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Comparative assessment of clinically utilized CD20-directed antibodies in chronic lymphocytic leukemia cells reveals divergent NK cell, monocyte, and macrophage properties.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2013 Mar 15; Vol. 190 (6), pp. 2702-11. Date of Electronic Publication: 2013 Feb 15. - Publication Year :
- 2013
-
Abstract
- CD20 is a widely validated, B cell-specific target for therapy in B cell malignancies. Rituximab is an anti-CD20 Ab that prolongs survival of chronic lymphocytic leukemia (CLL) patients when combined with chemotherapy. Ofatumumab and GA101 (obinutuzumab) are CD20-directed Abs currently being developed as alternative agents to rituximab in CLL based upon different properties of enhanced direct cell death, NK cell-mediated Ab-dependent cellular cytotoxicity, or complement-dependent cytotoxicity. Despite widespread study, ofatumumab and GA101 have not been compared with each other, nor studied for their interactions with monocytes and macrophages which are critical for the efficacy of anti-CD20 Abs in murine models. In CLL cells, we show that direct cell death and complement-dependent cytotoxicity are greatest with GA101 and ofatumumab, respectively. GA101 promotes enhanced NK cell activation and Ab-dependent cellular cytotoxicity at high Ab concentrations. Ofatumumab elicits superior Ab-dependent cellular phagocytosis with monocyte-derived macrophages. GA101 demonstrated reduced activation of monocytes with diminished pERK, TNF-α release, and FcγRIIa recruitment to lipid rafts. These data demonstrate that GA101 and ofatumumab are both superior to rituximab against CLL cells via different mechanisms of potential tumor elimination. These findings bear relevance to potential combination strategies with each of these anti-CD20 Abs in the treatment of CLL.
- Subjects :
- Antibodies, Neoplasm therapeutic use
Antigens, CD20 metabolism
Cell Line, Tumor
Cytotoxicity Tests, Immunologic
Humans
Killer Cells, Natural metabolism
Killer Cells, Natural pathology
Leukemia, Lymphocytic, Chronic, B-Cell pathology
Macrophages metabolism
Macrophages pathology
Monocytes metabolism
Monocytes pathology
Tumor Cells, Cultured
Antibodies, Neoplasm toxicity
Antigens, CD20 immunology
Drug Delivery Systems methods
Killer Cells, Natural immunology
Leukemia, Lymphocytic, Chronic, B-Cell immunology
Leukemia, Lymphocytic, Chronic, B-Cell therapy
Macrophages immunology
Monocytes immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 190
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 23418626
- Full Text :
- https://doi.org/10.4049/jimmunol.1202588