A Novel Bispecific Antibody for the Treatment of Idiopathic Pulmonary Fibrosis

项目摘要 我们的目标是制备能够结合两种促炎细胞因子的双特异性抗体VTC-890， LIGHT（TNFSF 14）和TL 1A（TNFSF 15），用于治疗特发性肺纤维化（IPF）。IPF是一种 一种慢性纤维化肺病，特征是肺部广泛的进行性瘢痕形成。IPF患者 显示肺功能下降导致早期死亡5，47。我们将证明VTC-890可以有效地阻断 LIGHT和TL 1A的受体结合结构域，从而减少促纤维化蛋白的下游活化， 导致IPF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 最近引入的两种新的抗纤维化药物， 减缓呼吸下降速度的炎症药物。不幸的是， 相对较轻，IPF通常在约3.5年内仍然总是致命的。当前治疗未停止，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。在这方面，委员会注意到， 我们的研究小组发表了第一份报告，即TNF超家族细胞因子LIGHT和 阻断LIGHT与其受体（HVEM/TNFRSF 14和LTβR/TNFRSF 14）结合，强烈减少肺功能 组织重塑和纤维化。我们还表明，注射重组LIGHT蛋白， 进入肺促进了IPF的组织重塑特征13，14。在我们最近发表的研究中，我们 现在已经表明，TL 1A也在这些相同的模型中强烈促进组织重塑，并且注射TL 1A， 重组TL 1A进入小鼠肺驱动病理独立于光，这表明它发挥了重要作用。 补充和协同作用的光在组织重塑15。 该方案旨在生产和验证一种新型双特异性抗体VTC-890，其能够阻断 LIGHT和TL 1A两者的受体结合用于治疗IPF。高级目标是：1） 建立VTC-890生产和分析测定，以支持生产、纯化、生物活性 确定和配制; 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批准所需的剩余临床前数据集。成功 VTC-890的商业化最终将为IPF的治疗提供一种意义深远的一线疗法 以及潜在的其它纤维化疾病，例如系统性硬化症和哮喘。

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.