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

基本信息

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
项目类别：
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

项目摘要

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 项目摘要/摘要第一阶段 NHLBI IPF 是一种慢性、不可逆的纤维化肺部疾病，由反复损伤引起，导致进行性进展每年有 130,000 名 IPF 患者出现僵硬，最终导致肺功能丧失，5 年死亡率为 80% 的人迫切需要新疗法，迄今为止，传统疗法尚未阻止疾病。最近有 2 种新的 IPF 药物获得批准：抗纤维化药物吡非尼酮和尼达尼布酪氨酸激酶抑制剂，但两者只能适度延缓疾病进展。TGF−β 是疾病的关键驱动因素之一。 IPF 患者的纤维化，归因于其在肺部的水平升高和延长。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），过度产生胶原蛋白并增加纤连蛋白沉积在细胞外基质 (ECM) 中，逐渐阻碍 TGF−β- 的抑制。介导的纤维化有可能阻止甚至逆转 IPF 患者的疾病，但是 TGF−β 广泛存在。表达并在维持组织稳态中发挥重要作用，因此，TGF−β 抑制剂具有重要意义。人们对治疗纤维化抱有浓厚的兴趣，但由于重要的宿主（即，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，将提供差异化的治疗方案来满足这一重大未满足的需求。正在开发一流的抗体药物偶联物 (ADC) 平台，以选择性抑制 TGF− 驱动的在目标 1 中，我们将开发新型 ADC 治疗药物 (SYN301) 并进行演示。通过原胶原减少来评估 IPF 患者成纤维细胞纤维化的抑制在目标 2 中，我们将评估纤维化疾病的临床标志物的表达和 α 平滑肌肌动蛋白。 SYN301 在博来霉素诱导的肺纤维化体内模型中的功效。通过肺组织病理学测量来评估对疾病进展和肺纤维化的抑制，我们预计 SYN301 会导致炎症浸润、胶原沉积和 BALF 免疫细胞成分。与标准护理疗法相比，SYN301 将减少体外和体内纤维化标志物。同类首个能够安全阻断 IPF 患者 TGF-β 诱导的纤维化的疗法，它是第一个 ADC 分子。 SYN301 正在开发用于选择性阻断 TGF-β 驱动的纤维化。与当前的纤维化治疗相结合，以提高患者组织纤维化的总体缓解率。多种其他疾病的传播问题，如 NASH、肾纤维化和心脏纤维化，其中 TGF−β 是因此，我们的治疗平台广泛适用于多种疾病的纤维化。疾病，为最需要的患者提供新的治疗选择。