Native structure of the therapeutic IgG4 α4β5 integrin antibody natalizumab.

The native structure of natalizumab, an IgG4/κ α4β5 integrin monoclonal therapeutic antibody used for treatment of multiple sclerosis, was determined by a combination of chemical cross-linking, mass spectrometry, biophysical, and immunochemical methods. This revealed a compact, closed, m-shaped ellipsoidal structure with the paratopes at each end. Physicochemical stress, in the form of elevated temperature and lowered pH, induced an open, Y-shaped conformation of the antibody. This conformational change may reflect what is happening by binding of antibodies to their cognate antigens, e.g., in the form of pathogen-associated molecular patterns on the surface of microorganisms, where the antibodies have an intrinsic ability to change conformation and expose their effector function sites. Thus, in the absence of their cognate antigen, antibodies circulate as closed, m-shaped, inactive molecules.