Award Details:
Award Type: Accelerator
Award #: A-010
Proposal Title: Pre-Clinical Development of a Biased Antagonist of CCR3 for Allergic Diseases
PI(s): Steven Ackerman and Vadim Gaponenko (UIC)
Award Amount: $100,000.00
Application Cycle: Round 3 (Spring 2019)
Award Start Date: December 1, 2019
Award End Date: November 30, 2020
Abstract:
FDA-approved IL-5/IL-5R biologics incompletely block eosinophils in eosinophilic asthma. This is because signaling pathways unrelated to IL-5 can activate eosinophils. In eosinophilic asthma, CCR3, via eotaxin ligands, recruits eosinophils into the lungs and airways leading to pulmonary pathologies. Small molecule CCR3 antagonists failed in clinical trials, the mode of CCR3 inhibition being the likely reason; these unbiased antagonists inhibit both chemotaxis and receptor endocytosis, leading to surface accumulation and drug tolerance. Our novel biased CCR3 antagonist, R321, selectively inhibits eosinophil chemotaxis with nanomolar potency without blocking CCR3 internalization/degradation. R321 peptide auto-assembles into nanoparticles, protecting it from degradation. Intravenous R321 blocks eosinophil recruitment into the blood, lungs and airways in therapeutic and prophylactic acute mouse asthma models, completely blocking airway hyperreactivity. We propose determining whether R321 is therapeutically effective in chronic allergic and severe transgenic mouse models of eosinophilic asthma, and in allergen- and transgene-driven mouse models of Eosinophilic Esophagitis (EoE).