Novel Therapeutic Antibody Targeting of Extracellular NAMPT in Ventilator-Induced Lung Injury (VILI)
呼吸机引起的肺损伤 (VILI) 中细胞外 NAMPT 的新型治疗抗体
基本信息
- 批准号:10026453
- 负责人:
- 金额:$ 75万
- 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:2019-06-01 至 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAdult Respiratory Distress SyndromeAffectAffinityAlveolarAntibodiesArizonaAttenuatedAvidityBiological ProductsBiotechnologyCanis familiarisCaringCellsClinicalClinical ResearchClinical TrialsCollaborationsContractsCritical CareCritical IllnessDevelopmentDrug KineticsExhibitsFDA approvedFab ImmunoglobulinsFloodsGoalsHalf-LifeHealth Care CostsHumanHuman ResourcesHypoxemiaIn VitroIncidenceInflammatoryIntensive Care UnitsIntubationInvestigational DrugsLeadLibrariesLigandsLungLung InflammationMechanical ventilationMechanicsModelingMorbidity - disease rateMusNew Drug ApprovalsOutcomePatientsPhage DisplayPharmacodynamicsPharmacology StudyPharmacology and ToxicologyPhasePreventive therapyPrivatizationProtocols documentationRattusRespiratory FailureScientistSeveritiesSignal TransductionSmall Business Technology Transfer ResearchStimulusTLR4 geneTherapeuticTherapeutic InterventionTherapeutic antibodiesTimeToxicologyUnited StatesUniversitiesVascular PermeabilitiesVentilator-induced lung injuryWorkcytokinecytokine release syndromedesignextracellularhuman monoclonal antibodiesimmunogenicimprovedin vivoin vivo Modelinflammatory lung diseaseinnovationlung injurymanmeetingsmortalityneutralizing antibodynicotinamide phosphoribosyltransferasenovelnovel therapeuticspharmacokinetics and pharmacodynamicspre-clinicalpreventprophylacticpublic health relevancesuccesstherapeutic targetventilation
项目摘要
Mortality rates in intensive care units (ICUs) are unacceptably high and are directly related to the duration
of mechanical ventilation that is required to support patients with respiratory failure. For example, acute respiratory
distress syndrome (ARDS) is a vexing acute inflammatory lung disease requiring mechanical ventilatory
support as the result of severe hypoxemia and respiratory failure. The estimated 200,000 ARDS cases/yr (U.S.)
exhibit a mortality rate of 30-40% with ventilator-induced lung injury (VILI), a potent stimulus for lung inflammation
and release of multiple inflammatory cytokines (known as cytokine storm), a significant contributor to
ARDS severity and mortality. VILI may also ensue in mechanically ventilated patients with respiratory failure in
intensive care units (ICUs) even when ARDS is not present. As no clinical therapeutic intervention in the ICU
has significantly addressed VILI, there remains a serious unmet need for effective preventive therapies for VILI.
Aqualung Therapeutics scientists have identified nicotinamide phosphoribosyltransferase (NAMPT) as a
novel upstream therapeutic target in the development of VILI, and have developed human monoclonal antibodies
(Fabs or fragment antigen-binding) designed to neutralize circulating extracellular NAMPT (or eNAMPT).
Given the lack of approved VILI therapies, ALT seeks to improve ICU outcomes by developing the human monoclonal
Fab, eNamptor™, as an innovative strategy to reduce or eliminate VILI, targeting circulating eNAMPT.
eNamptor™ will be given prophylactically at the time of intubation in critically ill ICU patients receiving mechanical
ventilation, a marked advantage compared with prior ICU strategies. We expect that eNamptor™ will reduce or
eliminate VILI incidence and severity, reduce the number of days ICU patients require mechanical ventilation,
reduce healthcare costs, and improve ICU survival. With this background, the goal of this STTR Phase I/II Fast
Track application is to evaluate NAMPT-neutralizing pegylated and non-pegylated human monoclonal eNamptor™
Fab candidates for efficacy in attenuating eNAMPT-induced NFkB in vitro signaling and preclinical
murine VILI in vivo models (STTR Phase I). In addition, we will conduct pharmacokinetic/pharmacodynamic and
toxicology studies with lead eNamptor™ Fab candidates in rat and canine models (STTR Phase II). This STTR
Phase I/II Fast Track application represents a collaboration between a biotech startup company (Aqualung
Therapeutics Corporation), an academic entity (University of Arizona) and a private company (Gennova Biopharmaceutical
Ltd.). Together, we will address a serious and important unmet need by validating eNamptor™ as a
viable VILI therapeutic approach. We anticipate these efforts will lead to submission of a IND application to the
FDA to promote eNamptor™ as a therapeutic strategy for VILI in man.
