A Ligand-Specific Blockade of the Integrin Mac-1 Selectively Targets Pathologic Inflammation While Maintaining Protective Host-Defense

Nat Commun. 2018 Feb 6;9(1):525. doi: 10.1038/s41467-018-02896-8.

Abstract

Integrin-based therapeutics have garnered considerable interest in the medical treatment of inflammation. Integrins mediate the fast recruitment of monocytes and neutrophils to the site of inflammation, but are also required for host defense, limiting their therapeutic use. Here, we report a novel monoclonal antibody, anti-M7, that specifically blocks the interaction of the integrin Mac-1 with its pro-inflammatory ligand CD40L, while not interfering with alternative ligands. Anti-M7 selectively reduces leukocyte recruitment in vitro and in vivo. In contrast, conventional anti-Mac-1 therapy is not specific and blocks a broad repertoire of integrin functionality, inhibits phagocytosis, promotes apoptosis, and fuels a cytokine storm in vivo. Whereas conventional anti-integrin therapy potentiates bacterial sepsis, bacteremia, and mortality, a ligand-specific intervention with anti-M7 is protective. These findings deepen our understanding of ligand-specific integrin functions and open a path for a new field of ligand-targeted anti-integrin therapy to prevent inflammatory conditions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Binding Sites
  • CD40 Ligand / metabolism
  • Host-Pathogen Interactions / drug effects
  • Humans
  • Inflammation / drug therapy*
  • Inflammation / pathology
  • Leukocytes / drug effects
  • Leukocytes / pathology
  • Macrophage-1 Antigen / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Molecular Targeted Therapy / methods*
  • Neutrophils / drug effects
  • Sepsis / drug therapy

Substances

  • Antibodies, Monoclonal
  • Macrophage-1 Antigen
  • CD40 Ligand