NEW AWARD: Congratulations Dr. Nelson Ruiz-Opazo!!

TITLE: Humanized anti-DEspR antibody therapy for acute respiratory distress syndrome
INSTITUTION: Boston University

DESCRIPTION: Acute respiratory distress syndrome (ARDS) and its progression to multi-organ failure (MOF) affects ~200,000 ICU patients each year in the US, with high mortality and healthcare costs. ARDS is driven by hyperinflammation-injury cycles that begin as a normal injury response but become dysregulated causing secondary-tissue injury in the lung and other vital organs, culminating in MOF and death. An actionable key culprit that drives secondary-tissue injury is the activated neutrophil that continually releases bacterio/cyto-toxic enzymes. To date, there is no pharmacotherapy to stop neutrophil-driven secondary-tissue injury in ARDS-MOF. DEspR (Dual Endothelin-1/signal peptide Receptor) is a receptor for endothelin-1 and VEGF-signal peptide expressed by activated neutrophils as a survival factor that allows them to escape apoptosis and perpetuate vicious cycles of secondary-tissue injury in ARDS. Our B-BIC Pilot project provided proof-of-concept data that ABTM-468, a humanized-IgG4[S228P] anti-DEspR antibody, reduces the survival of an activated-neutrophil subset associated with poor outcomes, and reduced downstream components of a vicious cycle. Thus, ABTM468 may stop hyper-inflammatory vicious cycles in ARDS. In this DRIVE proposal, we aim to advance the testing of ABTM-468 efficacy ex vivo in ARDS patient blood samples to confirm and extend the Pilot efficacy data (Aim 1), identify biomarkers of responders and surrogate markers of early response and toxicity (Aim 2), and test for involvement in lung injury from the epithelial side (Aim 3). These data will provide a solid foundation for the clinical development of ABTM-468 in ARDS.