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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Herbst, R; Wang, Y; Gallagher, S; Mittereder, N; Kuta, E; Damschroder, M; Woods, R; Rowe, DC; Cheng, L; Cook, K; Evans, K; Sims, GP; Pfarr, DS; Bowen, MA; Dall'Acqua, W; Shlomchik, M; Tedder, TF; Kiener, P; Jallal, B; Wu, H; Coyle, AJ

Published Date

  • October 2010

Published In

Volume / Issue

  • 335 / 1

Start / End Page

  • 213 - 222

PubMed ID

  • 20605905

Pubmed Central ID

  • 20605905

Electronic International Standard Serial Number (EISSN)

  • 1521-0103

Digital Object Identifier (DOI)

  • 10.1124/jpet.110.168062

Language

  • eng

Conference Location

  • United States