Novel FGFR4-Targeting Single-Domain Antibodies for Multiple Targeted Therapies against Rhabdomyosarcoma
The fibroblast growth factor receptor 4 (FGFR4) is overexpressed in rhabdomyosarcoma (RMS) and represents a promising target for treatments based on specific and efficient antibodies. Despite progress, there is an urgent need for targeted treatment options to improve survival rates, and to limit lon...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-11-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/11/3313 |
| _version_ | 1797548320895270912 |
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| author | Nagjie Alijaj Sandrine Moutel Zelia L. Gouveia Maxim Gray Maurizio Roveri Dzhangar Dzhumashev Florian Weber Gianmarco Meier Paola Luciani Jochen K. Rössler Beat W. Schäfer Franck Perez Michele Bernasconi |
| author_facet | Nagjie Alijaj Sandrine Moutel Zelia L. Gouveia Maxim Gray Maurizio Roveri Dzhangar Dzhumashev Florian Weber Gianmarco Meier Paola Luciani Jochen K. Rössler Beat W. Schäfer Franck Perez Michele Bernasconi |
| author_sort | Nagjie Alijaj |
| collection | DOAJ |
| description | The fibroblast growth factor receptor 4 (FGFR4) is overexpressed in rhabdomyosarcoma (RMS) and represents a promising target for treatments based on specific and efficient antibodies. Despite progress, there is an urgent need for targeted treatment options to improve survival rates, and to limit long-term side effects. From phage display libraries we selected FGFR4-specific single-domain antibodies (sdAb) binding to recombinant FGFR4 and validated them by flow cytometry, surface plasmon resonance, and fluorescence microscopy. The specificity of the selected sdAb was verified on FGFR4-wild type and FGFR4-knock out cells. FGFR4-sdAb were used to decorate vincristine-loaded liposomes and to generate chimeric antigen receptor (CAR) T cells. First, incubation of RMS cells with FGFR4-sdAb revealed that FGFR4-sdAb can block FGF19-FGFR4 signaling via the MAPK pathway and could therefore serve as therapeutics for FGFR4-dependent cancers. Second, FGFR4-targeted vincristine-loaded liposomes bound specifically to RMS cells and were internalized by the receptor, demonstrating the potential for active drug delivery to the tumor. Third, FGFR4-CAR T cells, generated with one sdAb candidate, demonstrated strong and specific cytotoxicity against FGFR4 expressing RMS cells. We selected novel FGFR4-sdAb with high specificity and nano- to picomolar affinities for FGFR4 which have the potential to enable multiple FGFR4-targeted cancer therapy approaches. |
| first_indexed | 2024-03-10T14:57:42Z |
| format | Article |
| id | doaj.art-3da7e409a0ec439c974dc5e8bdae98f3 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T14:57:42Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-3da7e409a0ec439c974dc5e8bdae98f32023-11-20T20:24:42ZengMDPI AGCancers2072-66942020-11-011211331310.3390/cancers12113313Novel FGFR4-Targeting Single-Domain Antibodies for Multiple Targeted Therapies against RhabdomyosarcomaNagjie Alijaj0Sandrine Moutel1Zelia L. Gouveia2Maxim Gray3Maurizio Roveri4Dzhangar Dzhumashev5Florian Weber6Gianmarco Meier7Paola Luciani8Jochen K. Rössler9Beat W. Schäfer10Franck Perez11Michele Bernasconi12Department of Oncology, Children’s Research Center, University Children’s Hospital Zurich, 8032 Zurich, SwitzerlandInstitut Curie, PSL Research University, CNRS UMR144, 75248 Paris, FranceInstitut Curie, PSL Research University, CNRS UMR144, 75248 Paris, FranceDepartment of Oncology, Children’s Research Center, University Children’s Hospital Zurich, 8032 Zurich, SwitzerlandDepartment of Oncology, Children’s Research Center, University Children’s Hospital Zurich, 