Journal
CANCERS
Volume 12, Issue 11, Pages -Publisher
MDPI
DOI: 10.3390/cancers12113313
Keywords
rhabdomyosarcoma; FGFR4; single-domain antibody; targeted liposomes; CAR T cells
Categories
Funding
- Krebsliga Zurich
- Werner und Hedy Berger-Janser Foundation
- Kurt und Senta Hermann Foundation
- Olga Mayenfisch Foundation
- Hartmann Muller Stiftung
- Bernese Foundation for Children and Adolescents with Cancer
- Institut Curie
- Centre National de la Recherche Scientifique
- Institut National du Cancer [2018-1-PL BIO-04-ICR-1, INCa 2018-1-PL BIO-04-1]
- Labex CelTisPhyBio [11-LBX-0038]
- Idex Paris Sciences et Lettres [ANR-10-IDEX-0001-02 PSL]
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Simple Summary 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.
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