone MarrowCXCL1 geneCXCL2 geneCellsClinical TrialsComplicationCreatinineDataDevelopmentDiseaseDoseDrug KineticsDyesEpithelial CellsEvans blue stainFutureGenesGoalsHalf-LifeHeartHemorrhageHistologicHistopathologyHourImmunoglobulin GIn VitroInflammatoryInjectionsInjuryInterleukin-1 betaInterleukin-6IntravenousInvestigational New Drug ApplicationIschemiaKidneyLaparotomyLifeLiquid substanceLiverLungMacrophageMeasuresMesenteryMolecularMonoclonal AntibodiesMusNeutrophil InfiltrationNormal salinePatientsPatternPermeabilityPeroxidasesPharmaceutical PreparationsPharmacologyPlasmaPre-Clinical ModelPropertyProteinsPulmonary EdemaPulmonary InflammationRNA-Binding ProteinsRattusRecombinantsSafetySepsisSerumSmall IntestinesSurface Plasmon ResonanceTNF geneTechnologyTestingTherapeuticTherapeutic Monoclonal AntibodiesTimeToxicologyWaterWestern Blottingalveolar epitheliumattenuationcecal ligation puncturecell typechemokinecytokineeffective therapyextracellularimmunogenicityimprovedin vivointerstitialintravenous injectionlung injurymortalityneutralizing monoclonal antibodiesneutrophilnovelnovel therapeuticspharmacologicpneumocytepublic health relevancesepsis induced acute lung injurysepticseptic patients
项目摘要
PROJECT DESCRIPTION: The primary objective of this project is to demonstrate the feasibility of
developing the extracellular cold-inducible RNA-binding protein (eCIRP)-neutralizing monoclonal antibody
#14 (mAb14) as a novel treatment for septic patients with acute lung injury (ALI). ALI is a critical
component of the elevated mortality rate in sepsis no specific treatment has yet been approved to reduce
the mortality of such patients. We have discovered that eCIRP is a critical inducer of ALI caused by
sepsis and other inflammatory diseases. In our recent studies, we have shown that increased levels of
eCIRP aggravated ALI in mice with sepsis induced by cecal ligation and puncture (CLP). Injection of
recombinant eCIRP was sufficient to induce ALI in otherwise healthy mice. In our preliminary studies, we
have generated a large panel of anti-eCIRP monoclonal antibodies to develop an eCIRP-targeting treatment
for ALI, and screened them for their inhibition of eCIRP-induced release of TNF-α by macrophages. We
then used the most effective anti-eCIRP monoclonal antibody, mAb14, to treat mice with CLP-induced ALI.
Compared with non-immunized IgG (control), CLP mice treated with mAb14 had attenuated lung
inflammation as indicated by the decreased lung gene and protein levels of TNF-α, IL-1β, IL-6, CXCL1, and
CXCL2, as well as the decreased neutrophil infiltration of the lungs as indicated by the myeloperoxidase
activity. Based on these novel findings, we hypothesize that mAb14 can be developed as a new and
effective drug to treat ALI caused by sepsis. In this project, we will further determine mAb14’s eCIRP
neutralization ability in vitro and in vivo. We will then optimize mAb14’s dose to attenuate sepsis-induced
ALI and therapeutic window to improve the survival of septic mice. We will also evaluate mAb14’s
pharmacokinetics (PK) and pharmacotoxicity properties. Our future steps will include developing a
humanized form of mAb14 and then conducting its ADME, PK, advanced toxicology, and immunogenicity
studies. We will then file with the FDA an investigational new drug (IND) application to initiate clinical trials
to treat ALI in patients with sepsis. Our ultimate goal is to obtain commercial utilization of mAb14 as a safe
and effective drug to treat patients with ALI in the context of sepsis.
项目描述:本项目的主要目的是论证
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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Max Brenner其他文献
Max Brenner的其他文献
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{{ truncateString('Max Brenner', 18)}}的其他基金
The Role of Ionizing Radiation in Alzheimer’s Disease
电离辐射在阿尔茨海默病中的作用
- 批准号:
10288222 - 财政年份:2017
- 资助金额:
$ 12.98万 - 项目类别:
Mechanisms of Radiation-induced Vascular Endothelial Cell Injury and Its Correction
辐射引起的血管内皮细胞损伤的机制及其纠正
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10415147 - 财政年份:2017
- 资助金额:
$ 12.98万 - 项目类别:
Mechanisms of Radiation-induced Vascular Endothelial Cell Injury and Its Correction
辐射引起的血管内皮细胞损伤的机制及其纠正
- 批准号:
10159192 - 财政年份:2017
- 资助金额:
$ 12.98万 - 项目类别:
Mechanisms of Radiation-induced Vascular Endothelial Cell Injury and Its Correction
辐射引起的血管内皮细胞损伤的机制及其纠正
- 批准号:
10614233 - 财政年份:2017
- 资助金额:
$ 12.98万 - 项目类别:
rhMFG-E8 as an Effective Adjuvant Therapy for Hemorrhagic Shock
rhMFG-E8 作为失血性休克的有效辅助疗法
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10201721 - 财政年份:2016
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rhMFG-E8 as an Effective Adjuvant Therapy for Hemorrhagic Shock
rhMFG-E8 作为失血性休克的有效辅助疗法
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10005406 - 财政年份:2016
- 资助金额:
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