Efalizumab binding to the LFA-1 alphaL I domain blocks ICAM-1 binding via steric hindrance.
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| Abstract |
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.
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| Authors | Sheng Li, Hao Wang, Baozhen Peng, Meilan Zhang, Daipong Zhang, Sheng Hou, Yajun Guo, Jianping Ding |
| Journal | Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 106 Issue 11 Pg. 4349-54 (Mar 17 2009) ISSN: 1091-6490 [Electronic] United States |
| PMID | 19258452 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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