A mAb against surface-expressed FSHR engineered to engage adaptive immunity for ovarian cancer immunotherapy
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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-11-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.162553 |
| _version_ | 1797634380933365760 |
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| author | Devivasha Bordoloi Pratik S. Bhojnagarwala Alfredo Perales-Puchalt Abhijeet J. Kulkarni Xizhou Zhu Kevin Liaw Ryan P. O’Connell Daniel H. Park Daniel W. Kulp Rugang Zhang David B. Weiner |
| author_facet | Devivasha Bordoloi Pratik S. Bhojnagarwala Alfredo Perales-Puchalt Abhijeet J. Kulkarni Xizhou Zhu Kevin Liaw Ryan P. O’Connell Daniel H. Park Daniel W. Kulp Rugang Zhang David B. Weiner |
| author_sort | Devivasha Bordoloi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:06:52Z |
| format | Article |
| id | doaj.art-a607704c926640839bde5206f6333f01 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:06:52Z |
| publishDate | 2022-11-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-a607704c926640839bde5206f6333f012023-11-07T16:24:51ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-11-01722A mAb against surface-expressed FSHR engineered to engage adaptive immunity for ovarian cancer immunotherapyDevivasha BordoloiPratik S. BhojnagarwalaAlfredo Perales-PuchaltAbhijeet J. KulkarniXizhou ZhuKevin LiawRyan P. O’ConnellDaniel H. ParkDaniel W. KulpRugang ZhangDavid B. WeinerDespite 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.https://doi.org/10.1172/jci.insight.162553OncologyTherapeutics |
| spellingShingle | Devivasha Bordoloi Pratik S. Bhojnagarwala Alfredo Perales-Puchalt Abhijeet J. Kulkarni Xizhou Zhu Kevin Liaw Ryan P. O’Connell Daniel H. Park Daniel W. Kulp Rugang Zhang David B. Weiner A mAb against surface-expressed FSHR engineered to engage adaptive immunity for ovarian cancer immunotherapy JCI Insight Oncology Therapeutics |
| title | A mAb against surface-expressed FSHR engineered to engage adaptive immunity for ovarian cancer immunotherapy |
| title_full | A mAb against surface-expressed FSHR engineered to engage adaptive immunity for ovarian cancer immunotherapy |
| title_fullStr | A mAb against surface-expressed FSHR engineered to engage adaptive immunity for ovarian cancer immunotherapy |
| title_full_unstemmed | A mAb against surface-expressed FSHR engineered to engage adaptive immunity for ovarian cancer immunotherapy |
| title_short | A mAb against surface-expressed FSHR engineered to engage adaptive immunity for ovarian cancer immunotherapy |
| title_sort | mab against surface expressed fshr engineered to engage adaptive immunity for ovarian cancer immunotherapy |
| topic | Oncology Therapeutics |
| url | https://doi.org/10.1172/jci.insight.162553 |
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