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

基本信息

  • 批准号:
    10011266
  • 负责人:
  • 金额:
    $ 30万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-06-01 至 2021-05-31
  • 项目状态:
    已结题

项目摘要

ABSTRACT The development of radiation-induced lung injury (RILI) is a potentially fatal toxicity in cancer patients undergoing thoracic radiotherapy or in individuals exposed to ionizing radiation (IR) from a nuclear incident. The pathobiology of radiation pneumonitis and radiation-induced lung fibrosis (RILF) is complex but includes the deleterious effects of unchecked inflammation (reactive oxygen species, cytokines, inflammatory cells) that increase vascular permeability, impair gas transfer and promote fibrosis. Although Toll-like receptors (TLRs) and cytokines are potential therapeutic targets for reducing RILI, experimental and clinical strategies to neutralize IR- induced proinflammatory cytokine effects or to block inflammatory cell infiltration have been disappointing. The standard of care, high dose corticosteroids, remains controversial due to long term complications and frequent, potentially fatal relapses. Thus, there is an unmet need to identify novel RILI therapeutic targets and effective therapeutic anti-inflammatory strategies. Our preclinical studies utilizing whole lung thoracic irradiation (WTLI), identified a cytozyme, nicotinamide phosphoribosyltransferase (NAMPT), as a novel RILI therapeutic target. NAMPT exists as both an intracellular enzyme (iNAMPT) catalyzing nicotinamide adenine dinucleotide (NAD) synthesis and as an extracellular inflammatory cytokine (eNAMPT). We have shown that eNAMPT is a damage- associated molecular pattern protein (DAMP) and a ligand for TLR4 to potently induce the dysregulated inflammatory response that results in cytokine storm, organ dysfunction, and death in severe critical illnesses. We have also shown that NAMPT expression and secretion is markedly increased by radiation and is a key contributor to RILI development and severity as NAMPT heterozygous mice exhibit reduced WTLI-induced RILI. Furthermore, a polyclonal eNAMPT pAb effectively reduces WTLI-induced pneumonitis and fibrosis. We have developed eNamptorTM, an effective eNAMPT-neutralizing humanized mAb that is now in stable cell line development. This STTR Fast Track Phase I/II application seeks to confirm that eNamptorTM is a novel therapeutic strategy in preclinical models of WTLI and PBI/BM5 (partial body irradiation, 5% bone marrow sparing). We speculate that eNamptorTM will surpass the protection observed in mice receiving high dose corticosteroids, thereby addressing a serious unmet need to reduce the risk and severity of RILI following IR exposure. Aqualung Therapeutics (ALT), an early stage biotechnology start-up, in collaboration with its academic partner (Univ. of Arizona) has assembled a highly skilled multidisciplinary team to evaluate eNamptorTM as a therapeutic strategy in preclinical murine models of WTLI (SA #1) and PBI/BM5 (SA #2). We will also assess the utility of a radiolabeled-NAMPT mAb probe, ProNAmptorTM, as a companion diagnostic strategy that defines organ-specific sites of IR-induced NAMPT expression. STTR Phase II studies will profile the pharmacodynamic (PD) and pharmacokinetic (PK) (SA #4) and toxicological characteristics of eNamptorTM mAb (SA #5). The proof of concept of eNamptorTM’s utility in RILI will lead to a successful FDA IND application.
摘要

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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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:
    $ 30万
  • 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:
    $ 30万
  • 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:
    $ 30万
  • 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:
    $ 30万
  • 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:
    $ 30万
  • 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:
    $ 30万
  • 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:
    $ 30万
  • 项目类别:
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
  • 批准号:
    10026453
  • 财政年份:
    2019
  • 资助金额:
    $ 30万
  • 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:
    $ 30万
  • 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:
    $ 30万
  • 项目类别:
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