8032 Zurich, SwitzerlandDepartment of Pediatric Hematology and Oncology, Inselspital, Bern University Hospital, 3010 Bern, SwitzerlandDepartment of Chemistry and Biochemistry, University of Bern, 3012 Bern, SwitzerlandInstitute of Medical Microbiology, University of Zurich, 8006 Zurich, SwitzerlandDepartment of Chemistry and Biochemistry, University of Bern, 3012 Bern, SwitzerlandDepartment of Pediatric Hematology and Oncology, Inselspital, Bern University Hospital, 3010 Bern, SwitzerlandDepartment of Oncology, Children’s Research Center, University Children’s Hospital Zurich, 8032 Zurich, SwitzerlandInstitut Curie, PSL Research University, CNRS UMR144, 75248 Paris, FranceDepartment of Oncology, Children’s Research Center, University Children’s Hospital Zurich, 8032 Zurich, SwitzerlandThe fibroblast growth factor receptor 4 (FGFR4) is overexpressed in rhabdomyosarcoma (RMS) and represents a promising target for treatments based on specific and efficient antibodies. Despite progress, there is an urgent need for targeted treatment options to improve survival rates, and to limit long-term side effects. From phage display libraries we selected FGFR4-specific single-domain antibodies (sdAb) binding to recombinant FGFR4 and validated them by flow cytometry, surface plasmon resonance, and fluorescence microscopy. The specificity of the selected sdAb was verified on FGFR4-wild type and FGFR4-knock out cells. FGFR4-sdAb were used to decorate vincristine-loaded liposomes and to generate chimeric antigen receptor (CAR) T cells. First, incubation of RMS cells with FGFR4-sdAb revealed that FGFR4-sdAb can block FGF19-FGFR4 signaling via the MAPK pathway and could therefore serve as therapeutics for FGFR4-dependent cancers. Second, FGFR4-targeted vincristine-loaded liposomes bound specifically to RMS cells and were internalized by the receptor, demonstrating the potential for active drug delivery to the tumor. Third, FGFR4-CAR T cells, generated with one sdAb candidate, demonstrated strong and specific cytotoxicity against FGFR4 expressing RMS cells. We selected novel FGFR4-sdAb with high specificity and nano- to picomolar affinities for FGFR4 which have the potential to enable multiple FGFR4-targeted cancer therapy approaches.https://www.mdpi.com/2072-6694/12/11/3313rhabdomyosarcomaFGFR4single-domain antibodytargeted liposomesCAR T cells |
| spellingShingle | Nagjie Alijaj Sandrine Moutel Zelia L. Gouveia Maxim Gray Maurizio Roveri Dzhangar Dzhumashev Florian Weber Gianmarco Meier Paola Luciani Jochen K. Rössler Beat W. Schäfer Franck Perez Michele Bernasconi Novel FGFR4-Targeting Single-Domain Antibodies for Multiple Targeted Therapies against Rhabdomyosarcoma Cancers rhabdomyosarcoma FGFR4 single-domain antibody targeted liposomes CAR T cells |
| title | Novel FGFR4-Targeting Single-Domain Antibodies for Multiple Targeted Therapies against Rhabdomyosarcoma |
| title_full | Novel FGFR4-Targeting Single-Domain Antibodies for Multiple Targeted Therapies against Rhabdomyosarcoma |
| title_fullStr | Novel FGFR4-Targeting Single-Domain Antibodies for Multiple Targeted Therapies against Rhabdomyosarcoma |
| title_full_unstemmed | Novel FGFR4-Targeting Single-Domain Antibodies for Multiple Targeted Therapies against Rhabdomyosarcoma |
| title_short | Novel FGFR4-Targeting Single-Domain Antibodies for Multiple Targeted Therapies against Rhabdomyosarcoma |
| title_sort | novel fgfr4 targeting single domain antibodies for multiple targeted therapies against rhabdomyosarcoma |
| topic | rhabdomyosarcoma FGFR4 single-domain antibody targeted liposomes CAR T cells |
| url | https://www.mdpi.com/2072-6694/12/11/3313 |
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