Cancer therapy via neoepitope-specific monoclonal antibody cocktails
Abstract Cellular heterogeneity presents a significant challenge to cancer treatment. Antibody therapies targeting individual tumor-associated antigens can be extremely effective but are not suited for all patients and often fail against tumors with heterogeneous expression as tumor cells with low o...
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| Format: | Article |
| Language: | English |
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Springer
2025-05-01
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| Series: | Cancer Immunology, Immunotherapy |
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| Online Access: | https://doi.org/10.1007/s00262-025-04075-3 |
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| author | Colin J. Hartman Asmaa O. Mohamed Girja S. Shukla Stephanie C. Pero Yu-Jing Sun Roberto S. Rodríguez-Jimenez Nicholas F. Genovese Nico M. Kohler Thomas R. Hemphill Yina H. Huang David N. Krag Margaret E. Ackerman |
| author_facet | Colin J. Hartman Asmaa O. Mohamed Girja S. Shukla Stephanie C. Pero Yu-Jing Sun Roberto S. Rodríguez-Jimenez Nicholas F. Genovese Nico M. Kohler Thomas R. Hemphill Yina H. Huang David N. Krag Margaret E. Ackerman |
| author_sort | Colin J. Hartman |
| collection | DOAJ |
| description | Abstract Cellular heterogeneity presents a significant challenge to cancer treatment. Antibody therapies targeting individual tumor-associated antigens can be extremely effective but are not suited for all patients and often fail against tumors with heterogeneous expression as tumor cells with low or no antigen expression escape targeting and develop resistance. Simultaneously targeting multiple tumor-specific proteins with multiple antibodies has the potential to overcome this barrier and improve efficacy, but relatively few widely expressed cancer-specific antigens are known. In contrast, neoepitopes, which arise from mutations unique to tumor cells, are considerably more abundant. However, since neoepitopes are not commonly shared between individuals, a patient-customized approach is necessary and motivates efforts to develop an efficient means to identify suitable target mutations and isolate neoepitope-specific monoclonal antibodies. Here, focusing on the latter goal, we use directed evolution in yeast and phage display systems to engineer antibodies from nonimmune, human antibody fragment libraries that are specific for neoepitopes previously reported in the B16F10 melanoma model. We demonstrate proof-of-concept for a pipeline that supports rapid isolation and functional enhancement of multiple neoepitope peptide-targeted monoclonal antibodies and demonstrate their robust binding to B16F10 cells and potent effector functions in vitro. These antibodies were combined and evaluated in vivo for anticancer activity in tumor-bearing mice, where they suppressed B16F10 tumor growth and prolonged survival. These findings emphasize the potential for clinical application of patient-customized antibody cocktails in the treatment of the many cancers poorly addressed by current therapies. |
| format | Article |
| id | doaj-art-82467b5cb252464b85c6eb4d1e26cf71 |
| institution | DOAJ |
| issn | 1432-0851 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Springer |
| record_format | Article |
| series | Cancer Immunology, Immunotherapy |
| spelling | doaj-art-82467b5cb252464b85c6eb4d1e26cf712025-08-20T02:39:47ZengSpringerCancer Immunology, Immunotherapy1432-08512025-05-0174712010.1007/s00262-025-04075-3Cancer therapy via neoepitope-specific monoclonal antibody cocktailsColin J. Hartman0Asmaa O. Mohamed1Girja S. Shukla2Stephanie C. Pero3Yu-Jing Sun4Roberto S. Rodríguez-Jimenez5Nicholas F. Genovese6Nico M. Kohler7Thomas R. Hemphill8Yina H. Huang9David N. Krag10Margaret E. Ackerman11Department of Microbiology and Immunology, Geisel School of Medicine at DartmouthDepartment of Microbiology and Immunology, Geisel School of Medicine at DartmouthLarner College of Medicine, University of VermontLarner College of Medicine, University of VermontLarner College of Medicine, University of VermontThayer School of Engineering, Dartmouth CollegeThayer School of Engineering, Dartmouth CollegeThayer School of Engineering, Dartmouth CollegeThayer School of Engineering, Dartmouth CollegeDepartment of Microbiology and Immunology, Geisel School of Medicine at DartmouthLarner College of Medicine, University of VermontDepartment of Microbiology and Immunology, Geisel School of Medicine at DartmouthAbstract Cellular heterogeneity presents a significant challenge to cancer treatment. Antibody therapies targeting individual tumor-associated antigens can be extremely effective but are not suited for all patients and often fail against tumors with heterogeneous expression as tumor cells with low or no antigen expression escape targeting and develop resistance. Simultaneously targeting multiple tumor-specific proteins with multiple antibodies has the potential to overcome this barrier and improve efficacy, but relatively few widely expressed cancer-specific antigens are known. In contrast, neoepitopes, which arise from mutations unique to tumor cells, are considerably more abundant. However, since neoepitopes are not commonly shared between individuals, a patient-customized approach is necessary and motivates efforts to develop an efficient means to identify suitable target mutations and isolate neoepitope-specific monoclonal antibodies. Here, focusing on the latter goal, we use directed evolution in yeast and phage display systems to engineer antibodies from nonimmune, human antibody fragment libraries that are specific for neoepitopes previously reported in the B16F10 melanoma model. We demonstrate proof-of-concept for a pipeline that supports rapid isolation and functional enhancement of multiple neoepitope peptide-targeted monoclonal antibodies and demonstrate their robust binding to B16F10 cells and potent effector functions in vitro. These antibodies were combined and evaluated in vivo for anticancer activity in tumor-bearing mice, where they suppressed B16F10 tumor growth and prolonged survival. These findings emphasize the potential for clinical application of patient-customized antibody cocktails in the treatment of the many cancers poorly addressed by current therapies.https://doi.org/10.1007/s00262-025-04075-3Monoclonal antibodyNeoepitopePhage displayYeast displayMelanomaEffector function |
| spellingShingle | Colin J. Hartman Asmaa O. Mohamed Girja S. Shukla Stephanie C. Pero Yu-Jing Sun Roberto S. Rodríguez-Jimenez Nicholas F. Genovese Nico M. Kohler Thomas R. Hemphill Yina H. Huang David N. Krag Margaret E. Ackerman Cancer therapy via neoepitope-specific monoclonal antibody cocktails Cancer Immunology, Immunotherapy Monoclonal antibody Neoepitope Phage display Yeast display Melanoma Effector function |
| title | Cancer therapy via neoepitope-specific monoclonal antibody cocktails |
| title_full | Cancer therapy via neoepitope-specific monoclonal antibody cocktails |
| title_fullStr | Cancer therapy via neoepitope-specific monoclonal antibody cocktails |
| title_full_unstemmed | Cancer therapy via neoepitope-specific monoclonal antibody cocktails |
| title_short | Cancer therapy via neoepitope-specific monoclonal antibody cocktails |
| title_sort | cancer therapy via neoepitope specific monoclonal antibody cocktails |
| topic | Monoclonal antibody Neoepitope Phage display Yeast display Melanoma Effector function |
| url | https://doi.org/10.1007/s00262-025-04075-3 |
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