title: Small molecule agonists of integrin CD11b/CD18 do not induce global conformational changes and are significantly better than activating antibodies in reducing vascular injury.
abstract: BACKGROUND
  CD11b/CD18 is a key adhesion receptor that mediates leukocyte adhesion, migration and immune functions. We recently identified novel compounds, leukadherins, that allosterically enhance CD11b/CD18-dependent cell adhesion and reduce inflammation 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 could also become therapeutic leads following this mechanism of action.
  
  
  METHODS
  We compared the two types of agonists using in vitro cell adhesion and wound-healing assays and using animal model systems. We also studied effects of the two types of agonists on outside-in signaling in treated cells.
  
  
  RESULTS
  Both types of agonists similarly enhanced integrin-mediated cell adhesion and decreased cell migration. However, unlike leukadherins, the activating antibodies produced significant CD11b/CD18 macro clustering and induced phosphorylation of key proteins involved in outside-in signaling. Studies using conformation reporter antibodies showed that leukadherins did not induce global conformational changes in CD11b/CD18 explaining the reason behind their lack of ligand-mimetic outside-in signaling. In vivo, leukadherins reduced vascular injury in a dose-dependent fashion, but, surprisingly, the anti-CD11b activating antibody ED7 was ineffective.
  
  
  CONCLUSIONS
  Our results suggest that small molecule allosteric agonists of CD11b/CD18 have clear advantages over the biologic activating antibodies and provide a mechanistic basis for the difference.
  
  
  CONCLUSIONS
  CD11b/CD18 activation represents a novel strategy for reducing inflammatory injury. Our study establishes small molecule leukadherins as preferred agonists over activating antibodies for future development as novel anti-inflammatory therapeutics.
authors: Department of Medicine, University of Miami, Miami, FL 33136, USA.
authors: Mohd Hafeez
authors: MH
authors: Faridi
authors: Mehmet M
authors: MM
authors: Altintas
authors: Camilo
authors: C
authors: Gomez
authors: Juan Camilo
authors: JC
authors: Duque
authors: Roberto I
authors: RI
authors: Vazquez-Padron
authors: Vineet
authors: V
authors: Gupta
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000235:genetics; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology*; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism*; D018821:CD18 Antigens / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D006801:Humans; D007083:Iliac Artery / Q000293:injuries* / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020014:K562 Cells; D051379:Mice; D020836:Protein Structure, Quaternary; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D058846:Antibodies, Monoclonal, Murine-Derived; D039481:CD11b Antigen; D018821:CD18 Antigens; C509295:ITGAM protein, human