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：
10594937
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/10594937
关键词：
Address Affinity Animal Model Animals Anti-Inflammatory Agents Antibodies Antibody Affinity Antibody Therapy Asthma Autoimmune Diseases 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 Light Lung Macaca fascicularis Mammalian Cell Measures Medical Minor Modeling Mus Mutagenesis Mutagens Pathology Pathway interactions Patients Phage Display Pharmaceutical Preparations Phase Phase I Clinical Trials Play Positioning Attribute Process Production Profibrotic signal Publishing Pulmonary Fibrosis Pulmonary Inflammation Quality of life Recombinants Recommendation Reporting Research Research Design Rheumatoid Arthritis Role Site Small Business Innovation Research Grant Structure of parenchyma of lung Symptoms System Systemic Scleroderma TNF gene TNFSF15 gene Testing Therapeutic Tissues Toxicology Ulcerative Colitis cell bank cell type chemokine commercialization cytokine design fibrotic lung fibrotic lung disease first-in-human herpesvirus entry mediator idiopathic pulmonary fibrosis immune cell infiltrate immunogenicity improved inhibitor therapy lead candidate lymphotoxin beta receptor manufacture novel pharmacokinetics and pharmacodynamics pre-Investigational New Drug meeting pre-clinical prevent pulmonary function decline receptor receptor binding respiratory side effect vascular injury vector

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.

项目概要我们的目标是生产一种双特异性抗体 VTC-890，能够结合两种促炎细胞因子， LIGHT (TNFSF14) 和 TL1A (TNFSF15)，用于治疗特发性肺纤维化 (IPF)。以肺部广泛进行性疤痕为特征的慢性纤维化肺病，患有 IPF 的患者。显示肺功能下降导致过早死亡 5, 47.我们将证明 VTC-890 可以有效阻止 LIGHT 和 TL1A 的受体结合域，从而减少促纤维化的下游激活导致 IPF 组织重塑的途径。 IPF 的病因很复杂，包括遗传和环境暴露，但与最近引入的两种新的抗纤维化、抗- 不幸的是，减缓呼吸衰退速度的炎症药物的治疗效果并不好。相对较小，IPF 仍然总是致命的，通常在大约 3.5 年内不停止治疗或。逆转疾病的进展，患者有时会停止治疗由于副作用5。 IPF 进展的重要特征是组织重塑和纤维化22。我们的团队发表了第一份报告，指出 TNF 超家族细胞因子 LIGHT 和阻断 LIGHT 与其受体（HVEM/TNFRSF14 和 LTβR/TNFRSF14）结合，严重降低肺功能我们还展示了注射重组 LIGHT 蛋白对动物模型的组织重塑和纤维化的影响。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15，我们现在已经表明，TL1A 对这些相同模型中的组织重塑也有很大贡献，并且注射重组 TL1A 进入小鼠肺部可独立于光驱动病理学，表明它发挥着光在组织重塑中的互补和协同作用15。该提案旨在生产和验证一种新型双特异性抗体 VTC-890，该抗体能够阻断 LIGHT 和 TL1A 的受体结合用于治疗 IPF 的高级目标是：1) 建立 VTC-890 生产和分析测定以支持制造、纯化、生物活性确定和制定；2) 完成支持我们的临床研究设计所需的动物研究； 3) 确定成功获得 FDA IND 批准所需的剩余临床前数据集。 VTC-890的商业化最终将为IPF的治疗提供深刻的一线疗法以及其他潜在的纤维化疾病，例如系统性硬化症和哮喘。