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 LTßR/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.
Public Health Relevance Statement: Project Narrative Idiopathic Pulmonary Fibrosis (IPF) is a chronic pulmonary disease characterized by vascular injury and progressive fibrosis of the lungs. This project aims to develop a bispecific antibody, VTC-890, for the treatment of IPF. Since present therapies for IPF fail to prevent death or improve quality of life for patients, successful commercialization of VTC-890 would ultimately provide profound relief for an incurable, fatal disease.
Project Terms: Animals; Anti-Inflammatory Agents; Anti-Inflammatories; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; antiinflammatory; Antibodies; Antibody Affinity; antigen antibody affinity; Rheumatoid Arthritis; Atrophic Arthritis; rheumatic arthritis; Asthma; Bronchial Asthma; Automobile Driving; driving; Biological Assay; Assay; Bioassay; Biologic Assays; Blood; Blood Reticuloendothelial System; Cell Line; CellLine; Strains Cell Lines; cultured cell line; Cells; Cell Body; Clinical Research; Clinical Study; Ulcerative Colitis; Ulcerated Colitis; Crohn's disease; Crohn disease; Crohn's; Crohn's disorder; Granulomatous Enteritis; eleocolitis; regional enteritis; Cessation of life; Death; Disease; Disorder; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Environmental Exposure; Family; Fibroblasts; Fibrosis; Goals; Hyperplasia; Hyperplastic; Immunoglobulin G; 7S Gamma Globulin; IgG; Laboratories; Lead; Pb element; heavy metal Pb; heavy metal lead; Libraries; Lung; Lung Respiratory System; pulmonary; Macaca fascicularis; Cynomolgus Monkey; Cynomolgus macaque; M fascicularis; M. fascicularis; Crab-Eating Macaque; Crab-Eating Monkey; Minor; Mus; Mice; Mice Mammals; Murine; Pathology; Patients; Play; Production; Publishing; Lung Tissue Fibrosis; fibrosis in the lung; lung fibrosis; Pulmonary Fibrosis; QOL; Quality of life; Research; Study Type; study design; Research Design; social role; Role; Systemic Sclerosis; progressive systemic sclerosis; Systemic Scleroderma; Testing; Tissues; Body Tissues; Toxicology; cytokine; Measures; Mutagenesis; Genetics-Mutagenesis; Mutagenesis Molecular Biology; Data Set; Dataset; base; improved; Chronic; Clinical; Phase; Medical; Bispecific Antibodies; Bi-specific antibodies; Bifunctional Antibodies; bsAb; Disease Progression; lymphotoxin ß receptor; lymphotoxin-beta-specific receptor; lymphotoxin beta receptor; antibody based therapies; antibody treatment; antibody-based therapeutics; antibody-based treatment; Antibody Therapy; Chemotactic Cytokines; Homologous Chemotactic Cytokines; Intercrines; SIS cytokines; chemoattractant cytokine; chemokine; Blocking Antibodies; Therapeutic; Genetic; Inflammatory; Rivers; Complex; Side; Clinic; cell type; System; respiratory; HVEM protein; HveA protein; TNFRSF14; TR2 protein; tumor necrosis factor receptor subfamily, member 14; herpesvirus entry mediator; meetings; HVEM; high voltage electron microscopy; Receptor Protein; receptor; receptor bound; receptor binding; Animal Models and Related Studies; model of animal; model organism; Animal Model; TNFSF14 gene product; LIGHT protein; novel; Reporting; Position; Positioning Attribute; chronic pulmonary disease; Chronic lung disease; (TNF)-a; Cachectin; Macrophage-Derived TNF; Monocyte-Derived TNF; TNF; TNF A; TNF Alpha; TNF-a; TNFA; TNFa; Tumor Necrosis Factor; Tumor Necrosis Factor-alpha; TNF gene; Lung Parenchyma; Lung Tissue; Structure of parenchyma of lung; Modeling; cell bank; Molecular Interaction; Binding; preventing; prevent; TL1; TNF Ligand-Related Molecule 1; TNF15; TNFSF15; Tumor Necrosis Factor Ligand Superfamily Member 15; VEGI; Vascular Endothelial Growth Inhibitor; TNFSF15 gene; Address; Dose; Symptoms; Affinity; Mammalian Cell; Recombinants; Phage Display; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Characteristics; Process; Development; developmental; Pathway interactions; pathway; pre-clinical; preclinical; pulmonary function decline; lung function decline; immunogenicity; design; designing; commercialization; Formulation; Injections; Tumor-infiltrating immune cells; Immune infiltrates; T cell infiltration; T cell tumor trafficking; immune cell infiltrate; immune infiltration; intratumoral immune cell; tumor immune cell; lead candidate; first-in-human; first in man; idiopathic pulmonary fibrosis; Fibrosing Alveolitis; diffuse interstitial pulmonary fibrosis; pharmacokinetics and pharmacodynamics; PK/PD; vascular injury; injury to the vasculature; Vectorial capacity; Vectoral capacity; Autoimmune; fibrotic lung disease; fibrotic pulmonary disease; fibrotic lung; Fibrotic lesions in lung; Lung scar; Lung tissue scar; Pulmonary Scar; Pulmonary Tissue fibrosis; Scarring at the lung; Scarring in the lung; Profibrotic signal; Profibrotic factor; inhibitor therapy; inhibitor drug; inhibitor therapeutic
