A novel anti-CD19 monoclonal antibody (GBR 401) with high killing activity against B cell malignancies.

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Serval ID
serval:BIB_01E6AE78E68F
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
A novel anti-CD19 monoclonal antibody (GBR 401) with high killing activity against B cell malignancies.
Journal
Journal of Hematology and Oncology
Author(s)
Breton C.S., Nahimana A., Aubry D., Macoin J., Moretti P., Bertschinger M., Hou S., Duchosal M.A., Back J.
ISSN
1756-8722 (Electronic)
ISSN-L
1756-8722
Publication state
Published
Issued date
2014
Peer-reviewed
Oui
Volume
7
Pages
33
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: epublish PDF : research
Abstract
BACKGROUND: CD19 is a B cell lineage specific surface receptor whose broad expression, from pro-B cells to early plasma cells, makes it an attractive target for the immunotherapy of B cell malignancies. In this study we present the generation of a novel humanized anti-CD19 monoclonal antibody (mAb), GBR 401, and investigate its therapeutic potential on human B cell malignancies.
METHODS: GBR 401 was partially defucosylated in order to enhance its cytotoxic function. We analyzed the in vitro depleting effects of GBR 401 against B cell lines and primary malignant B cells from patients in the presence or in absence of purified NK cells isolated from healthy donors. In vivo, the antibody dependent cellular cytotoxicity (ADCC) efficacy of GBR 401 was assessed in a B cell depletion model consisting of SCID mice injected with healthy human donor PBMC, and a malignant B cell depletion model where SCID mice are xenografted with both primary human B-CLL tumors and heterologous human NK cells. Furthermore, the anti-tumor activity of GBR 401 was also evaluated in a xenochimeric mouse model of human Burkitt lymphoma using mice xenografted intravenously with Raji cells. Pharmacological inhibition tests were used to characterize the mechanism of the cell death induced by GBR 401.
RESULTS: GBR 401 exerts a potent in vitro and in vivo cytotoxic activity against primary samples from patients representing various B-cell malignancies. GBR 401 elicits a markedly higher level of ADCC on primary malignant B cells when compared to fucosylated similar mAb and to Rituximab, the current anti-CD20 mAb standard immunotherapeutic treatment for B cell malignancies, showing killing at 500 times lower concentrations. Of interest, GBR 401 also exhibits a potent direct killing effect in different malignant B cell lines that involves homotypic aggregation mediated by actin relocalization.
CONCLUSION: These results contribute to consolidate clinical interest in developing GBR 401 for treatment of hematopoietic B cell malignancies, particularly for patients refractory to anti-CD20 mAb therapies.
Pubmed
Web of science
Open Access
Yes
Create date
16/05/2014 16:52
Last modification date
20/08/2019 12:24
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