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.

摘要 肺动脉高压（PAH）是一种致命性疾病（无治愈性治疗）， 炎症通路失调此A1 R42 Fast Track STTR应用程序侧重于eNAMPT（额外- 细胞烟酰胺磷酸核糖基转移酶）作为一种新的，高度有吸引力的PAH目标。Aqualung治疗 已经开发了一种人源化的eNAMPT中和mAb，ALT-100，以解决未满足的治疗需求， 改善右心室（RV）功能障碍/衰竭和PAH生存率。循环eNAMPT是一种损害相关的， 活化分子模式蛋白（DAMP），可强烈激活先天免疫驱动的炎症通路 通过连接Toll样受体4（TLR 4）。我们已发表/未发表的数据强烈支持参与 eNAMPT在人类PH病理生物学中的作用。首先，我们已经报道了NAMPT RNA和蛋白表达， PAH患者的PBMC和重塑肺血管中， 过程高度上调PAH相关刺激，包括生长因子和缺氧通过HIF-2α信号。 其次，血浆eNAMPT水平升高，与PAH受试者的RV功能障碍相关。第三， NAMPT多态性（SNPs）以前与炎症严重程度（包括ARDS死亡率）相关，现在与急性呼吸窘迫综合征（ARDS）相关。 与PAH严重程度相关，包括大型PAH GWAS中RV功能障碍的心脏插管指数。最后， 我们已经令人信服地证明了eNAMPT是一个高度可药物化的靶点， mAb，ALT-100，深度减弱和逆转临床前PAH血管重塑和RV指数 心衰支持ALT-100作为PAH治疗的可行性，我们已完成非IND批准 药代动力学（PK）研究表明，静脉给药ALT-100 mAb的T1/2半衰期为1/2 -14天 在大鼠中进行的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，生成了研究细胞库和主细胞库， 完成了200 L GMP生物反应器运行（表达量6 gms/L）;滴度确保了非常低的商品和市场成本 以低价入场。将完成ALT-100用于ARDS适应症的急性IND使能研究 到2021年11月，再次促进PAH的FDA IND申请成功。STTR第一阶段设计用于 优化ALT-100 mAb的给药途径（SubQ vs IM）和剂量，并进一步验证ALT-100作为一种有效的 两种临床前PAH大鼠模型（野百合碱、缺氧/Sugen）中的策略（SA #1）。我们将提供证据- 验证ALT-100靶向大鼠肺组织和PBMC中eNAMPT/TLR 4通路的概念基因组数据 作为ALT-100显著阻止PAH进展并可能逆转PAH严重程度的机制， PAH（SA #2）。在大鼠和小型猪中进行的II期研究将表征PK和药效学 (PD)ALT-100 mAb（SA #3）和ALT-100毒代动力学特性（SA #4）的特征。成功 完成这些I/ II期STTR研究后，将能够提交FDA IND申请， 将允许快速开展PAH临床试验，以解决PAH中重大未满足的需求。