Tissue Factor Antagonists for ALI/ARDS

DESCRIPTION (provided by applicant): The objective of this project is to develop an anti-tissue factor antibody, Sunol-cH36, as a treatment for Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS). The association between coagulation and inflammation has been well established and a central role in the coagulopathy of ALI/ARDS has been attributed to tissue factor (TF). TF binding to Factor VIIa (FVIIa) activates FX to FXa, forming a transient ternary complex, TF-FVIIa-FXa, which is involved in inflammatory signaling by generating downstream products of activated coagulation and by signal initiation by the TF complex itself. The latter involves signal transduction through the cytoplasmic tail of TF or sequential presentation of FVIIa and FXa to protease activated receptors (PARs) on the cell surface. In vitro, TF-dependent FVIIa and FXa action on PARs have independent, pro-inflammatory effects that include upregulation of cytokine gene expression. These discrete signaling events (signal transduction by the TF intracellular domain and TF activation of PARs) represent unique opportunities for intervention. We hypothesized that blockade of FX binding to established TF-FVIIa complex by Sunol-cH36 would attenuate coagulation-dependent inflammatory responses in ALI and ARDS. In addition, TF blockade by Sunol-cH36 may also attenuate the coagulation-independent intracellular signaling. The safety of Sunol-cH36 has been previously established in numerous preclinical studies and in a phase 1 clinical trial for coronary artery disease. The specific aims of the current proposal will evaluate the pharmacokinetics and toxicity of Sunol-cH36 when multiple doses are administered to cynomolgus monkeys. The results from the current proposal will complete pre-clinical pharmacokinetic and toxicology studies to support a regulatory approval from the FDA to advance the molecule into clinical development using a multiple dose regimen.