title: Prevention of acute graft-versus-host disease in a xenogeneic SCID mouse model by the humanized anti-CD74 antagonistic antibody milatuzumab.
abstract: Prevention and treatment of graft-versus-host disease (GVHD) remains a major challenge, given that current T-cell depletion and mainstay immunosuppressive therapies compromise preexisting T-cell immunity, often leading to severe infections and disease relapse. Thus, there is a critical need for novel anti-GVHD agents that can spare protective T-cell memory. Here we show that milatuzumab (hLL1), a humanized anti-CD74 antagonist monoclonal antibody, can moderately reduce the numbers of CD74-expressing B cells and myeloid dendritic cells, but has no effect on the survival of T cells that are CD74(-). Consequently, milatuzumab inhibits allogeneic T-cell proliferation in mixed leukocyte reactions. In a human/mouse xenogeneic SCID mouse model in which GVHD is induced and mediated by engrafted human CD4(+) T cells and dendritic cells, milatuzumab effectively prevents the onset and manifestations of acute GVHD, suppresses serum levels of human IFN-γ and IL-5, eliminates the infiltration of human lymphocytes into GVHD target organs (ie, lung, liver, and spleen), and significantly promotes survival (90% versus 20% for controls; P = .0012). Importantly, exposure to milatuzumab does not affect the number of cytomegalovirus-specific, IFN-γ-producing human CD8(+) T cells in allogeneic mixed leukocyte reactions. These encouraging results warrant further exploration of milatuzumab as a possible new therapeutic agent for GVHD.
authors.affiliation: Center for Molecular Medicine and Immunology, Garden State Cancer Center, Morris Plains, New Jersey 07950, USA. mchen@gscancer.org
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Chen
authors.forename: Chien-Hsing
authors.initials: CH
authors.lastname: Chang
authors.forename: Rhona
authors.initials: R
authors.lastname: Stein
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Cardillo
authors.forename: David V
authors.initials: DV
authors.lastname: Gold
authors.forename: David M
authors.initials: DM
authors.lastname: Goldenberg
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000944:Antigens, Differentiation, B-Lymphocyte; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D004195:Disease Models, Animal; D005260:Female; D006086:Graft vs Host Disease / Q000097:blood / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D000949:Histocompatibility Antigens Class II; D006801:Humans; D007371:Interferon-gamma / Q000097:blood / Q000276:immunology; D015848:Interleukin-5 / Q000097:blood / Q000276:immunology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D014183:Transplantation, Heterologous
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; C573415:IFNG protein, human; C508599:IL5 protein, human; D015848:Interleukin-5; C045084:invariant chain; C540932:milatuzumab; D007371:Interferon-gamma