Chimeric Anti-CD20 (IDEC-C2B8) Monoclonal Antibody Sensitizes a B Cell Lymphoma Cell Line to Cell Killing by Cytotoxic Drugs

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Abstract
More than 50% of patients with aggressive Blymphomas and the majority of patients with low grade lymphomas are not cured by current therapeutic strategies. The lymphomas express the B cell antigen CD20 on the cell surface and this antigen serves as target for antibody-directed therapies. Clinical studies with encouraging results have been underway with the use of achimeric anti-CD20 antibody (IDEC-C2B8), consisting of human IgGl-6 constant regions and variable regions from the murine monoclonal anti-CD20 antibody IDEC-2B8. This study investigated the potential anti-tumor the rapeutic value of combination treatment with anti-C2B8 and cytotoxic drugs. The in vitro study examined the sensitizing effect of C2B8 antibody on the DHL-4 B lymphoma line to various cytotoxic agents. Cytotoxicity was determined by the MTT assay. Surface and cytoplasmic proteins were determined by flow cytometry. Pretreatment of DHL-4 with C2B8 resulted in inhibition of cell proliferation and cell death and a fraction of the cells underwent apoptosis. While the DHL-4 tumor cells were relatively resistant to several cytotoxic drugs, pretreatment with C2B8 rendered the cells sensitive to TNF-a, ricin, diphtheria toxin (DTX), adriamycin and cisplatin but not to VP-16. Chemosensitization of DHL-4 tumor cells was not due to downmodulation of either the MDR-1 or bcl-2 gene products. However, treatment of DHL-4 with C2B8 inhibited TNF-α, secretion. These findings demonstrate that C2B8 antibody potentiates the sensitivity of DHL-4 tumor cells to several cytotoxic agents. Further, the findings suggestthat combination treatments with C2B8 antibody and drugs may be of clinical benefit in the treatment of patients