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; Vincent K Tuohy

doi:10.18632/oncotarget.27585

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

Oncotarget. 2020 May 19;11(20):1894-1910. doi: 10.18632/oncotarget.27585.

Authors

Suparna Mazumder^{1

2

3}, Valerie Swank¹, Anton A Komar^{4

5}, Justin M Johnson^{1

4}, Vincent K Tuohy^{1

2

3

4}

Affiliations

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.

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.

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