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.
Footnotes
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.168062.
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ABBREVIATIONS:
- DLBCL
- diffuse large B-cell lymphoma
- mAb
- monoclonal antibody
- ADCC
- antibody-dependent cellular cytotoxicity
- Tg
- transgenic
- CDC
- complement-dependent cytotoxicity
- NK
- natural killer
- PBMC
- peripheral blood mononuclear cell
- PBS
- phosphate-buffered saline
- LDH
- lactate dehydrogenase
- FACS
- fluorescence-activated cell sorting
- CoVF
- cobra venom factor
- BM
- bone marrow.
- Received March 16, 2010.
- Accepted July 2, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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