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Immunotherapy of ovarian cancer with a monoclonal antibody specific for the extracellular domain of anti-Mullerian 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 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.

SUBMITTER: Mazumder S

PROVIDER: S-EPMC7244012 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Mazumder Suparna S Swank Valerie V Komar Anton A AA Johnson Justin M JM Tuohy Vincent K VK

Oncotarget 20200519 20

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 Ig ...[more]

PMID: 32499873

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Project description:Background: The ability of anti-Müllerian hormone (AMH) to predict ovarian response has been studied extensively in gonadotropin-releasing hormone agonist and antagonist treatments, but no information is available regarding its value in progestin-primed ovarian stimulation (PPOS) protocol. Methods: This retrospective data analysis included 523 patients without polycystic ovary syndrome who underwent their first in vitro fertilization/intracytoplasmic sperm injection cycle with PPOS protocol at our center between Jan. 2015 and Jul. 2018. Serum AMH measurements were acquired within 12 months prior to ovarian stimulation using the automated Access AMH assay. Results: AMH exhibited a significantly positive correlation with the number of retrieved oocytes (r = 0.744, P < 0.001). For the prediction of poor (<4 oocytes) and high (>15 oocytes) response, AMH had an area under the receiver operating characteristic curve (AUC) of 0.861 and 0.773, corresponding with an optimal cutoff point of 1.26 and 4.34 ng/mL, respectively. When stratified according to the dose of medroxyprogesterone acetate (MPA) (4 mg vs. 10 mg per day), AMH retained its similarly high predictive value for poor (AUC = 0.829 and 0.886, respectively) and high response (AUC = 0.770 and 0.814, respectively) in both groups. Amongst the 314 women who received their first frozen embryo transfer (FET) following PPOS protocol, no significant differences were observed on the rates of biochemical pregnancy, clinical pregnancy, implantation, early miscarriage, multiple pregnancy and ectopic pregnancy (all P > 0.05) across AMH quartiles (≤1.43, 1.44-2.55, 2.56-4.35, >4.35 ng/mL). In a multivariable logistic regression model, age was suggested to be the only independent risk factor for clinical pregnancy (P = 0.011). Conclusions: Our data demonstrated that AMH is an adequate predictor of both high and poor ovarian response in PPOS protocol regardless of MPA dose, but it does not associate with pregnancy outcomes in the first FET cycles in a freeze-all strategy.

Project description:Müllerian inhibiting substance/anti-Müllerian hormone (MIS/AMH) is a regulator of the female reproductive system, an indicator of ovarian reserve and a growth inhibitor of Müllerian duct-derived tumors in vivo and in vitro. The objective of the present study was to analyze MIS/AMH type II receptor (MIS/AMHRII) protein and mRNA expression in healthy human endometria compared with patients with endometrial hyperplasia and endometrial cancer, providing a foundation for MIS/AMH as a biological modifier for treatment of endometrial hyperplasia and endometrial cancer. The present study included healthy endometrial tissues (n=20), simple endometrial hyperplasia tissues without atypia (n=17), complex endometrial hyperplasia tissues without atypia (n=24) and endometrial cancer tissues (n=8). The location and variation of MIS/AMHRII protein expression was observed by immunohistochemistry. The expression was graded by two pathologists and was categorized as follows: Negative, weakly positive, moderately positive or strongly positive. Reverse transcription-quantitative polymerase chain reaction was used to quantify MIS/AMHRII mRNA expression. The expression of MIS/AMHRII protein was observed in the cytoplasm of healthy human endometria, endometrial hyperplasia and endometrial cancer cells. The frequency of MIS/AMHRII protein expression was 20.22±10.35% in the proliferative phase of the healthy endometrium and 24.09±11.73% in the secretory phase of the healthy endometrium. However, no differences were observed in the menstrual cycle phases. The frequency was 54.50±16.59% in endometrial hyperplasia without atypia, 55.10±15.87% in endometrial hyperplasia with atypia and 73.88±15.70% in endometrial cancer, indicating that expression was enhanced as the disease progressed from healthy to malignant status. In endometrial hyperplasia, MIS/AMHRII protein expression was significantly associated with histological complexity compared with atypia status. The present study demonstrated that MIS/AMHRII is present in healthy endometria, endometrial hyperplasia and endometrial cancer. The low expression frequency of MIS/AMHRII was not significantly different among normal endometrial tissues, however, the protein expression was elevated in endometrial hyperplasia and endometrial cancer. These findings indicated that the study of bioactive MIS/AMH, as a possible treatment for tumors expressing the MIS/AMH receptor, is essential.

Dataset Information

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

Publications

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

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