Bonavida B.,University of California at Los Angeles |
Huerta-Yepez S.,University of California at Los Angeles |
Huerta-Yepez S.,Hospital Infantil Of Mexico |
Jazirehi A.R.,University of California at Los Angeles |
And 6 more authors.
Forum on Immunopathological Diseases and Therapeutics | Year: 2010
A large number of hematologic malignancies of B-cell origin express the CD20 receptor on the cell surface. CD20 is expressed in the B-cell lineage and is absent in plasma cells. Antibodies directed against CD20 result in the elimination of normal and malignant B cells and, hence, led to the development of a therapeutic antibody, rituximab, that has been approved by the U.S. Food and Drug Administration for the treatment of B-non-Hodgkin's lymphoma (NHL). Antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), in part, cause depletion of B cells by rituximab in vivo. In addition, we have found that rituximab and several novel anti-CD20 monoclonal antibodies signal the cells and inhibit several intracellular pathways. For instance, we have demonstrated that treatment of B-NHL cell lines with anti-CD20 monoclonal antibody (mAb) resulted in the inhibition of constitutively activated transcription factors NF-κB and Yin Yang 1 (YY1). Inhibition of YY1 by anti-CD20 mAb was caused, in part, by the inhibition of NF-κB and induction of the Raf-1 kinase inhibitor protein (RKIP). Inhibition of YY1 with siRNA YY1 resulted in sensitization of B-NHL to apoptosis by drugs. These findings demonstrate that anti-CD20 mAb-induced cell sensitization is the result of inhibition of YY1 activity and expression. Similar findings were observed with the humanized anti-CD20 mAb, BM-ca, and anti-CD80 mAb, galiximab. Hence, YY1 is suggested to be a therapeutic target that can be used in conjunction with anti-CD20 antibodies and other therapeutic antibodies in the reversal of resistance in B-NHL and other malignancies. © 2010 by Begell House, Inc.
Nishida M.,Kyoto University |
Uematsu N.,BioMedics Japan Inc. |
Kobayashi H.,BioMedics Japan Inc. |
Matsunaga Y.,BioMedics Japan Inc. |
And 6 more authors.
International Journal of Oncology | Year: 2011
Rituximab (chimeric anti-CD20 mAb) is currently used in the treatment of B-NHL and B cell malignancies, alone or in combination with chemotherapy. However, subsets of patients do not initially respond and/or develop resistance to additional treatments. Hence, there is a need to develop more effective anti-CD20 mAbs that may improve clinical response. BM-ca is a novel humanized anti-CD20 mAb that was tested against several B-NHL cell lines and was compared to several anti-CD20 mAbs (Rituximab, ofatumumab, 2H7, B1 and B-Ly1). BM-ca was shown to strongly induce both homotypic cell aggregation and redistribution of CD20 to membrane lipid rafts. BM-ca was also able to induce programmed cell death (apoptosis) without the need for cross-linking and demonstrated potent complement-dependent cytotoxicity (CDC). BM-ca was more cytotoxic than rituximab even in malignant B cells expressing low amounts of membrane CD20. Type I anti-CD20 mAbs typically induce minimal levels of homotypic cell aggregation and apoptosis but strong localization of CD20 to lipid rafts and potent CDC. Type II anti-CD20 mAbs typically exert the reverse activities. Noteworthy, BM-ca exhibits properties that are shared by both type I and type II anti-CD20 mAbs, which may reflect the recognition of a new CD20 epitope and/or exhibit different molecular signaling. Overall, the present data show that BM-ca is a novel anti-CD20 mAb that may be classified as a type I/II. The therapeutics efficacy of BM-ca awaits its use in clinical trials.