A Novel Bispecific Antibody for the Treatment of Idiopathic Pulmonary Fibrosis

一种治疗特发性肺纤维化的新型双特异性抗体

基本信息

批准号：
10482438
负责人：
Neil A Fanger
金额：
$ 30.65万
依托单位：
VIRTICI, LLC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2023-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10482438
关键词：
Address Affinity Animal Model Animals Anti-Inflammatory Agents Antibodies Antibody Affinity Antibody Therapy Asthma Autoimmune Automobile Driving Binding Biological Assay Bispecific Antibodies Blocking Antibodies Blood Cell Line Cells Cessation of life Characteristics Chronic Chronic lung disease Clinic Clinical Clinical Research Complex Crohn&apos s disease Data Set Development Disease Disease Progression Dose Environmental Exposure Family Fibroblasts Fibrosis Formulation Genetic Goals Hyperplasia Immunoglobulin G Inflammatory Injections LIGHT protein Laboratories Lead Libraries Lung Macaca fascicularis Mammalian Cell Measures Medical Minor Modeling Mus Mutagenesis Pathology Pathway interactions Patients Phage Display Pharmaceutical Preparations Phase Play Positioning Attribute Process Production Profibrotic signal Publishing Pulmonary Fibrosis Quality of life Recombinants Reporting Research Research Design Rheumatoid Arthritis Rivers Role Side Small Business Innovation Research Grant Structure of parenchyma of lung Symptoms System Systemic Scleroderma TNF gene TNFSF15 gene Testing Therapeutic Tissues Toxicology Tumor-infiltrating immune cells Ulcerative Colitis Vectorial capacity base cell bank cell type chemokine commercialization cytokine design fibrotic lung fibrotic lung disease first-in-human herpesvirus entry mediator high voltage electron microscopy idiopathic pulmonary fibrosis immunogenicity improved inhibitor therapy lead candidate lymphotoxin beta receptor meetings novel pharmacokinetics and pharmacodynamics pre-clinical prevent pulmonary function decline receptor receptor binding respiratory vascular injury

Address Affinity Animal Model Animals Anti-Inflammatory Agents Antibodies Antibody Affinity Antibody Therapy Asthma Autoimmune Automobile Driving Binding Biological Assay Bispecific Antibodies Blocking Antibodies Blood Cell Line Cells Cessation of life Characteristics Chronic Chronic lung disease Clinic Clinical Clinical Research Complex Crohn&apos s disease Data Set Development Disease Disease Progression Dose Environmental Exposure Family Fibroblasts Fibrosis Formulation Genetic Goals Hyperplasia Immunoglobulin G Inflammatory Injections LIGHT protein Laboratories Lead Libraries Lung Macaca fascicularis Mammalian Cell Measures Medical Minor Modeling Mus Mutagenesis Pathology Pathway interactions Patients Phage Display Pharmaceutical Preparations Phase Play Positioning Attribute Process Production Profibrotic signal Publishing Pulmonary Fibrosis Quality of life Recombinants Reporting Research Research Design Rheumatoid Arthritis Rivers Role Side Small Business Innovation Research Grant Structure of parenchyma of lung Symptoms System Systemic Scleroderma TNF gene TNFSF15 gene Testing Therapeutic Tissues Toxicology Tumor-infiltrating immune cells Ulcerative Colitis Vectorial capacity base cell bank cell type chemokine commercialization cytokine design fibrotic lung fibrotic lung disease first-in-human herpesvirus entry mediator high voltage electron microscopy idiopathic pulmonary fibrosis immunogenicity improved inhibitor therapy lead candidate lymphotoxin beta receptor meetings novel pharmacokinetics and pharmacodynamics pre-clinical prevent pulmonary function decline receptor receptor binding respiratory vascular injury

