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

التفاصيل البيبلوغرافية
العنوان: A novel anti-CD19 monoclonal antibody (GBR 401) with high killing activity against B cell malignancies
المؤلفون: Michel A. Duchosal, Pierre Moretti, Samuel Hou, Jonathan Back, Martin Bertschinger, Julie Macoin, Dominique Aubry, Caroline S. Breton, Aimable Nahimana
المصدر: Journal of Hematology & Oncology
Journal of Hematology and Oncology, vol. 7, pp. 33
بيانات النشر: BioMed Central, 2014.
سنة النشر: 2014
مصطلحات موضوعية: Cancer Research, medicine.medical_treatment, Antigens, CD19, Mice, SCID, CD19, Therapeutic antibody, Mice, Antigen, Cell Line, Tumor, medicine, Cytotoxic T cell, Animals, Humans, B cell malignancies, GBR 401, Molecular Biology, B cell, Antibody-dependent cell-mediated cytotoxicity, biology, Research, Antibodies, Monoclonal, Immunotherapy, Hematology, Burkitt Lymphoma, Xenograft Model Antitumor Assays, Raji cell, medicine.anatomical_structure, Oncology, Immunology, biology.protein, Cancer research, Antibody, ADCC, Anti-CD19 monoclonal antibody
الوصف: 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.
وصف الملف: application/pdf
اللغة: English
تدمد: 1756-8722
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4d62ee6b21ed6d1dd3bd43a7fb08c2edTest
http://europepmc.org/articles/PMC4021825Test
حقوق: OPEN
رقم الانضمام: edsair.doi.dedup.....4d62ee6b21ed6d1dd3bd43a7fb08c2ed
قاعدة البيانات: OpenAIRE