RT Journal Article
SR Electronic
T1 B-Cell Depletion In Vitro and In Vivo with an Afucosylated Anti-CD19 Antibody
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 213
OP 222
DO 10.1124/jpet.110.168062
VO 335
IS 1
A1 Ronald Herbst
A1 Yue Wang
A1 Sandra Gallagher
A1 Nanette Mittereder
A1 Ellen Kuta
A1 Melissa Damschroder
A1 Rob Woods
A1 Daniel C. Rowe
A1 Li Cheng
A1 Kim Cook
A1 Krista Evans
A1 Gary P. Sims
A1 David S. Pfarr
A1 Michael A. Bowen
A1 William Dall'Acqua
A1 Mark Shlomchik
A1 Thomas F. Tedder
A1 Peter Kiener
A1 Bahija Jallal
A1 Herren Wu
A1 Anthony J. Coyle
YR 2010
UL http://jpet.aspetjournals.org/content/335/1/213.abstract
AB 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.