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

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 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.

Structure of AMH bound to AMHR2 provides insight into a unique signaling pair in the TGF-β family

“…While efforts have been made to model the structure of AMH bound to AMHR2, the exact fold of the receptor-and ligand-binding interface remained unclear (19,20,28,29). Furthermore, some of these studies have used these models in an attempt to characterize antibodies designed to bind AMHR2, specifically for use in targeted cancer cells expressing high levels of AMHR2 (19,28). Interestingly, all models of AMHR2 were inaccurate and unable to predict the fold of the finger 1 loop extension in the receptor.…”

Formulation of an ovarian cancer vaccine with the squalene-based AddaVax adjuvant inhibits the growth of murine epithelial ovarian carcinomas

“…We and others have shown that anti-Müllerian hormone receptor type II (AMHR2) is expressed in approximately 92% of primary EOCs, 78% of borderline malignancies, 77%–86% of non-EOC ovarian tumors, and 56% of malignant ascites from grades III-IV ovarian cancers [ 9 10 11 12 ]. AMHR2 is a serine/threonine kinase receptor homologous to type II receptors of the transforming growth factor-beta superfamily [ 13 ].…”