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

• 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
• 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' 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

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)。IPF是一种 以肺部广泛的进行性疤痕为特征的慢性纤维性肺病。特发性肺间质纤维化患者 显示肺功能下降导致早逝5，47.我们将证明VTC-890可以有效地阻断 LIGH和TL1a的受体结合域，从而减少促纤维化的下游激活 导致肺间质纤维化组织重塑的途径。 IPF的原因是复杂的，包括遗传和环境暴露，但参与 最近推出的两种新的抗纤维化药物--抗纤维化药物--证明了细胞因子依赖的过程。 减缓呼吸衰退速度的炎症性药物。不幸的是，治疗的好处是 相对较轻，IPF仍然总是致命的，通常在大约3.5年内。目前的治疗没有停止或 逆转疾病的发展，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。在这方面， 我们的团队发表了第一份报告，即肿瘤坏死因子超家族细胞因子的遗传缺陷 阻断与其受体(HVEM/TNFRSF14和LTβR/TNFRSF14)的光结合，使肺明显减少 动物模型中的组织重塑和纤维化。我们还发现，注射重组LIGH蛋白 促进了IPF13，14的组织重塑特征。在我们最近发表的研究15中，我们 现在已经表明，在这些相同的模型中，TL1a也强烈地促进了组织重塑，并且注射了 重组TL1a进入小鼠的肺部驱动病理不依赖于光，这表明它发挥了 光在组织重建中的互补和协同作用15。 这项提议旨在生产和验证一种新型的双特异性抗体VTC-890，能够阻断 LIGHT和TL1a治疗特发性肺纤维化的受体结合高层目标是：1) 建立VTC-890生产和分析测试，以支持生产、纯化、生物活性 2)完成支持我们的临床研究设计所需的动物研究； 以及3)确定获得FDA IND批准所需的其余临床前数据集。成功 VTC-890的商业化最终将为IPF的治疗提供一种深刻的一线治疗方法 以及潜在的其他纤维化疾病，如系统性硬化症和哮喘。