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项目摘要/摘要阶段I NHLBI IPF是一种长期不可逆的纤维化肺部疾病，通过反复损伤，导致进行性 僵硬并最终，肺功能丧失。每年有13万名IPF患者，5年死亡率为5年 80％，需要新疗法。迄今为止，常规疗法尚未停止疾病 最近批准了2种新的IPF药物：pirfenidone，一种抗纤维化剂，Nintedanib，A 酪氨酸激酶抑制剂，但两者仅适度延迟疾病的进展。 TGF-是 IPF患者的纤维化，由于其肺部水平升高和延长。在细胞级别，TGF-驱动器 激活的肌纤维细胞是疾病的主要肇事者，以过度生产胶原蛋白并增加纤连蛋白 细胞外基质（ECM）中的沉积，该基质逐渐阻断了肺功能。抑制TGF-- IPF患者中介导的纤维化可能会停止甚至逆转疾病。但是，TGF-广泛 表达并具有维持组织稳态的重要作用。尽管TGF-抑制剂是 治疗纤维化的重大兴趣，由于宿主的明显而阻碍了治疗的发展（即 心脏）毒性。在IPF患者中有选择性阻断纤维化的更安全的TGF-r抑制剂，但仍保护宿主 组织将提供区分的治疗选择，以满足这种巨大的未满足需求。在这个SBIR奖中，我们 正在开发类抗体药物缀合物（ADC）平台中的第一个以选择性抑制TGF-驱动器 IPF患者的纤维化。在AIM 1中，我们将开发新颖的ADC疗法（SYN301）并证明 通过降低胶原素评估，抑制来自IPF患者的成纤维细胞中的纤维细胞抑制 表达和α平滑肌肌动蛋白在体外，纤维化疾病的临床标志物。在AIM 2中，我们将评估 Syn301在行业标准中的效率，体内博来霉素诱导的肺纤维化。 Syn301将 通过肺组织病理学测量，可以评估抑制疾病进展和肺纤维化的抑制 炎性浸润，胶原蛋白沉积和BALF免疫细胞组成。我们预计Syn301 与护理疗法的标准相比，将在体外和体内减少纤维化的标记。 Syn301是 首先是在类疗法中，可以安全地阻止IPF患者诱导TGF-诱导的纤维化。这是第一个ADC分子 开发以选择性地阻断TGF-驱动纤维化。此外，SYN301也可以在 结合当前的纤维化疗法，以提高患者的总体反应率。组织纤维化是一个宽的 在其他多种疾病中的传播问题，例如NASH，肾脏纤维化和心脏纤维化，其中TGF-是 也有助于驱动疾病。这，我们的治疗平台广泛适用于多个的纤维化 疾病，为需要它最需要的患者提供新的热选择。