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Forum on Immunopathological Diseases and Therapeutics
SJR: 0.309 SNIP: 0.041 CiteScore™: 0.18

ISSN Print: 2151-8017
ISSN Online: 2151-8025

Archives: Volume 1, 2010 to Volume 7, 2016

Forum on Immunopathological Diseases and Therapeutics

DOI: 10.1615/ForumImmunDisTher.v2.i2.30
pages 119-126

Induction of RKIP Expression by Anticancer Therapeutic Antibodies and Its Role in the Reversal of Chemo- and Immunoresistance

Benjamin Bonavida
Department of Microbiology, Immunology, & Molecular Genetics, David Geffen School of Medicine, Johnson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90025-1747

ABSTRACT

Immunotherapy against human cancers has gained momentum after a long silence. Both cell-mediated and antibody-mediated therapies have been utilized with successful clinical responses. The first antibody that is targeted and FDA approved is rituximab, a chimeric anti-CD20 monoclonal antibody (mAb) for the treatment of B non-Hodgkin’s lymphoma (B-NHL), both as a single agent and in combination with CHOP. Over 20 mAbs have been subsequently developed and approved by the FDA in the treatment of a variety of solid and hematological malignancies. The mechanisms underlying antibody-mediated therapeutic effects have been postulated to consist of antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), and seldom direct apoptosis. Earlier studies with rituximab demonstrated that in addition to above mechanisms, cell signaling takes place following rituximab interaction with CD20, leading to inhibition of intracellular survival and antiapoptotic pathways. These inhibitory effects were shown to be responsible, in large part, for rituximab-mediated sensitization to apoptosis by both chemotherapeutic and immunotherapeutic drugs. Similar findings shown with rituximab were also observed with other anti-CD20 mAbs and with galiximab (humanized anti-CD80 mAb). Rituximab and other anti-CD20 mAbs as well as galiximab were shown, following treatment with B-NHL cells, to induce and upregulate Raf-1 kinase inhibitor protein (RKIP) expression. The induction of RKIP was the result, in part, of antibody-mediated inhibition of the constitutively activated NF-κB pathway and downstream inhibition of the RKIP transcription repressor Snail. The antibody-mediated induction of RKIP plays a pivotal role in the sensitization and reversal of tumor cell resistance. The induction of RKIP by therapeutic antibodies may serve as a marker for clinical response and reversal of resistance when the therapeutic antibody is used in combination with cytotoxic drugs. Likewise, failure to induce RKIP by the antibody may suggest failure of a clinical response by the combination treatment of antibody and drugs. Furthermore, it is proposed that levels of RKIP expression may be of prognostic significance, and RKIP may be considered as a target for therapeutic intervention in hematological malignancies.


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