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项目摘要

Project Summary Our objective is to produce a bispecific antibody, VTC-890, capable of binding two proinflammatory cytokines, LIGHT (TNFSF14) and TL1A (TNFSF15), for the treatment of Idiopathic Pulmonary Fibrosis (IPF). IPF is a chronic fibrotic lung disease characterized by widespread progressive scarring of the lungs. Patients with IPF show declining lung function leading to early death 5, 47.We will demonstrate that VTC-890 can effectively block the receptor binding domains of LIGHT and TL1A, thereby reducing downstream activation of pro-fibrotic pathways that lead to tissue remodeling in IPF. The causes of IPF are complex and include genetics and environmental exposure, but the involvement of cytokine-dependent processes is demonstrated by the recent introduction of two new antifibrotic, anti- inflammatory medications that slow the rate of respiratory decline. Unfortunately, therapeutic benefits are relatively minor and IPF is still invariably fatal, typically in about 3.5 years. No present treatment stops or reverses the progression of the disease, and patients sometimes discontinue treatment with the therapeutics due to side effects5. Important characteristic features of the progression of IPF are tissue remodeling and fibrosis22. In this regard, our team published the first reports that a genetic deficiency in the TNF superfamily cytokine LIGHT and blocking LIGHT binding to its receptors (HVEM/TNFRSF14 and LTβR/TNFRSF14), strongly reduced lung tissue remodeling and fibrosis in animal models. We also showed that injection of recombinant LIGHT protein into the lungs promoted the tissue remodeling characteristic of IPF13, 14. In our recent published studies15, we have now show that TL1A also strongly contributes to tissue remodeling in these same models, and injection of recombinant TL1A into the lungs of mice drives pathology independent of LIGHT, suggesting it plays a complementary and synergistic role to LIGHT in tissue remodeling15. This proposal is designed to produce and validate a novel bispecific antibody, VTC-890, capable of blocking the receptor binding of both LIGHT and TL1A for the treatment of IPF. The high-level objectives are to: 1) establish VTC-890 production and analytical assays to support manufacturing, purification, bioactivity determination, and formulation; 2) complete the animal studies required to support our clinical study design; and 3) identify the remaining preclinical datasets necessary to obtain FDA IND approval. Successful commercialization of VTC-890 would ultimately provide a profound front-line therapy for the treatment of IPF and potentially other fibrotic diseases, such as systemic sclerosis and asthma.

项目摘要我们的目标是产生双特异性抗体VTC-890，能够结合两种促炎细胞因子，即光（TNFSF14）和TL1A（TNFSF15），用于治疗特发性肺纤维化（IPF）。 IPF是一个慢性纤维化肺部疾病的特征是肺部的宽度进行性疤痕。 IPF患者显示导致早期死亡的肺功能下降5，47。我们将证明VTC-890可以有效阻止光和TL1A的受体结合结构域，从而减少了促纤维化的下游激活导致IPF中组织重塑的途径。 IPF的原因很复杂，包括遗传学和环境暴露，但参与细胞因子依赖性过程是通过最近引入两种新的抗纤维化抗抗抗抗抗曲率的炎症药物减慢呼吸道下降速度。不幸的是，治疗益处是相对较小，IPF仍然总是致命的，通常在大约3。5年之内。没有目前的治疗停止或逆转疾病的进展，患者有时会停止治疗治疗由于副作用5。 IPF进展的重要特征是组织重塑和纤维化22。在这方面，我们的团队发表了第一个报道，TNF超家族细胞因子光和阻塞光结合其受体（HVEM/TNFRSF14和LTβR/TNFRSF14），肺强烈降低动物模型中的组织重塑和纤维化。我们还表明注射重组光蛋白进入肺部促进了IPF13，14的组织重塑特征。在我们最近发表的研究中，我们现在已经表明，TL1A在这些模型中也有很大贡献的组织重塑，并注射重组TL1A进入小鼠的肺部，驱动病理学独立于光，这表明它在在组织重塑中完全有效地发挥作用15。该建议旨在生产和验证一种新型的双特异性抗体VTC-890，能够阻止光和TL1A的接收器结合用于治疗IPF。高级目标是：1）建立VTC-890生产和分析测定，以支持制造，纯化，生物活性决心和公式； 2）完成支持我们的临床研究设计所需的动物研究； 3）确定获得FDA IND批准所需的其余临床前数据集。成功的 VTC-890的商业化最终将为IPF治疗提供深刻的前线疗法以及潜在的其他纤维化疾病，例如全身性硬化和哮喘。