A Novel LIGHT/TL1A Bispecific Antibody for the Treatment of Fibrotic Diseases

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 Systemic Sclerosis (SSc). SSc is a chronic multisystem autoimmune disease characterized by widespread vascular injury and progressive fibrosis of the skin and internal organs 1. Patients with SSc have decreased life expectancy, with pulmonary involvement as the main cause of death. We will demonstrate that VTC-890 can effectively block the receptor binding domains of LIGHT and TL1A thereby reducing downstream activation of pro-inflammatory pathways that lead to fibrosis and tissue remodeling in SSc. Recent advances in understanding disease-causing pathways have yet to provide clinical benefit 2. It is generally accepted that the disease is a complex interplay between endothelial damage (vascular), inflammation, and activation of fibroblasts that leads to skin fibrosis 3. The etiology of the skin fibrosis is thought to be thickened dermis due to uncontrolled excessive deposition of various extracellular matrix components. To treat SSc, systemic corticosteroids and immunosuppressants are usually considered 4. Unfortunately, the efficacy of anti-inflammatory and cytotoxic immunosuppressive therapeutics is short-lived, as the effect of corticosteroids and immunosuppressants are known to decline in the late stages of the sclerosis 5 and are associated with significant adverse effects. Characteristic features of SSc are tissue remodeling, inflammation and fibrosis 1. In this regard, our team published the first research demonstrating that a genetic deficiency in the TNF superfamily cytokine LIGHT and blocking LIGHT binding to its receptors (HVEM/TNFRSF14 and LTβR/TNFRSF14) strongly reduced tissue remodeling and fibrosis in models of SSc and severe asthma. We also showed that injection of recombinant LIGHT protein into the lungs promoted tissue remodeling, which is characteristic of these diseases 6, 7. We have also shown that TL1A also strongly contributes to inflammation in the same models of SSc and asthma, 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 remodeling. This proposal is designed to produce and validate a novel bispecific antibody, VTC-890, against LIGHT and TL1A for the treatment of SSc. The specific aims are to: 1) Select LIGHT and TL1A binding Fabs from our in- house phage display library; 2) Produce the top twenty antibody candidates and characterize their activity in vitro; and 3) Create bispecific LIGHT/TL1A antibodies using the top four LIGHT and TL1A antibodies. Through this SBIR, we will select a lead bispecific antibody candidate, VTC-890, which has the potential to serve as a front-line therapy for the treatment of SSc as well as other fibrotic diseases.Project Narrative Systemic sclerosis (SSc) is a chronic multisystem autoimmune disease characterized by widespread vascular injury and progressive fibrosis of the skin and internal organs. This project aims to develop a bispecific antibody, VTC-890, for the treatment of SSc. Since therapies for SSc are lacking in both efficacy as well as safety, successful commercialization of VTC-890 would ultimately provide profound relief to patients seeking effective treatments for SSc.