Targeting CD14: A Novel Therapeutic Approach for Acute Respiratory Distress Syndrome

PROJECT SUMMARY/ ABSTRACT: Acute respiratory distress syndrome (ARDS) is associated with a 28-day mortality as high as 30-40%. However, there are no effective pharmacologic interventions specifically targeted at ARDS pathogenesis that improve outcomes. An unrestrained innate immune response in the lungs contributes to the pathogenesis of ARDS. Cluster of differentiation 14 (CD14) is a key activator of innate immunity in response to infection and products of tissue injury. Targeting innate immunity by blocking CD14 could regulate host response to infection and tissue injury, thereby reducing immunopathology and improving clinical outcomes. In recent years, COVID-19 emerged as a prevalent cause of ARDS and the innate immune hyperinflammatory milieu observed in this specific form of ARDS echoes that of the broader ARDS population. CD14-blockade with the novel monoclonal antibody IC14 was studied for the treatment of severe COVID-19 in two small clinical trials. While these studies were not powered to detect differences in clinical outcomes, there was a trend suggesting a potential mortality benefit, and IC14 exhibited on-target pharmacodynamic and biological effects. Additionally, a biologically credible CD14-pathway biomarker, presepsin, a soluble fragment of CD14, was found to be a potential predictor IC14 treatment response. Dr. Mabrey's proposal aims to build upon the encouraging results observed in COVID-19 by examining CD14 as a potential therapeutic target in ARDS through three Specific Aims: (1) Determine the effects of IC14 on cellular targets through analysis of blood leukocyte bulk RNA sequencing data from the I-SPY COVID trial. (2) Determine the relationship between presepsin and key clinical parameters in ARDS. (3) Conduct a Pilot randomized trial of IC14 treatment for ARDS to test lung-specific effects and to determine the feasibility of incorporating rapid presepsin measurements. The Career Development Plan for this grant proposal is designed to provide training in the analysis of high dimensional molecular data, novel clinical biomarker evaluation, and design and conduct of clinical trials integrating translational elements. These new skills will augment her background in epidemiology and facilitate her overall goal of developing into an independent clinical and translational physician-scientist who can use translational research as a platform to conduct biologically-grounded clinical trials in patients with ARDS. Armed with the data generated by this project as well as the training outlined in the Career Development Plan, Dr. Mabrey will have the infrastructure and skills necessary to submit a competitive R01 grant proposal at the end of her proposed K23 funding period. Future projects will build upon results from these proposed studies and could include a Phase II clinical trial testing IC14 treatment in ARDS with a biomarker-based precision medicine component, investigation of novel CD14-pathway biomarkers discovered through this project, and collaboration with other ARDS investigators to examine other emerging pharmacotherapies.