Therapy of B-cell malignancies by anti-HLA-DR humanized monoclonal antibody, IMMU-114, is mediated through hyper-activation of ERK and JNK MAP kinase signaling pathways.
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Therapy of B-cell malignancies by anti-HLA-DR humanized monoclonal antibody, IMMU-114, is mediated through hyper-activation of ERK and JNK MAP kinase signaling pathways.
Blood. 2010 Jan 25;
Authors: Stein R, Gupta P, Chen X, Cardillo TM, Furman RR, Chen S, Chang CH, Goldenberg DM
The expression of HLA-DR on hematological malignancies has stimulated interest in its development as a target for antibody-based therapy. A humanized IgG4 anti-HLA-DR mAb (IMMU-114), engineered to avoid side effects associated with complement-activation, was examined for binding and cytotoxicity on leukemia, lymphoma, and multiple myeloma cell lines (MM) and chronic lymphocytic leukemia (CLL) patient specimens, followed by evaluation of the effects of IMMU-114 on ERK and JNK signaling pathways. HLA-DR was expressed on the vast majority of these cells at markedly higher levels than CD20, CD22, and CD74. IMMU-114 was toxic to mantle cell lymphoma, CLL, acute lymphoblastic leukemia, hairy cell leukemia, non-Hodgkin lymphoma (including rituximab-resistant), and MM cell lines, and also patient CLL cells. IMMU-114 induced disease-free survival in tumor-bearing SCID mice with early-stage disease and in models that are relatively resistant to anti-CD20 mAbs. Despite positive staining, acute myelogenous leukemia cells were not killed by IMMU-114. The ability of IMMU-114 to induce activation of ERK and JNK signaling correlated with cytotoxicity and differentiates the mechanism of action of IMMU-114 from mAbs against CD20 and CD74. Thus, antigen expression is not sufficient for cytotoxicity; antibody-induced hyper-activation of ERK and JNK MAP kinase signaling pathways also are required.
PMID: 20101022 [PubMed - as supplied by publisher]