Next Article in Journal
SARS-CoV-2 Infection and Cardioncology: From Cardiometabolic Risk Factors to Outcomes in Cancer Patients
Previous Article in Journal
Effect of Varying Expression of EpCAM on the Efficiency of CTCs Detection by SERS-Based Immunomagnetic Optofluidic Device
Article

Novel FGFR4-Targeting Single-Domain Antibodies for Multiple Targeted Therapies against Rhabdomyosarcoma

1
Department of Oncology, Children’s Research Center, University Children’s Hospital Zurich, 8032 Zurich, Switzerland
2
Department of Pediatric Hematology and Oncology, Inselspital, Bern University Hospital, 3010 Bern, Switzerland
3
Department for BioMedical Research (DBMR), University of Bern, 3008 Bern, Switzerland
4
Institut Curie, PSL Research University, CNRS UMR144, 75248 Paris, France
5
Recombinant Antibody Platform (TAb-IP), Institut Curie, 75248 Paris, France
6
Honing Biosciences, 75004 Paris, France
7
Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland
8
Department of Chemistry and Biochemistry, University of Bern, 3012 Bern, Switzerland
9
Institute of Medical Microbiology, University of Zurich, 8006 Zurich, Switzerland
*
Authors to whom correspondence should be addressed.
These authors contributed equally as Co-first authors.
These authors contributed equally as Co-last authors.
Cancers 2020, 12(11), 3313; https://doi.org/10.3390/cancers12113313
Received: 12 October 2020 / Revised: 2 November 2020 / Accepted: 4 November 2020 / Published: 10 November 2020
(This article belongs to the Section Methods and Technologies Development)
Rhabdomyosarcoma (RMS) accounts for more than 50% of all soft tissue sarcomas in childhood and adolescence. Despite progress and intensified multimodality treatment, prognoses are extremely poor with an overall survival rate of approximately 20% in the advanced stage. Therefore, there is an urgent need for targeted treatment options to improve overall survival rates, and to limit long-term side effects. The fibroblast growth factor receptor 4 (FGFR4) is overexpressed in RMS and other tumors as well. The goal of this work was to select FGFR4 specific single-domain antibodies (sdAb) and to develop FGFR4-targeted therapies. We could show that FGFR4-targeted liposomes have the potential to deliver drugs specifically to FGFR4-positive tumor cells and that chimeric antigen receptor T cells built with the selected antibodies can kill specifically FGFR4-expressing RMS cells.
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. View Full-Text
Keywords: rhabdomyosarcoma; FGFR4; single-domain antibody; targeted liposomes; CAR T cells rhabdomyosarcoma; FGFR4; single-domain antibody; targeted liposomes; CAR T cells
Show Figures

Graphical abstract

MDPI and ACS Style

Alijaj, N.; Moutel, S.; Gouveia, Z.L.; Gray, M.; Roveri, M.; Dzhumashev, D.; Weber, F.; Meier, G.; Luciani, P.; Rössler, J.K.; Schäfer, B.W.; Perez, F.; Bernasconi, M. Novel FGFR4-Targeting Single-Domain Antibodies for Multiple Targeted Therapies against Rhabdomyosarcoma. Cancers 2020, 12, 3313. https://doi.org/10.3390/cancers12113313

AMA Style

Alijaj N, Moutel S, Gouveia ZL, Gray M, Roveri M, Dzhumashev D, Weber F, Meier G, Luciani P, Rössler JK, Schäfer BW, Perez F, Bernasconi M. Novel FGFR4-Targeting Single-Domain Antibodies for Multiple Targeted Therapies against Rhabdomyosarcoma. Cancers. 2020; 12(11):3313. https://doi.org/10.3390/cancers12113313

Chicago/Turabian Style

Alijaj, Nagjie, 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, and Michele Bernasconi. 2020. "Novel FGFR4-Targeting Single-Domain Antibodies for Multiple Targeted Therapies against Rhabdomyosarcoma" Cancers 12, no. 11: 3313. https://doi.org/10.3390/cancers12113313

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop