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Targeting the eNAMPT/TLR4 pathway to reduce Inflammatory Bowel Disease severity

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
负责人:
Joe G. N. Garcia
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
项目状态:
已结题
起止时间:
2022-09-19 至 2023-07-31
关键词:
AcuteAcute Respiratory Distress SyndromeAddressArizonaAttentionAttenuatedBiological Response Modifier TherapyBioreactorsBiotechnologyCandidate Disease GeneChronicClinical ResearchClinical TrialsCollaborationsColonic inflammationDataDevelopmentDiseaseDoctor of PhilosophyDoseDrug KineticsExhibitsFamily suidaeFibrosisFormulationGenetic PolymorphismGenetic TranscriptionGoalsGrowth FactorHalf-LifeHumanInflammationInflammatoryInflammatory Bowel DiseasesInjuryIntestinesInvestigational DrugsItalyLigationLinkLungMalignant NeoplasmsMalignant neoplasm of prostateMiniature SwineMolecularMonoclonal AntibodiesMusNatural ImmunityNew Drug ApprovalsNiacinamidePathway interactionsPatientsPatternPharmacodynamicsPhasePhysiciansPlasmaPropertyProteinsPublishingPulmonary HypertensionRadiationRadiation FibrosisRattusResearchRouteRunningSafetyScienceScientistSeveritiesSeverity of illnessSmall Business Technology Transfer ResearchSprague-Dawley RatsStimulusTLR4 geneTalentsTherapeuticTherapeutic InterventionTissuesToxic effectToxicokineticsToxicologyTransferaseUniversitiescell bankcurative treatmentscytokinedruggable targetefficacy trialextracellularfirst-in-humangenome wide association studyhealthy volunteerhumanized monoclonal antibodiesimprovedindexingmouse modelmurine colitisneutralizing monoclonal antibodiesnew therapeutic targetnicotinamide phosphoribosyltransferasenovelnovel therapeuticsorgan injurypharmacokinetic characteristicphase 2 studypre-clinicalprofessorprotein expressionpublic health relevanceresponsestable cell linesystemic inflammatory responsetherapeutic candidate

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中文摘要
翻译
摘要 炎症性肠病(IBD)是一种严重影响身体虚弱的疾病(没有根治方法)。 通过失调的炎症途径。这款A0 R42 STTR应用程序专注于高度新颖的人性化 靶向并中和eNAMPT(细胞外烟酰胺)的单抗ALT-100 磷酸核糖基转移酶),一种损伤相关的分子模式蛋白(DAMP),它能强烈激活 通过结扎Toll样受体4(TLR4)的先天免疫驱动的炎症通路。我们推测 ENAMPT-中和ALT-100单抗将成为一种战略,以解决限制治疗的未满足需求 炎症性肠损伤/纤维化,减轻IBD的严重程度。强劲的已发布和未发布数据 支持eNAMPT参与人类IBD病理生物学。首先,NAMPT RNA和蛋白质的表达是 IBD患者肠道组织中显著升高,并在IBD相关刺激下高度上调 包括生长因子和细胞因子。第二,IBD患者血浆/血清eNAMPT水平升高 并与疾病严重程度和对抗TNFa治疗的反应相关。第三,NAMPT多态 (SNPs),以前与ARDS和肺动脉高压(PH)的炎症性疾病严重程度有关, 与GWAS研究中IBD的严重程度相关。最后,令人信服的发布数据表明,eNAMPT是一种 高度可下药的靶点,ALT-100单抗可深度减弱多种临床前系统 炎症/器官损伤(ARDS、PH、辐射导致的纤维化、癌症)。重要的是,ALT-100单抗 降低临床前IBD严重程度、结肠炎和纤维化。ALT-100单抗作为抗ALT-100单抗的可行性研究 IBD治疗得到了已完成的急性IND药代动力学(PK)研究和28天毒性的支持 研究表明,IV ALT-100单抗制剂的T1/2半衰期为10天,没有明显的毒性 (老鼠和猪)。此外,我们还完成了CMC制造开发(稳定细胞系, 研究/主细胞库)和200L GMP生物反应器运行(表达6gms/L)的IV ALT-1000mAb 制剂(10 mg/m L)。我们预计FDA将于2022年5月提交ARDS IND申请。在这架R-42的第一阶段 STTR阶段I/II快速通道应用,特定目标#1/2将评估以下药物的药效学(PD)特性 ALT-100单抗在急性(7天)和慢性(28天)DSS诱导的小鼠结肠炎中的作用 ALT-100单抗剂量(0.4 mg/kg、1 mg/kg、4 mg/kg)和给药途径(IV与SubQ)的模型和优化 使用静脉制剂(10毫克/毫升)和SubQ制剂(100毫克/毫升)。在对大鼠进行的第二阶段研究中 和小型猪,特定目标#3将表征SubQ和IV的药代动力学(PK)特征 ALT-100单抗制剂和特定目标#4将评估慢性亚Q ALT-100单抗的毒代动力学 属性。成功完成这些I/II期STTR研究将使ALT-100单抗成为一种可行的 IBD治疗,并允许提交FDA IND申请,以允许Aquung进行IBD临床 将ALT-100单抗作为一种新的治疗方法来解决重症患者未得到满足的需求的试验 IBD,特别是在生物治疗失败的受试者中。
英文摘要
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.
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Preclinical Development of a Novel eNAMPT-Neutralizing mAb for Pulmonary Hypertension
  • 批准号:
    10723260
  • 项目类别:
  • 资助金额:
    $80.9万
  • 财政年份:
    2022
  • 负责人:
    Joe G. N. Garcia
  • 依托单位:
Role of Endothelial eNAMPT Secretion and TLR4 Signaling in the ARDS Vascular Endotype
  • 批准号:
    10440855
  • 项目类别:
  • 资助金额:
    $23.27万
  • 财政年份:
    2022
  • 负责人:
    Joe G. N. Garcia
  • 依托单位:
Preclinical Development of a Novel eNAMPT-Neutralizing mAb for Pulmonary Hypertension
  • 批准号:
    10489982
  • 项目类别:
  • 资助金额:
    $25.96万
  • 财政年份:
    2022
  • 负责人:
    Joe G. N. Garcia
  • 依托单位:
Targeting the eNAMPT/TLR4 pathway to reduce Inflammatory Bowel Disease severity
  • 批准号:
    10771493
  • 项目类别:
  • 资助金额:
    $97.52万
  • 财政年份:
    2022
  • 负责人:
    Joe G. N. Garcia
  • 依托单位:
海外基金