Development of a targeted TGF-b therapeutic that selectively blocks lung fibrosis in idiopathic pulmonary fibrosis (IPF) patients

开发选择性阻断特发性肺纤维化 (IPF) 患者肺纤维化的靶向 TGF-b 疗法

• 批准号: 10697961
• 负责人: Dori A Thomas-Karyat
• 金额: $ 29.99万
• 依托单位: SYNTHIS THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10697961
• 关键词: Actins; Animals; Antibodies; Antibody-drug conjugates; Automobile Driving; Award; Biotechnology; Bleomycin; Cardiac; Cells; Chronic; Clinical Markers; Collagen; Couples; Deposition; Development; Disease; Disease Progression; Dose; Extracellular Matrix; Fibroblasts; Fibronectins; Fibrosis; Goals; Histopathology; Homeostasis; Human; Hypertrophy; Immune; In Vitro; Industry Standard; Inflammatory Infiltrate; Injury; Lung; Measurement; Measures; Mediating; Modeling; Mus; Myofibroblast; National Heart, Lung, and Blood Institute; Oncology; Outcome; Patients; Pharmaceutical Preparations; Phase; Pirfenidone; Prevention; Procollagen; Pulmonary Fibrosis; Rattus; Role; Safety; Scleroderma; Severity of illness; Signal Transduction; Small Business Innovation Research Grant; Smooth Muscle; Technology; Testing; Therapeutic; Tissues; Toxic effect; Transforming Growth Factor beta; Tyrosine Kinase Inhibitor; antagonist; antifibrotic treatment; biomarker validation; commercial application; conventional therapy; coronary fibrosis; cytotoxic; efficacy evaluation; epithelial injury; fibroblast activation protein alpha; fibrotic lung disease; idiopathic pulmonary fibrosis; improved; in vivo; in vivo Model; indium-bleomycin; inhibitor; interest; kidney fibrosis; mortality; mouse model; nintedanib; nonalcoholic steatohepatitis; novel; novel therapeutics; patient response; perpetrators; pharmacokinetics and pharmacodynamics; pulmonary function; receptor; standard of care; therapy development; tumor

Synthis Project Summary/Abstract Phase I NHLBI IPF is a chronic, irreversible fibrotic lung disease driven by repeated injury, resulting in progressive stiffening and ultimately, loss of lung function. With 130,000 IPF patients annually and a 5 year mortality rate of 80%, there is significant need for new therapies. To date, conventional therapies have not halted disease progression. Recently 2 new IPF drugs were approved: pirfenidone, an anti-fibrotic agent and, nintedanib, a tyrosine kinase inhibitor, but both only modestly delay disease progression. TGF− is one of the key drivers of fibrosis in IPF patients, due to its elevated and prolonged levels in the lung. On a cellular level, TGF− drives activated myofibroblasts, the major perpetrators of disease, to over-produce collagen and increase fibronectin deposition in the extracellular matrix (ECM), which progressively blocks lung function. Inhibition of TGF−- mediated fibrosis could potentially stop or even reverse disease in IPF patients. However, TGF− is widely expressed and has essential roles in maintaining tissue homeostasis. Thus, although TGF− inhibitors are of significant interest to treat fibrosis, development of therapies has been hindered due to significant host (i.e., cardiac) toxicity. Safer TGF− inhibitors that selectively block fibrosis in IPF patients, but still protect host tissues, would provide differentiated treatment options to fill this significant unmet need. In this SBIR award, we are developing a first in class antibody drug conjugate (ADC) platform to selectively inhibit TGF− driven fibrosis in IPF patients. In Aim 1, we will develop our novel ADC therapeutic (SYN301) and demonstrate inhibition of fibrosis in fibroblasts derived from IPF patients, as assessed by a decrease in procollagen expression and alpha smooth muscle actin in vitro, clinical markers of fibrotic disease. In Aim 2, we will assess the efficacy of SYN301 in an industry standard, in vivo model of bleomycin induced lung fibrosis. SYN301 will be assessed for inhibition of disease progression and lung fibrosis as measured by lung histopathology, inflammatory infiltrates, collagen deposition and BALF immune cell composition. We anticipate that SYN301 will reduce markers of fibrosis both in vitro and in vivo, compared to standard of care therapies. SYN301 is a first in class therapy that will safely block TGF− induced fibrosis in IPF patients. It is the first ADC molecule being developed to selectively block TGF− driven fibrosis. Moreover, SYN301 could also be used in combination with current fibrosis therapies, to increase overall patient response rates. Tissue fibrosis is a wide spread issue in multiple other diseases, such as NASH, kidney fibrosis and cardiac fibrosis, of which TGF− is also instrumental in driving disease. Thus, our therapeutic platform is widely applicable to fibrosis in multiple diseases, providing novel therapeutic options for patients that need it the most.

Synthis项目总结/摘要第I阶段NHLBI IPF是一种慢性、不可逆的纤维化肺病，由反复损伤驱动，导致进行性 变硬并最终丧失肺功能每年有130，000例IPF患者，5年死亡率为 80%，因此需要新的治疗方法。到目前为止，传统疗法还没有阻止疾病 进展最近批准了2种新的IPF药物：吡非尼酮（抗纤维化药物）和尼达尼布（抗纤维化药物）。 酪氨酸激酶抑制剂，但两者都只能适度延迟疾病进展。TGF-β是一个关键的驱动力， 在IPF患者中，由于其在肺中的升高和延长的水平，导致纤维化。在细胞水平上，TGF-β驱动 激活肌成纤维细胞，疾病的主要肇事者，过度产生胶原蛋白和增加纤维连接蛋白 细胞外基质（ECM）中的沉积，逐渐阻断肺功能。抑制TGF-β- 介导的纤维化可能阻止甚至逆转IPF患者的疾病。然而，TGF-β广泛 表达，并在维持组织稳态中发挥重要作用。因此，虽然TGF-β抑制剂是 治疗纤维化的重要意义在于，由于大量宿主（即， 心脏）毒性。更安全的TGF− β抑制剂可选择性阻断IPF患者的纤维化，但仍能保护宿主 组织，将提供不同的治疗选择，以填补这一重大未满足的需求。在这个SBIR奖项中，我们 正在开发第一个同类抗体药物偶联物（ADC）平台，以选择性抑制TGF-β驱动的 IPF患者的纤维化。在目标1中，我们将开发我们的新型ADC治疗剂（SYN 301），并证明 通过前胶原减少评估的IPF患者来源的成纤维细胞中纤维化的抑制 表达和α平滑肌肌动蛋白，纤维化疾病的临床标志物。在目标2中，我们将评估 SYN 301在博来霉素诱导的肺纤维化的工业标准体内模型中的功效。SYN 301将 评估通过肺组织病理学测量的疾病进展和肺纤维化的抑制， 炎性浸润、胶原沉积和BALF免疫细胞组成。我们预计SYN 301 与标准护理疗法相比，将减少体外和体内的纤维化标志物。SYN 301是一种 在IPF患者中安全阻断TGF-β诱导的纤维化的一流疗法。这是第一个ADC分子 被开发用于选择性阻断TGF-β驱动的纤维化。此外，SYN 301还可用于 与目前的纤维化治疗相结合，以提高患者的总体反应率。组织纤维化是一种广泛的 在多种其他疾病中存在传播问题，例如NASH、肾纤维化和心脏纤维化，其中TGF-β是 也会导致疾病因此，我们的治疗平台广泛适用于多种疾病中的纤维化。 疾病，为最需要的患者提供新的治疗选择。