Project Abstract The goal of this Fast-Track SBIR application is to develop a novel drug candidate to treat Idiopathic pulmonary fibrosis (IPF). IPF is a fatal disease that remains uncurable and carries a median survival of 2-3 years post diagnosis. The two current FDA-approved drugs Nintedanib and Pirfenidone marginally extend quality-adjusted life years while presenting severe life-altering side effects, resulting in extremely poor compliance. Current pipeline therapeutics are focused on more effective targets to improve functional outcomes but many, if not all, present significant safety concerns by targeting critical, systemically active receptors and intracellular signaling proteins. Our tool compound, VSR-H5, has demonstrated an ability to 1) specifically target only regions of ongoing fibrosis within diagnosed IPF patient lung tissues while not binding healthy tissues/regions; 2) selectively inhibit activation of patient-derived fibroblasts’ on pro-fibrotic mimetic extracellular matrix (ECM) in vitro; and 3) mitigate fibrosis progression in multiple in vivo mouse models of lung fibrosis and a clean tox profile. Our approach specifically avoids systemic disruption of critical, normal receptor engagement by targeting a unique, cryptic epitope that is only exposed in tissues undergoing active fibrosis. In this proposal we will first (Phase I) perform affinity maturation and liability assessment and removal to create a pool of candidate antibody drugs. Then in Phase II we will perform successive selection assays to establish our primary drug candidate from the pool generated in Phase I and then further establish its translatability through a series of PK/PD, toxicity/safety, and efficacy analyses in established animal models, while exploring potential formulations for future process development and manufacturing. At the successful conclusion of this project, we will be poised to design and initiate IND-enabling studies.