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

Autor: Mazumder S; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA.; Case Comprehensive Cancer Center, Cleveland, OH, USA., Swank V; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA., Komar AA; Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, OH, USA.; Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, OH, USA., Johnson JM; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.; Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, OH, USA., Tuohy VK; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA.; Case Comprehensive Cancer Center, Cleveland, OH, USA.; Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, OH, USA.
Jazyk: angličtina
Zdroj: Oncotarget [Oncotarget] 2020 May 19; Vol. 11 (20), pp. 1894-1910. Date of Electronic Publication: 2020 May 19 (Print Publication: 2020).
DOI: 10.18632/oncotarget.27585
Abstrakt: 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 IgG 1 that shows high affinity antigen-specific binding to the 7-mer 20 KTLGELL 26 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.
Competing Interests: CONFLICTS OF INTEREST SM, VKT, and JMJ declare that they are the inventors on a provisional patent application related to this mAb technology. All other authors have no conflicts of interest and have no financial interest to be gained by the publication of the contents of the manuscript.
(Copyright: © 2020 Mazumder et al.)
Databáze: MEDLINE
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