重症监护室(ICU)的死亡率高得令人无法接受,并且与持续时间直接相关。
支持呼吸衰竭患者所需的机械通气。例如,急性呼吸道疾病
窘迫综合征(ARDS)是一种急性炎症性肺病,需要机械通气治疗,
严重低氧血症和呼吸衰竭导致的支持。估计每年有20万例ARDS病例(美国)
呼吸机诱导的肺损伤(VILI)的死亡率为30-40%,VILI是肺部炎症的有力刺激物
和多种炎性细胞因子的释放(称为细胞因子风暴),这是
ARDS严重程度和死亡率。VILI也可能发生在呼吸衰竭的机械通气患者中,
重症监护室(ICU),即使不存在ARDS。由于ICU中没有临床治疗干预
尽管已经显著地解决了VILI,但是对于VILI的有效预防性疗法仍然存在严重的未满足的需求。
Aqualung Therapeutics的科学家已经将烟酰胺磷酸核糖基转移酶(NAMPT)鉴定为一种
VILI开发中的新型上游治疗靶点,并已开发出人单克隆抗体
(Fabs或片段抗原结合),其设计用于中和循环细胞外NAMPT(或eNAMPT)。
鉴于缺乏批准的VILI疗法,ALT寻求通过开发人单克隆抗体来改善ICU结果。
Fab,eNamptor™,作为减少或消除VILI的创新策略,靶向循环中的eNAMPT。
在接受机械通气的重症ICU患者中,将在插管时辅助给予eNamptor™
与先前的ICU策略相比,通气具有显著优势。我们预计eNamptor™将减少或
消除VILI的发生率和严重程度,减少ICU患者需要机械通气的天数,
降低医疗成本,提高ICU生存率。在此背景下,本STTR I/II期快速
Track应用旨在评价NAMPT中和聚乙二醇化和非聚乙二醇化人单克隆eNamptor™
用于在体外和临床前减弱eNAMPT诱导的NFkB信号传导的功效的Fab候选物
鼠VILI体内模型(STTR I期)。此外,我们将进行药代动力学/药效学研究,
在大鼠和犬模型中使用前导eNamptor™ Fab候选物的毒理学研究(STTR II期)。这个STTR
I/II期快速通道申请代表了一家生物技术初创公司(Aqualung)
Therapeutics Corporation)、学术实体(亚利桑那大学)和私营公司(Gennova Biopharmacology
Ltd.)。通过验证eNamptor™作为
可行的VILI治疗方法。我们预计,这些努力将导致提交IND申请,
FDA将eNamptor™作为人类VILI的治疗策略进行推广。
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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Joe G. N. Garcia其他文献
Lysocardiolipin Acyltransferase (lycat) Is A Novel Candidate Gene In Radiation-Induced Pulmonary Fibrosis
溶心磷脂酰基转移酶 (lycat) 是辐射诱发肺纤维化的新候选基因
- DOI:
- 发表时间:
2011 - 期刊:
- 影响因子:0
- 作者:
B. Mathew;Longshuang Huang;I. Noth;Shwu;N. Kaminski;Yutong Zhao;M. Wade;E. Berdyshev;J. Siegler;J. Jacobson;Ralph R. Weishelbaum;V. Natarajan;Joe G. N. Garcia - 通讯作者:
Joe G. N. Garcia
Endothelial cell myosin light chain kinase (MLCK) regulates TNFα‐induced NFκB activity
内皮细胞肌球蛋白轻链激酶 (MLCK) 调节 TNFα 诱导的 NFκB 活性
- DOI:
- 发表时间:
2005 - 期刊:
- 影响因子:0
- 作者:
R. Wadgaonkar;L. Linz;A. Zaiman;Joe G. N. Garcia - 通讯作者:
Joe G. N. Garcia
acute lung injury by simvastatin 4 in the attenuation of murine β Critical role for integrin
辛伐他汀 4 在减弱小鼠β整合素的关键作用中对急性肺损伤的影响
- DOI:
- 发表时间:
2012 - 期刊:
- 影响因子:0
- 作者:
J. Jacobson;Weiguo Chen;S. Sammani;Sumegha Mitra;Shwu;Joe G. N. Garcia - 通讯作者:
Joe G. N. Garcia
Intracellular interaction of myosin light chain kinase with macrophage migration inhibition factor (MIF) in endothelium
肌球蛋白轻链激酶与内皮巨噬细胞迁移抑制因子(MIF)的细胞内相互作用
