title: Molecular evidence of transient therapeutic effectiveness of natalizumab despite high-titre neutralizing antibodies.
abstract: Natalizumab is a humanized monoclonal antibody directed against the alpha-4 integrin subunit of very late activation antigen-4 (VLA-4). Natalizumab neutralizing antibodies (NAB) have been found to significantly reduce beneficial effects of natalizumab treatment in multiple sclerosis. We investigated interactions of NAB with natalizumab by serial measurements of alpha-4 integrin levels on peripheral blood mononuclear cells using flow cytometry. In addition, serum concentrations of soluble vascular cell adhesion molecule-1 (sVCAM-1), the endothelial ligand of VLA-4, and serum NAB were serially determined. Natalizumab infusion led to a transient reduction in alpha-4 integrin levels on immune cells and serum sVCAM-1 levels along with serum negativity of NAB lasting for a few days post-infusion. Apparently, the high-dose effect of freshly infused natalizumab resulted in a transient neutralization of NAB possibly involving a transient therapeutic effectiveness.
authors.affiliation: Paracelsus Medical University, Salzburger Landeskliniken, Christian-Doppler-Klinik, Department of Neurology, Salzburg, Austria. georg.pilz@salk.at
authors.forename: G
authors.initials: G
authors.lastname: Pilz
authors.forename: A
authors.initials: A
authors.lastname: Harrer
authors.forename: K
authors.initials: K
authors.lastname: Oppermann
authors.forename: P
authors.initials: P
authors.lastname: Wipfler
authors.forename: S
authors.initials: S
authors.lastname: Golaszewski
authors.forename: S
authors.initials: S
authors.lastname: Afazel
authors.forename: E
authors.initials: E
authors.lastname: Haschke-Becher
authors.forename: E
authors.initials: E
authors.lastname: Trinka
authors.forename: J
authors.initials: J
authors.lastname: Kraus
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000627:therapeutic use*; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000627:therapeutic use*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D039041:Integrin alpha4beta1 / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000276:immunology*; D000069442:Natalizumab; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D039041:Integrin alpha4beta1; D000069442:Natalizumab; D019010:Vascular Cell Adhesion Molecule-1