Related Experiment Video
Updated: Aug 17, 2025
Analyzing Tumor and Tissue Distribution of Target Antigen Specific Therapeutic Antibody
Published on: May 16, 2020
A mAb against surface-expressed FSHR engineered to engage adaptive immunity for ovarian cancer immunotherapy
Devivasha Bordoloi1, Pratik S Bhojnagarwala1, Alfredo Perales-Puchalt1
1Vaccine & Immunotherapy Center and.
Abstract:
Despite advances in ovarian cancer (OC) therapy, recurrent OC remains a poor-prognosis disease. Because of the close interaction between OC cells and the tumor microenvironment (TME), it is important to develop strategies that target tumor cells and engage components of the TME. A major obstacle in the development of OC therapies is the identification of targets with expression limited to tumor surface to avoid off-target interactions. The follicle-stimulating hormone receptor (FSHR) has selective expression on ovarian granulosa cells and is expressed on 50%-70% of serous OCs. We generated mAbs targeting the external domain of FSHR using in vivo-expressed FSHR vector. By high-throughput flow analysis, we identified multiple clones and downselected D2AP11, a potent FSHR surface-targeted mAb. D2AP11 identifies important OC cell lines derived from tumors with different mutations, including BRCA1/2, and lines resistant to a wide range of therapies. We used D2AP11 to develop a bispecific T cell engager. In vitro addition of PBMCs and T cells to D2AP11-TCE induced specific and potent killing of different genetic and immune escape OC lines, with EC50s in the ng/ml range, and attenuated tumor burden in OC-challenged mouse models. These studies demonstrate the potential utility of biologics targeting FSHR for OC and perhaps other FSHR-positive cancers.
Insights
Researchers developed a novel antibody targeting the follicle-stimulating hormone receptor (FSHR) to treat ovarian cancer (OC). This antibody, D2AP11, effectively eliminated OC cells and reduced tumor burden in preclinical models, showing promise for new ovarian cancer therapies.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Recurrent ovarian cancer (OC) presents a significant therapeutic challenge with poor prognosis.
- Targeting tumor cells while engaging the tumor microenvironment (TME) is crucial for effective OC treatment.
- Identifying tumor-specific surface targets is essential to minimize off-target effects in OC therapy.
Purpose of the Study:
- To develop novel biologics targeting the follicle-stimulating hormone receptor (FSHR) for ovarian cancer treatment.
- To generate and characterize a potent monoclonal antibody (mAb) against the external domain of FSHR.
- To evaluate the efficacy of an FSHR-targeted bispecific T cell engager (TCE) in preclinical OC models.
Main Methods:
- Generation of FSHR-targeting mAbs using an in vivo-expressed FSHR vector.
- High-throughput flow analysis for mAb clone selection, identifying D2AP11.
- Development of a D2AP11-based bispecific T cell engager (TCE).
- In vitro assessment of D2AP11-TCE-mediated T cell killing of OC lines.
- Evaluation of D2AP11-TCE in reducing tumor burden in OC-challenged mouse models.
Main Results:
- D2AP11 effectively targets FSHR on various OC cell lines, including those with BRCA1/2 mutations and therapy resistance.
- D2AP11-TCE induced potent and specific killing of diverse genetic and immune-evasive OC lines in vitro.
- D2AP11-TCE demonstrated significant tumor burden reduction in preclinical OC mouse models.
- The D2AP11-TCE exhibited low EC50 values in the ng/ml range for OC cell killing.
Conclusions:
- FSHR is a viable surface target for ovarian cancer therapy.
- The D2AP11 mAb and its derived TCE show significant potential for treating ovarian cancer.
- Targeting FSHR may offer a new therapeutic strategy for FSHR-positive cancers, including ovarian cancer.
