title: The anti-CD74 humanized monoclonal antibody, milatuzumab, which targets the invariant chain of MHC II complexes, alters B-cell proliferation, migration, and adhesion molecule expression.
abstract: BACKGROUND
  Targeting CD74 as the invariant chain of major histocompatibility complexes (MHC) became possible by the availability of a specific humanized monoclonal antibody, milatuzumab, which is under investigation in patients with hematological neoplasms. CD74 has been reported to regulate chemo-attractant migration of macrophages and dendritic cells, while the role of CD74 on peripheral naïve and memory B cells also expressing CD74 remains unknown. Therefore, the current study addressed the influence of milatuzumab on B-cell proliferation, chemo-attractant migration, and adhesion molecule expression.
  
  
  METHODS
  Surface expression of CD74 on CD27- naïve and CD27+ memory B cells as well as other peripheral blood mononuclear cells (PBMCs) obtained from normals, including the co-expression of CD44, CXCR4, and the adhesion molecules CD62L, β7-integrin, β1-integrin and CD9 were studied after binding of milatuzumab using multicolor flow cytometry. The influence of the antibody on B-cell proliferation and migration was analyzed in vitro in detail.
  
  
  RESULTS
  In addition to monocytes, milatuzumab also specifically bound to human peripheral B cells, with a higher intensity on CD27+ memory versus CD27- naïve B cells. The antibody reduced B-cell proliferation significantly but moderately, induced enhanced spontaneous and CXCL12-dependent migration together with changes in the expression of adhesion molecules, CD44, β7-integrin and CD62L, mainly of CD27- naïve B cells. This was independent of macrophage migration-inhibitory factor as a ligand of CD74/CD44 complexes.
  
  
  CONCLUSIONS
  Milatuzumab leads to modestly reduced proliferation, alterations in migration, and adhesion molecule expression preferentially of CD27- naïve B cells. It thus may be a candidate antibody for the autoimmune disease therapy by modifying B cell functions.
authors.affiliation: Department of Medicine, Rheumatology and Clinical Immunology, Charité - University Medicine Berlin, Chariteplatz 1, Berlin 10117, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Frölich
authors.forename: Daniela
authors.initials: D
authors.lastname: Blassfeld
authors.forename: Karin
authors.initials: K
authors.lastname: Reiter
authors.forename: Claudia
authors.initials: C
authors.lastname: Giesecke
authors.forename: Capucine
authors.initials: C
authors.lastname: Daridon
authors.forename: Henrik E
authors.initials: HE
authors.lastname: Mei
authors.forename: Gerd R
authors.initials: GR
authors.lastname: Burmester
authors.forename: David M
authors.initials: DM
authors.lastname: Goldenberg
authors.forename: Abdulagabar
authors.initials: A
authors.lastname: Salama
authors.forename: Thomas
authors.initials: T
authors.lastname: Dörner
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000378:metabolism / Q000502:physiology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism*; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D059805:HLA-DR alpha-Chains / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000944:Antigens, Differentiation, B-Lymphocyte; D015815:Cell Adhesion Molecules; D059805:HLA-DR alpha-Chains; D000949:Histocompatibility Antigens Class II; C045084:invariant chain; C540932:milatuzumab