title: B-cell depletion in vitro and in vivo with an afucosylated anti-CD19 antibody.
abstract: The pan B-cell surface antigen CD19 is an attractive target for therapeutic monoclonal antibody (mAb) approaches. We have generated a new afucosylated anti-human (hu)CD19 mAb, MEDI-551, with increased affinity to human FcγRIIIA and mouse FcγRIV and enhanced antibody-dependent cellular cytotoxicity (ADCC). During in vitro ADCC assays with B-cell lines, MEDI-551 is effective at much lower mAb concentrations than the fucosylated parental mAb anti-CD19-2. Furthermore, the afucosylated CD19 mAb MEDI-551 depleted B cells from normal donor peripheral blood mononuclear cell samples in an autologous ADCC assay, as well as blood and tissue B cells in human CD19/CD20 double transgenic (Tg) mice at lower concentrations than that of the positive control mAb rituximab. In huCD19/CD20 Tg mice, both macrophage-mediated phagocytosis and complement-dependent cytotoxicity contribute to depletion with rituximab; MEDI-551 did not require complement for maximal B-cell depletion. Furthermore, extended B-cell depletion from the blood and spleen was achieved with MEDI-551, which is probably explained by bone marrow B-cell depletion in huCD19/CD20 Tg mice relative to the control mAb rituximab. In summary, MEDI-551 has potent B-cell-depleting activity in vitro and in vivo and may be a promising new approach for the treatment of B-cell malignancies and autoimmune diseases.
authors.affiliation: Department of Research, Respiratory, Inflammation, and Autoimmunity, MedImmune, LCC, Gaithersburg, MD 20787, USA. herbstr@medimmune.com
authors.forename: Ronald
authors.initials: R
authors.lastname: Herbst
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: Sandra
authors.initials: S
authors.lastname: Gallagher
authors.forename: Nanette
authors.initials: N
authors.lastname: Mittereder
authors.forename: Ellen
authors.initials: E
authors.lastname: Kuta
authors.forename: Melissa
authors.initials: M
authors.lastname: Damschroder
authors.forename: Rob
authors.initials: R
authors.lastname: Woods
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Rowe
authors.forename: Li
authors.initials: L
authors.lastname: Cheng
authors.forename: Kim
authors.initials: K
authors.lastname: Cook
authors.forename: Krista
authors.initials: K
authors.lastname: Evans
authors.forename: Gary P
authors.initials: GP
authors.lastname: Sims
authors.forename: David S
authors.initials: DS
authors.lastname: Pfarr
authors.forename: Michael A
authors.initials: MA
authors.lastname: Bowen
authors.forename: William
authors.initials: W
authors.lastname: Dall'Acqua
authors.forename: William
authors.initials: W
authors.lastname: Dall'Aqua
authors.forename: Mark
authors.initials: M
authors.lastname: Shlomchik
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Tedder
authors.forename: Peter
authors.initials: P
authors.lastname: Kiener
authors.forename: Bahija
authors.initials: B
authors.lastname: Jallal
authors.forename: Herren
authors.initials: H
authors.lastname: Wu
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Coyle
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D058846:Antibodies, Monoclonal, Murine-Derived; D000920:Antibody-Dependent Cell Cytotoxicity; D018941:Antigens, CD19 / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D005643:Fucose / Q000737:chemistry; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D015202:Protein Engineering; D000069283:Rituximab
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018941:Antigens, CD19; D007074:Immunoglobulin G; D005643:Fucose; D000069283:Rituximab