Efalizumab binding to the LFA-1 alphaL I domain blocks ICAM-1 binding via steric hindrance

Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4349-54. doi: 10.1073/pnas.0810844106. Epub 2009 Mar 3.


Lymphocyte function-associated antigen 1 (LFA-1) plays important roles in immune cell adhesion, trafficking, and activation and is a therapeutic target for the treatment of multiple autoimmune diseases. Efalizumab is one of the most efficacious antibody drugs for treating psoriasis, a very common skin disease, through inhibition of the binding of LFA-1 to the ligand intercellular adhesion molecule 1 (ICAM-1). We report here the crystal structures of the Efalizumab Fab alone and in complex with the LFA-1 alpha(L) I domain, which reveal the molecular mechanism of inhibition of LFA-1 by Efalizumab. The Fab binds with an epitope on the inserted (I) domain that is distinct from the ligand-binding site. Efalizumab binding blocks the binding of LFA-1 to ICAM-1 via steric hindrance between its light chain and ICAM-1 domain 2 and thus inhibits the activities of LFA-1. These results have important implications for the development of improved antibodies and new therapeutic strategies for the treatment of autoimmune diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal, Humanized
  • Autoimmune Diseases / drug therapy
  • Binding Sites
  • Cell Migration Inhibition / drug effects*
  • Epitopes
  • Humans
  • Intercellular Adhesion Molecule-1 / metabolism*
  • Lymphocyte Function-Associated Antigen-1 / metabolism*
  • Protein Binding / drug effects


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Epitopes
  • Lymphocyte Function-Associated Antigen-1
  • Intercellular Adhesion Molecule-1
  • efalizumab

Associated data

  • PDB/3EO9
  • PDB/3EOA
  • PDB/3EOB