Abstract 11971: Identification of Response Biomarkers and Signaling Pathways Associated With the LOX-1 Blockade by MEDI6570 in Type 2 Diabetes

Introduction : Elevated circulating soluble lectin-like oxidized low-density lipoprotein receptor 1 (sLOX-1) levels are associated with risk of MACE and heart failure following acute coronary syndrome (ACS), implying that LOX-1 signaling is a culprit in cardiovascular risk. MEDI6570 is a human monoclonal antibody in clinical trials that binds to LOX-1, antagonizing the interaction with ligands including oxLDL. Methods: To determine LOX-1 risk-related biomarkers and associated pathways in response to MEDI6570, we performed Sparse Partial-Least-Squares Discriminant Analysis on transcriptomics (PBMC) and serum proteomics (OLINK) in strong versus weak responders to MEDI6570 treatment, defined by a decrease in sLOX-1, in patients with type 2 diabetes (T2D) in a single ascending dose, placebo-controlled study (NCT03654313). Biomarkers that showed concordance at three or more timepoints during treatment were further tested in an independent high-risk (T2D and/or CVD) cohort (SUMMIT; n=1231), for correlation with sLOX-1. Results: We identified biomarkers of inflammation that predominated among others, including oxidative stress, apoptosis, cellular adhesion, and migration. Of these, IL-16 and IL-18 showed significant correlation to sLOX-1 (IL-16 r=0.43, p<0.001; IL-18 r=0.44, p<0.001) in the independent SUMMIT cohort. Additionally, in a subset of the SUMMIT cohort, significant correlations were observed between baseline and 20-year follow-up levels for sLOX-1 (r=0.271, p=0.012), IL-16 (r=0.243, p=0.025), and IL-18 (r=0.459, p<0.0001), demonstrating persistent long-term elevation of these inflammatory markers in patients. We also identified neutrophil-related markers (CEACAM8, PRTN3, PGLYRP1, CPB1, GRN, LTBR) in response to MEDI6570, which have not been previously associated with LOX-1. Conclusions: Findings indicate that IL-16 and IL-18 may be potential links between LOX-1 signaling and cardiovascular risk, being modified by treatment with MEDI6570. This study also identified neutrophil-related markers in response to MEDI6570 treatment, implicating a potential role for neutrophils in LOX-1-mediated effects. A phase 2 study in patients with recent ACS and treatment with MEDI6570 or placebo is ongoing (NCT04610892).