2. Academic Validation
  3. B-cell depletion in vitro and in vivo with an afucosylated anti-CD19 antibody

B-cell depletion in vitro and in vivo with an afucosylated anti-CD19 antibody

  • J Pharmacol Exp Ther. 2010 Oct;335(1):213-22. doi: 10.1124/jpet.110.168062.
Ronald Herbst 1,  Yue Wang,  Sandra Gallagher,  Nanette Mittereder,  Ellen Kuta,  Melissa Damschroder,  Rob Woods,  Daniel C Rowe,  Li Cheng,  Kim Cook,  Krista Evans,  Gary P Sims,  David S Pfarr,  Michael A Bowen,  William Dall'Acqua,  Mark Shlomchik,  Thomas F Tedder,  Peter Kiener,  Bahija Jallal,  Herren Wu,  Anthony J Coyle
Affiliations

Affiliation

  • 1 Department of Research, Respiratory, Inflammation, and Autoimmunity, MedImmune, LCC, Gaithersburg, MD 20787, USA. herbstr@medimmune.com
PMID: 20605905 DOI: 10.1124/jpet.110.168062
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.

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