Abstract 14524: Small Molecule Agonists of Integrin Cd11b/cd18 Are Significantly Better than Activating Antibodies in Reducing Vascular Injury
Integrin CD11b/CD18 is an adhesion receptor that is primarily expressed on leukocytes and mediates their adhesion, migration and biological functions. Leukocyte adhesion and migration is key to their immune function. We recently described the identification of a novel group of compounds, termed leukadherins, that bind to and allosterically enhance CD11b/CD18-dependent adhesion of leukocytes. Leukadherin treatment reduces cell migration and recruitment, thereby decreasing inflammatory injury in vivo, suggesting integrin activation to be a novel mechanism of action for the development of anti-inflammatory therapeutics. Since a number of well-characterized anti-CD11b/CD18 activating antibodies are currently available, we wondered if such biological agonists of integrins would be equally effective and reasonable to use in vivo to treat inflammation via this mechanism of action. Here, we describe the results of our investigations in head-to-head testing of the two types of agonists (the chemical leukadherins and the biological anti-CD11b/CD18 activating antibodies) in various in vitro and in vivo assays. We found that CD11b/CD18 activation via both types of agonists similarly enhanced integrin-mediated cell adhesion and similarly decreased cell migration and wound healing in vitro using human, murine and rat cells. However, we also found that while CD11b/CD18 activation with leukadherins did not induce integrin macro-clustering and outside-in signaling in treated cells, the activating antibodies produced significant CD11b/CD18 clustering and increased phosphorylation of key intracellular signaling proteins. This suggests that unlike leukadherins, CD11b/CD18 activating antibodies mimic a ligand-bound state and thus, may have additional unintended consequences on cellular functions. Finally, in a head-to-head comparison in a vascular injury model in vivo, we found that while leukadherins dose-dependently reduced vascular injury, the anti-CD11b activating antibody ED7 was ineffective. Our results suggest that small molecule allosteric agonists of CD11b/CD18 have a clear therapeutic advantage over the biologic activating antibody-based agonists.
- © 2012 by American Heart Association, Inc.