Oncotarget

Research Papers:

Immunotherapy of ovarian cancer with a monoclonal antibody specific for the extracellular domain of anti-Müllerian hormone receptor II

Suparna Mazumder _, Valerie Swank, Anton A. Komar, Justin M. Johnson and Vincent K. Tuohy

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Oncotarget. 2020; 11:1894-1910. https://doi.org/10.18632/oncotarget.27585

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Abstract

Suparna Mazumder1,2,3, Valerie Swank1, Anton A. Komar4,5, Justin M. Johnson1,4 and Vincent K. Tuohy1,2,3,4

1 Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

2 Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA

3 Case Comprehensive Cancer Center, Cleveland, OH, USA

4 Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, OH, USA

5 Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, OH, USA

Correspondence to:

Suparna Mazumder,email: mazumds@ccf.org

Keywords: monoclonal antibody; anti-Müllerian hormone receptor type II; immunotherapy; ovarian cancer; 4D12G1

Received: February 11, 2020     Accepted: April 14, 2020     Published: May 19, 2020

ABSTRACT

Epithelial ovarian carcinoma (EOC) is the most prevalent and lethal form of ovarian cancer. The low five-year overall survival after EOC diagnosis indicates an urgent need for more effective ways to control this disease. Anti-Müllerian hormone receptor 2 (AMHR2) is an ovarian protein overexpressed in the majority of human EOCs. We have previously found that vaccination against the ovarian-specific extracellular domain of AMHR2 (AMHR2-ED) significantly inhibits growth of murine EOCs through an IgG-mediated mechanism that agonizes receptor signaling of a Bax/caspase-3 dependent proapoptotic cascade. To determine if a single monoclonal antibody (mAb) could inhibit growth of human EOC, we generated a panel of mAbs specific for recombinant human AMHR2-ED and characterized a candidate mAb for humanization and use in clinical trials. We found that our candidate 4D12G1 mAb is an IgG1 that shows high affinity antigen-specific binding to the 7-mer 20KTLGELL26 sequence of AMHR2-ED that facilitates induction of programmed cell death in EOC cells. Most importantly, the 4D12G1 mAb significantly inhibits growth of primary human EOCs in patient-derived xenografts (PDXs) by inducing direct apoptosis of EOC tumors. Our results support the view that a humanized 4D12G1 mAb may be a much needed and effective reagent for passive immunotherapy of human EOC.


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