RECIPIENT:  Dr. Nelson Ruiz – Opazo
TITLE: Fully humanized anti-DEpR antibody therapy for acute lung injury (ALI)/Acute Respiratory Distress Syndrome (ARDS)
INDICATION: Acute Lung Injury / Acute Respiratory Distress Syndrome
INSTITUTION: Boston University
DESCRIPTION:The feed-forward progression of acute lung injury (ALI) towards acute respiratory distress syndrome (ARDS) and multi-organ failure (MOF) remains a high unmet need with ~200,000 cases per year (US) affecting both young and old. Mortality remains high at 40% despite intensive care supportive interventions.
To date, there is no curative-intent therapy despite research efforts. Regardless of etiology, neutrophils play key pathogenic roles, even in neutropenic patients, however, prior attempts at inhibiting neutrophils have not succeeded. To address these clinical and technological needs, we propose to study our fully humanized S228P hinge-stabilized  IgG4 antibody, that inhibits the dual endothelin1/signal peptide receptor, DEspR, 6g8-humab, as a novel therapy that has the potential to stop the feed-forward progression of ALI-ARDS-MOF driven by self-amplifying, excessive activated-neutrophil injury responses.
This therapeutic-target hypothesis is supported by data that 1-validate the target: increased DEspR expression on activated neutrophils, not present on quiescent neutrophils and normal lung tissue; 2-elucidate the proposed mechanism of action: DEspR inhibition decreases survival of activated neutrophils, and 3-validate pilot in vivo efficacy of the prototype anti-DEspR murine mAb (mumab) in an LPS-induced rat model of ARDS-MOF-early death tracking sepsis-related hemorrhagic encephalopathy.
Here, we propose the following. Aim1. Demonstrate that anti-DEspR 6g8-humab can stop or decrease ALI-ARDS-MOF progression thus increasing survival in a rat model of LPS-induced, sepsis-related ALI/ARDS. Aim2. Demonstrate lung target engagement of 6g8-humab and mechanism-based bioeffects in treated rats compared to isotype mock-treated ALI/ARDS-rats. Data obtained will inform Go/NoGo decision on 6g8-humab as potential novel first-in-class therapy for ALI-ARDS-MOF.