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.