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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Blood First Edition Paper, prepublished online January 25, 2010; DOI

10.1182/blood-2009-06-228288.

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

Rhona Stein1,*, Pankaj Gupta2, Xiaochuan Chen1, M. Cardillo2, R.

Furman3, Chen1, Chien-Hsing Chang2 and M. Goldenberg1

1 Garden State Cancer Center, Center for Molecular Medicine and Immunology,

Belleville, NJ; 2 Immunomedics, Inc., Plains, NJ; 3 Weill-Cornell Medical

College, New York, NY

* Corresponding author; email: rstein@...

Abstract

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.

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