PROJECT ABSTRACT The overarching goal of this Phase I STTR application is to evaluate the in vivo efficacy of a novel approach to hepatic fibrosis treatment and to explore its clinical translatability. Hepatic fibrosis is a progressive liver disease caused by multiple etiologies and can be seen in most patients with chronic liver injury. While initially reversible, hepatic fibrosis is often left untreated due to its asymptomatic nature and thus can progress into an irreversible late stage resulting in liver cirrhosis, portal hypertension, liver failure, and eventually, death. Unfortunately, there are currently no FDA-approved drugs available to treat liver fibrosis. VSR-H5 is a novel therapeutic that specifically targets a unique epitope within the extracellular matrix (ECM) only in areas of undergoing active ECM remodeling and fibrogenesis, disrupting pro-fibrotic myofibroblast activation. This novel approach specifically avoids systemic disruption of critical, normal integrin receptor engagement, thus represents an approach that can achieve both high potency and strong safety. In this proposal we will explore two aims: 1) establish the in vivo efficacy of VSR- H5 in treating liver fibrosis using a well-established Carbon tetrachloride (CCl4)-induced mouse liver fibrosis model; and 2) determine the clinical translatability of VSR-H5 by confirming the presence of the target epitope in human cirrhotic liver tissue and evaluating the antibody's ability to reverse fibrotic cellular phenotypes in primary human liver stellate cells our established and validated human in vitro fibrosis model. Successful completion of this Phase I STTR will provide the data necessary to justify further investment in this strategy toward treating liver fibrosis.