Therapy of B-cell malignancies by anti-HLA-DR humanized monoclonal antibody, IMMU-114, is mediated through hyperactivation of ERK and JNK MAP kinase signaling pathways.
A humanized IgG4 anti-HLA-DR monoclonal antibody (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 and chronic lymphocytic leukemia (CLL) patient specimens, followed by evaluation of the effects of IMMU-114 on extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways. HLA-DR was expressed on the 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 multiple myeloma 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 monoclonal antibodies. Despite positive staining, acute myelogenous leukemic 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 monoclonal antibodies against CD20 and CD74. Thus, antigen expression is not sufficient for cytotoxicity; antibody-induced hyperactivation of ERK and JNK mitogen activated protein kinase signaling pathways are also required.
Stein
Rhona
R
Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, NJ 07109, USA. rstein@gscancer.org
Gupta
Pankaj
P
Chen
Xiaochuan
X
Cardillo
Thomas M
TM
Furman
Richard R
RR
Chen
Susan
S
Chang
Chien-Hsing
CH
Goldenberg
David M
DM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000276:immunology / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006684:HLA-DR Antigens / Q000276:immunology* / Q000378:metabolism; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000276:immunology* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D016513:Mice, SCID
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D003603:Cytotoxins; D006684:HLA-DR Antigens; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4