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

基本信息

  • 批准号:
    10602227
  • 负责人:
  • 金额:
    $ 26.92万
  • 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:
    2022-09-19 至 2023-07-31
  • 项目状态:
    已结题

项目摘要

ABSTRACT Inflammatory bowel disease (IBD) is a debilitating disease (without curative therapies) that is critically influenced by dysregulated inflammatory pathways. This A0 R42 STTR application focuses on a highly novel humanized monoclonal antibody (mAb), ALT-100, to target and neutralize eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a damage-associated molecular pattern protein (DAMP) that robustly activates innate immunity-driven inflammatory pathways via ligation of the Toll-like receptor 4 (TLR4). We speculate the eNAMPT-neutralizing ALT-100 mAb to be a strategy to address the unmet need for therapies that limit inflammatory bowel injury/fibrosis and reduce the severity of IBD. Published and unpublished data strongly support involvement of eNAMPT in human IBD pathobiology. First, NAMPT RNA and protein expression are significantly increased in intestinal tissues from IBD patients and are highly upregulated by IBD-relevant stimuli including growth factors and cytokines. Second, plasma/serum eNAMPT levels are elevated in IBD subjects and correlate with disease severity and responses to anti-TNFa therapies. Thirdly, NAMPT polymorphisms (SNPs), previously linked to inflammatory disease severity in ARDS and pulmonary hypertension (PH), associate with IBD severity in GWAS studies. Lastly, compellingly published data demonstrate eNAMPT is a highly druggable target, with ALT-100 mAb profoundly attenuating multiple preclinical systemic inflammation/organ injuries (ARDS, PH, radiation-induced fibrosis, cancer). Importantly, ALT-100 mAb reduces preclinical IBD severity, colon inflammation and fibrosis. The feasibility of ALT-100 mAb as an IBD therapy is supported by completed acute IND-enabling pharmacokinetic (PK) studies and 28-day toxicity studies showing the IV ALT-100 mAb formulation has a T1/2 half-life of 10 days and is without discernable toxicity (rats and pigs). In addition, we have completed CMC manufacturing development (stable cell line, Research/Master Cell Banks) and a 200L GMP Bioreactor run (expression 6 gms/L) of the IV ALT-1000 mAb formulation (10mg/mL). We anticipate FDA IND submission for ARDS in May 2022. In PHASE I of this R-42 STTR PHASE I/II Fast Track application, Specific Aims #1/2 will assess pharmacodynamic (PD) properties of ALT-100 mAb in well-established acute (7 days) and chronic (28 days) preclinical DSS-induced murine colitis models and optimize ALT-100 mAb dosing (0.4 mg/kg, 1mg/kg, 4 mg/kg) and route of delivery (IV vs subQ) using IV formulations (10 mg/mL) and subQ formulations (100 mg/mL). In PHASE II studies conducted in rats and minipigs, Specific Aim #3 will characterize the pharmacokinetic (PK) characteristics of the subQ and IV ALT-100 mAb formulations and Specific Aim #4 will evaluate chronic subQ ALT-100 mAb toxicokinetic properties. Successful completion of these PHASE I/ II STTR studies will establish ALT-100 mAb as a viable IBD therapeutic and enable the submission of an FDA IND application to allow Aqualung to conduct IBD clinical trials that address ALT-100 mAb as a novel therapeutic to address the unmet needs in subjects with severe IBD, especially in subjects who fail biologic therapies.
摘要 炎症性肠病(IBD)是一种使人衰弱的疾病(没有治愈性疗法), 炎症通路失调该A0 R42 STTR应用专注于高度新颖的人源化 单克隆抗体(mAb)ALT-100,用于靶向和中和eNAMPT(细胞外烟酰胺 磷酸核糖转移酶),一种损伤相关分子模式蛋白(DAMP), 通过连接Toll样受体4(TLR 4)的先天免疫驱动的炎症途径。我们推测 eNAMPT-中和ALT-100 mAb是一种策略,以解决对限制ALT-100的治疗的未满足需求, 炎症性肠损伤/纤维化并降低IBD的严重程度。已发表和未发表的数据 支持eNAMPT参与人类IBD病理学。首先,NAMPT RNA和蛋白质表达是 在IBD患者的肠组织中显著增加,并被IBD相关刺激高度上调 包括生长因子和细胞因子。第二,IBD受试者的血浆/血清eNAMPT水平升高 并与疾病严重程度和对抗TNF α治疗的反应相关。第三,NAMPT多态性 (SNP),以前与ARDS和肺动脉高压(PH)中的炎性疾病严重程度相关, 在GWAS研究中与IBD严重程度相关。最后,令人信服的公布数据表明,eNAMPT是一个 ALT-100 mAb高度可药物化靶点,可显著减弱多种临床前系统性 炎症/器官损伤(ARDS、PH、辐射诱导的纤维化、癌症)。重要的是,ALT-100 mAb 降低临床前IBD严重程度、结肠炎症和纤维化。ALT-100单抗作为一种免疫抑制剂的可行性研究 IBD治疗得到已完成的急性IND启用药代动力学(PK)研究和28天毒性研究的支持 研究显示IV ALT-100 mAb制剂的T1/2半衰期为10天,且无明显毒性 (rats猪)。此外,我们已完成CMC生产开发(稳定细胞系, 研究/主细胞库)和IV ALT-1000 mAb的200 L GMP生物反应器运行(表达6 gms/L) 制剂(10 mg/mL)。我们预计将于2022年5月提交ARDS的FDA IND。在第一阶段的R-42 STTR I/II期快速通道申请,特定目标#1/2将评估 ALT-100 mAb在已确立的急性(7天)和慢性(28天)临床前DSS诱导的小鼠结肠炎中的应用 模型和优化ALT-100 mAb给药(0.4 mg/kg、1 mg/kg、4 mg/kg)和给药途径(IV vs subQ) 使用IV制剂(10 mg/mL)和subQ制剂(100 mg/mL)。在大鼠中进行的II期研究中 具体目标#3将表征subQ和IV给药的药代动力学(PK)特征 ALT-100 mAb制剂和特定目标4将评价慢性subQ ALT-100 mAb毒代动力学 特性.这些I/ II期STTR研究的成功完成将确立ALT-100 mAb作为可行的 IBD治疗,并能够提交FDA IND申请,以允许Aqualung进行IBD临床 将ALT-100 mAb作为一种新型治疗药物,以解决重度糖尿病受试者未满足的需求的试验 IBD,尤其是生物治疗失败的受试者。

项目成果

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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:
    $ 26.92万
  • 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:
    $ 26.92万
  • 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:
    $ 26.92万
  • 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:
    $ 26.92万
  • 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:
    $ 26.92万
  • 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:
    $ 26.92万
  • 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:
    $ 26.92万
  • 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:
    $ 26.92万
  • 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:
    $ 26.92万
  • 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:
    $ 26.92万
  • 项目类别:

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机械建模与机器学习相结合诊断急性呼吸窘迫综合征
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