Year: 2013
Type: article
Abstract: Natalizumab antibody to α 4 -integrins is used in therapy of multiple sclerosis and Crohn's disease. A crystal structure of the Fab bound to an α 4 integrin β-propeller and thigh domain fragment shows that natalizumab recognizes human-mouse differences on the circumference of the β-propeller domain. The epitope is adjacent to but outside of a ligand-binding groove formed at the interface with the β-subunit βI domain and shows no difference in structure when bound to Fab. Competition between Fab and the ligand vascular cell adhesion molecule (VCAM) for binding to cell surface α 4 β 1 shows noncompetitive antagonism. In agreement, VCAM docking models suggest that binding of domain 1 of VCAM to α 4 -integrins is unimpeded by the Fab, and that bound Fab requires a change in orientation between domains 1 and 2 of VCAM for binding to α 4 β 1 . Mapping of species-specific differences onto α 4 β 1 and α 4 β 7 shows that their ligand-binding sites are highly conserved. Skewing away from these conserved regions of the epitopes recognized by current therapeutic function-blocking antibodies has resulted in previously unanticipated mechanisms of action. Background: How does the multiple sclerosis therapeutic antibody natalizumab bind to α4 integrins? Results: Natalizumab binds the α4 β-propeller domain outside the ligand binding groove for domain 1 of vascular cell adhesion molecule (VCAM) and non-competitively antagonizes binding. Conclusion: Natalizumab may push domain 2 of VCAM into a non-preferred orientation upon integrin binding. Significance: Positioning of species-specific substitutions outside of ligand-binding sites leads to surprising antibody mechanisms of action.
Source: Journal of Biological Chemistry
Authors: Yamei Yu, Thomas Schürpf, Timothy A. Springer
Institutions: Boston Children's Hospital, Harvard University
Language: English
Subfield: Immunology and Allergy
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
OpenAlex ID: W2113266091