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
基本信息
- 批准号:10723260
- 负责人:
- 金额:$ 80.9万
- 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:2022-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
ABSTRACT
Pulmonary arterial hypertension (PAH) is a fatal disease (without curative therapies) that is critically influenced
by dysregulated inflammatory pathways. This A1 R42 Fast Track STTR application focuses on eNAMPT (extra-
cellular nicotinamide phosphoribosyltransferase) as a novel, highly attractive PAH target. Aqualung Therapeutics
has developed a humanized eNAMPT-neutralizing mAb, ALT-100, to address the unmet need for therapies that
improve right ventricular (RV) dysfunction/failure and PAH survival. Circulating eNAMPT is a damage-associ-
ated molecular pattern protein (DAMP) that robustly activates innate immunity-driven inflammatory pathways
via ligation of the Toll-like receptor 4 (TLR4). Our published/unpublished data strongly support involvement of
eNAMPT in the pathobiology of human PH. First, we have reported that NAMPT RNA and protein expression
and secretion are significantly increased in PBMCs and in remodeled lung vessels from PAH patients with these
processes highly upregulated by PAH-relevant stimuli, including growth factors and hypoxia via HIF-2α signaling.
Second, plasma eNAMPT levels are elevated and correlate with RV dysfunction in PAH subjects. Thirdly,
NAMPT polymorphisms (SNPs), previously linked to inflammatory severity including ARDS mortality, are asso-
ciated with PAH severity, including cardiac catherization indices of RV dysfunction in a large PAH GWAS. Lastly,
we have compellingly demonstrated that eNAMPT is a highly druggable target, with the eNAMPT-neutralizing
mAb, ALT-100, profoundly attenuating and reversing preclinical PAH vascular remodeling and indices of RV
heart failure. Supporting the feasibility of ALT-100 as a PAH therapy, we have completed non-IND-enabling
pharmacokinetic (PK) studies demonstrating that IV-delivered ALT-100 mAb exhibits a T1/2 half-life of 12-14 days
and 28-day toxicity studies in rats demonstrated that up to 50 mg/kg of ALT-100 is without discernable toxicity.
We have completed stable cell line development, generated both Research and Master Cell Banks, and have
completed a 200L GMP Bioreactor run (expression 6 gms/L); a titer assuring very low Cost of Goods and market
entry at a low price point. ALT-100’s acute IND-enabling studies for the indication of ARDS will to be completed
by November 2021, again facilitating a successful FDA IND application for PAH. STTR PHASE I is designed to
optimize route of delivery (SubQ vs IM) and dosing of ALT-100 mAb and further validate ALT-100 as an effective
strategy in two preclinical PAH rat models (monocrotaline, hypoxia/Sugen) (SA #1). We will provide proof-of-
concept genomic data validating ALT-100 targeting of the eNAMPT/TLR4 pathway in rat lung tissues and PBMCs
as the mechanism by which ALT-100 significantly halts PAH progression and potentially reverses the severity of
PAH (SA #2). PHASE II studies conducted in rats and minipigs will characterize the PK and pharmacodynamic
(PD) characteristics of the ALT-100 mAb (SA #3) and ALT-100 toxicokinetic properties (SA #4). Successful
completion of these PHASE I/ II STTR studies will enable submission of an FDA IND application whose approval
will allow rapid movement to conducting PAH clinical trials that address the significant unmet need in PAH.
摘要
肺动脉高压(PAH)是一种致命的疾病(没有根治方法),受到严重影响。
通过失调的炎症途径。此A1 R42 Fast Track STTR应用程序侧重于eNAMPT(额外-
细胞烟酰胺磷酸核糖转移酶)作为一种新的、极具吸引力的多环芳烃靶标。阿奎隆治疗公司
已经开发出一种人源化的eNAMPT中和单抗ALT-100,以解决未满足的治疗需求