- DOI:
- 发表时间:
2005 - 期刊:
- 影响因子:4
- 作者:
R. Wadgaonkar;S. Dudek;A. Zaiman;L. Linz;A. Verin;S. Nurmukhambetova;L. Romer;Joe G. N. Garcia - 通讯作者:
Joe G. N. Garcia
American medical education at a crossroads
美国医学教育正处于十字路口
- DOI:
10.1126/scitranslmed.aaa2039 - 发表时间:
2015 - 期刊:
- 影响因子:17.1
- 作者:
A. Feldman;M. Runge;Joe G. N. Garcia;A. Rubenstein - 通讯作者:
A. Rubenstein
Joe G. N. Garcia的其他文献
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{{ truncateString('Joe G. N. Garcia', 18)}}的其他基金
Preclinical Development of a Novel eNAMPT-Neutralizing mAb for Pulmonary Hypertension
治疗肺动脉高压的新型 eNAMPT 中和单克隆抗体的临床前开发
- 批准号:
10723260 - 财政年份:2022
- 资助金额:
$ 75万 - 项目类别:
Role of Endothelial eNAMPT Secretion and TLR4 Signaling in the ARDS Vascular Endotype
内皮 eNAMPT 分泌和 TLR4 信号传导在 ARDS 血管内型中的作用
- 批准号:
10440855 - 财政年份:2022
- 资助金额:
$ 75万 - 项目类别:
Preclinical Development of a Novel eNAMPT-Neutralizing mAb for Pulmonary Hypertension
治疗肺动脉高压的新型 eNAMPT 中和单克隆抗体的临床前开发
- 批准号:
10489982 - 财政年份:2022
- 资助金额:
$ 75万 - 项目类别:
Targeting the eNAMPT/TLR4 pathway to reduce Inflammatory Bowel Disease severity
靶向 eNAMPT/TLR4 通路以降低炎症性肠病的严重程度
- 批准号:
10771493 - 财政年份:2022
- 资助金额:
$ 75万 - 项目类别:
Targeting the eNAMPT/TLR4 pathway to reduce Inflammatory Bowel Disease severity
靶向 eNAMPT/TLR4 通路以降低炎症性肠病的严重程度
- 批准号:
10602227 - 财政年份:2022
- 资助金额:
$ 75万 - 项目类别:
eNamptorTM: A Humanized mAb To Reduce the Severity of Radiation Pneumonitis and Fibrosis
eNamptorTM:一种降低放射性肺炎和纤维化严重程度的人源化单克隆抗体
- 批准号:
10011266 - 财政年份:2020
- 资助金额:
$ 75万 - 项目类别:
eNamptorTM: A Humanized mAb To Reduce the Severity of Radiation Pneumonitis and Fibrosis
eNamptorTM:一种降低放射性肺炎和纤维化严重程度的人源化单克隆抗体
- 批准号:
10415224 - 财政年份:2020
- 资助金额:
$ 75万 - 项目类别:
eNamptorTM: A Humanized mAb To Reduce the Severity of Radiation Pneumonitis and Fibrosis
eNamptorTM:一种降低放射性肺炎和纤维化严重程度的人源化单克隆抗体
- 批准号:
10274779 - 财政年份:2020
- 资助金额:
$ 75万 - 项目类别:
Novel Involvement of NAMPT and TLR4 in PAH Vascular Remodeling
NAMPT 和 TLR4 在 PAH 血管重塑中的新参与
- 批准号:
10334432 - 财政年份:2019
- 资助金额:
$ 75万 - 项目类别:
Novel Involvement of NAMPT and TLR4 in PAH Vascular Remodeling
NAMPT 和 TLR4 在 PAH 血管重塑中的新参与
- 批准号:
10093119 - 财政年份:2019
- 资助金额:
$ 75万 - 项目类别:
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