B-cell depletion in vitro and in vivo with an afucosylated anti-CD19 antibody.
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.
Herbst
Ronald
R
Department of Research, Respiratory, Inflammation, and Autoimmunity, MedImmune, LCC, Gaithersburg, MD 20787, USA. herbstr@medimmune.com
Wang
Yue
Y
Gallagher
Sandra
S
Mittereder
Nanette
N
Kuta
Ellen
E
Damschroder
Melissa
M
Woods
Rob
R
Rowe
Daniel C
DC
Cheng
Li
L
Cook
Kim
K
Evans
Krista
K
Sims
Gary P
GP
Pfarr
David S
DS
Bowen
Michael A
MA
Dall'Acqua
William
W
Dall'Aqua
William
W
Shlomchik
Mark
M
Tedder
Thomas F
TF
Kiener
Peter
P
Jallal
Bahija
B
Wu
Herren
H
Coyle
Anthony J
AJ
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
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018941:Antigens, CD19; D007074:Immunoglobulin G; D005643:Fucose; D000069283:Rituximab