改善右室(RV)功能障碍/衰竭和PAH存活率。流传的eNAMPT是一种损害-关联-
激活天然免疫驱动的炎症途径的分子模式蛋白(DAMP)
通过连接Toll样受体4(TLR4)。我们已发布/未发布的数据有力地支持了
ENAMPT在人类PH病理生物学中的作用。首先,我们已经报道了NAMPT的RNA和蛋白质表达
PAH患者PBMCs和重塑的肺血管分泌显著增加。
PAH相关刺激,包括生长因子和缺氧通过HIF-2α信号通路高度上调的过程。
第二,PAH患者血浆eNAMPT水平升高,并与右室功能障碍相关。第三,
NAMPT多态(SNPs)以前与炎症严重程度有关,包括ARDS死亡率,现在也是如此。
与PAH严重程度相关,包括大型PAH患者右室功能障碍的心导管指数。最后,
我们已经令人信服地证明了eNAMPT是一个高度可下药的目标,eNAMPT-中和
MAb、ALT-100对临床前PAH血管重构和RV指标的影响
心力衰竭。支持ALT-100作为PAH治疗的可行性,我们已经完成了非IND使能
药代动力学(PK)研究表明,静脉注射ALT-100单抗的半衰期为12-14天
对大鼠的28天毒性研究表明,高达50 mg/kg的ALT-100没有明显的毒性。
我们已经完成了稳定的细胞系开发,产生了研究细胞库和主细胞库,并
完成了200L GMP生物反应器的运行(表达式6 gms/L);滴度保证了非常低的商品和市场成本
以较低的价格进入市场。ALT-100‘S对急性呼吸窘迫综合征适应证的急性期研究将完成
到2021年11月,再次促进FDA IND对PAH的成功申请。第一阶段的设计目的是
优化ALT-100单抗的给药途径(SubQ与IM)和剂量,进一步验证ALT-100的有效性
在两种临床前PAH大鼠模型(野百合碱、缺氧/SUGEN)中的策略(SA#1)。我们将提供证明-
概念基因组数据验证ALT-100靶向eNAMPT/TLR4途径在大鼠肺组织和PBMC中的作用
作为ALT-100显著阻止PAH进展并可能逆转其严重性的机制
PAH(SA#2)。在大鼠和小型猪身上进行的第二阶段研究将表征PK和药效学
(Pd)ALT-100单抗的特性(SA#3)和ALT-100毒代动力学特性(SA#4)。成功
完成这些I/II阶段STTR研究将能够提交FDA IND申请,其批准
将允许快速进行多环芳烃临床试验,以解决多环芳烃中未得到满足的重大需求。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
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
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Joe G. N. Garcia', 18)}}的其他基金
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:
$ 80.9万 - 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:
$ 80.9万 - 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:
$ 80.9万 - 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:
$ 80.9万 - 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:
$ 80.9万 - 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:
$ 80.9万 - 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:
$ 80.9万 - 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:
$ 80.9万 - 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:
$ 80.9万 - 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:
$ 80.9万 - 项目类别:
相似国自然基金
水稻边界发育缺陷突变体abnormal boundary development(abd)的基因克隆与功能分析
- 批准号:32070202
- 批准年份:2020
- 资助金额:58 万元
- 项目类别:面上项目
Development of a Linear Stochastic Model for Wind Field Reconstruction from Limited Measurement Data
- 批准号:
- 批准年份:2020
- 资助金额:40 万元
- 项目类别:
相似海外基金
Preclinical Development of a Novel Therapeutic Agent for Idiopathic Pulmonary Fibrosis
特发性肺纤维化新型治疗剂的临床前开发
- 批准号:
10696538 - 财政年份:2023
- 资助金额:
$ 80.9万 - 项目类别:
Preclinical development of a novel therapeutic for Parkinson's disease
帕金森病新型疗法的临床前开发
- 批准号:
10913244 - 财政年份:2023
- 资助金额:
$ 80.9万 - 项目类别:
Process Development and Preclinical Advancement of a Novel Nanoparticle Formulation for Immune Activation
用于免疫激活的新型纳米颗粒制剂的工艺开发和临床前进展
- 批准号:
10758714 - 财政年份:2023
- 资助金额:
$ 80.9万 - 项目类别:
Preclinical and Early Clinical Development of a Novel Drug for On-Demand Voiding
按需排尿新药的临床前和早期临床开发
- 批准号:
10875778 - 财政年份:2023
- 资助金额:
$ 80.9万 - 项目类别:
Preclinical and Early Clinical Development of a Novel Drug for On-Demand Voiding
按需排尿新药的临床前和早期临床开发
- 批准号:
10569279 - 财政年份:2023
- 资助金额:
$ 80.9万 - 项目类别:
Preclinical Development of a Novel Gene Therapeutic for Inclusion Body Myositis
包涵体肌炎新基因疗法的临床前开发
- 批准号:
10709907 - 财政年份:2022
- 资助金额:
$ 80.9万 - 项目类别:
Preclinical development of the novel inhibitor of apoptosis proteins S2/IAPinh for cancer therapy
用于癌症治疗的新型凋亡蛋白抑制剂 S2/IAPinh 的临床前开发
- 批准号:
10568409 - 财政年份:2022
- 资助金额:
$ 80.9万 - 项目类别:
Preclinical development of a novel antibody conjugate for intraoperative detection of pancreatic cancer
用于术中检测胰腺癌的新型抗体偶联物的临床前开发
- 批准号:
10584614 - 财政年份:2022
- 资助金额:
$ 80.9万 - 项目类别:
Preclinical development of a novel antibody conjugate for intraoperative detection of pancreatic cancer
用于术中检测胰腺癌的新型抗体偶联物的临床前开发
- 批准号:
10365729 - 财政年份:2022
- 资助金额:
$ 80.9万 - 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:
$ 80.9万 - 项目类别: