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
• 负责人: Joe G. N. Garcia
• 金额: $ 25.96万
• 依托单位: AQUALUNG THERAPEUTICS CORP.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10489982
• 关键词: Acute; Acute Respiratory Distress Syndrome; Address; Arizona; Attenuated; Biological Products; Bioreactors; Biotechnology; Blood Vessels; Candidate Disease Gene; Cardiac; Characteristics; Chronic; Clinical; Clinical Trials; Collaborations; Cyclic GMP; Data; Deterioration; Development; Disease; Dose; Drug Kinetics; Exhibits; Failure; Gene Expression Profiling; Genetic Polymorphism; Genetic Transcription; Genomics; Goals; Growth Factor; Half-Life; Human; Hypoxia; In Vitro; Inflammation; Inflammatory; Intramuscular; Ligation; Link; Lung; Lung diseases; Magnetic Resonance Imaging; Manufacturer Name; Miniature Swine; Modality; Modeling; Molecular; Monoclonal Antibodies; Monocrotaline; Movement; Natural Immunity; Parents; Pathway interactions; Patients; Pattern; Peripheral Blood Mononuclear Cell; Pharmacodynamics; Phase; Physicians; Plasma; Preclinical Testing; Price; Process; Property; Protein Secretion; Proteins; Publishing; Pulmonary Hypertension; Pulmonary vessels; RNA; Rattus; Reporting; Research; Right Ventricular Dysfunction; Risk; Role; Route; Running; Scientist; Severities; Signal Transduction; Single Nucleotide Polymorphism; Small Business Technology Transfer Research; Sprague-Dawley Rats; Stimulus; Structure of parenchyma of lung; TLR4 gene; Therapeutic; Therapeutic Intervention; Toxic effect; Toxicokinetics; Toxicology; Universities; Vascular remodeling; cell bank; cost; curative treatments; design; druggable target; extracellular; genome wide association study; genomic data; hypertension treatment; immunogenicity; improved; in vivo; indexing; mortality; murine monoclonal antibody; neutralizing monoclonal antibodies; new therapeutic target; nicotinamide phosphoribosyltransferase; novel; novel strategies; pharmacokinetics and pharmacodynamics; phase 1 study; phase 2 study; pre-clinical; preclinical development; protein expression; public health relevance; pulmonary arterial hypertension; right ventricular failure; right ventricular remodeling; scale up; stable cell line; therapeutic candidate; therapeutic target; therapeutically effective; transcription factor

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.

抽象的 肺动脉高压（PAH）是一种致命疾病（没有治愈疗法），受到严重影响 通过失调的炎症途径。此A1 R42快速轨道sttr应用程序着重于Enampt（超级 - 细胞烟酰胺磷酸贝糖基转移酶）是一种新型，具有吸引力的PAH靶标。 Aqualung Therapeutics 已经开发了人源化的陶器中和mab，alt-100，以满足对疗法的未满足需求 改善右心（RV）功能障碍/失败和PAH存活。循环装布是一种损坏 - ATED分子图案蛋白（潮湿）可牢固地激活先天免疫组织化学途径 通过连接收费接收器4（TLR4）的连接。我们已发布/未发表的数据强烈支持参与 人类病理生物学的陶器。首先，我们报道了NAMPT RNA和蛋白质表达 PBMC和PAH患者的重塑肺血管中的分泌显着增加 与PAH相关的刺激高度更新的过程，包括通过HIF-2α信号传导的生长因子和缺氧。 其次，血浆enampt水平升高并与PAH受试者的RV功能障碍相关。第三， NAMPT多态性（SNP）以前与包括ARDS死亡率在内的炎症严重程度有关 与PAH的严重程度相结合，包括大PAH GWAS中RV功能障碍的心脏结构指数。最后， 我们迫切地证明了ENAMPT是一个高度吸毒的目标，而ENAMPT中和 MAB，Alt-100，深刻衰减和逆转临床前PAH血管重塑和RV指标 心脏衰竭。支持Alt-100作为PAH疗法的可行性，我们已经完成了非启用 药代动力学（PK）的研究表明，IV递送的Alt-100 MAB表现出12-14天的T1/2半衰期 大鼠的28天毒性研究表明，高达50 mg/kg的Alt-100没有可见的毒性。 我们已经完成了稳定的细胞系开发，同时产生了研究和大型细胞库，并且 完成了200升GMP生物反应器运行（表达式6 gms/l）；确保商品和市场成本非常低的效率 以低价入场。 Alt-100的急性指示ARDS的急性辅助研究将完成 到2021年11月，再次支持了PAH的FDA IND申请。 STTR I期设计为 优化交付途径（subq vs im）和Alt-100 mAb的剂量，并进一步验证Alt-100作为有效的 两种临床前PAH大鼠模型（单蛋白，缺氧/SUGEN）（SA＃1）中的策略。我们将提供证明 概念基因组数据验证了大鼠肺组织和PBMC中eNAMPT/TLR4途径的靶向ALT-100的靶向 作为Alt-100显着停止PAH进展并有可能逆转严重程度的机制 PAH（SA＃2）。在大鼠和小型曲子中进行的II期研究将表征PK和药效学 （PD）Alt-100 mAb（SA＃3）和Alt-100毒素特性（SA＃4）的特性。成功的 这些阶段I/ II STTR研究的完成将使FDA IND申请提交其批准 将允许快速移动进行PAH临床试验，以解决PAH中明显未满足的需求。