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High-Affinity Internalizing Human scFv-Fc Antibody for Targeting FGFR1-Overexpressing Lung Cancer.
Mol Cancer Res 2017; 15(8):1040-1050MC

Abstract

Targeted delivery of anticancer drugs using antibodies specific for tumor-associated antigens represents one of the most important approaches in current immuno-oncology research. Fibroblast growth factor receptor 1 (FGFR1) has been demonstrated to be a high-frequency targetable oncogene specific for smoking-associated lung cancers, present in over 20% of lung squamous cell carcinoma cases. This report describes the generation of a potent, fully human antibody fragment in scFv-Fc format efficiently targeting FGFR1. Antibody phage display was used to select high-affinity scFv antibody fragments against the extracellular domain of FGFR1(IIIc). Enzyme immunoassay (ELISA) and surface plasmon resonance (SPR) analysis were used for antibody screening and characterization. The best binder (named D2) was cloned to diabody and Fc fusion formats. All D2 antibodies demonstrated high affinity for FGFR1 with dissociation constants of 18 nmol/L (scFvD2), 0.82 nmol/L (scFvD2 diabody), and 0.59 nmol/L (scFvD2-Fc). scFvD2 was found to be exquisitely selective for FGFR1 versus other FGFR family members and bound FGFR1 even in the presence of its natural ligand FGF2, as shown by competitive analysis. Confocal microscopy revealed that scFvD2-Fc was specifically and rapidly internalized by a panel of cell lines overexpressing FGFR1. Finally, it was demonstrated that scFvD2-Fc mediated specific delivery of a cytotoxic payload into lung cancer cells harboring oncogenic FGFR1 gene amplifications.Implications: This study reports a highly specific internalizing antibody fragment that can serve as a therapeutic targeting agent for efficient delivery of cytotoxic drugs into FGFR1-positive lung cancer cells. Mol Cancer Res; 15(8); 1040-50. ©2017 AACR.

Authors+Show Affiliations

Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland.Wroclaw Research Centre EIT+, Wroclaw, Poland.Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland.Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland.Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland.Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland. jacek.otlewski@uwr.edu.pl.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28483948

Citation

Sokolowska-Wedzina, Aleksandra, et al. "High-Affinity Internalizing Human scFv-Fc Antibody for Targeting FGFR1-Overexpressing Lung Cancer." Molecular Cancer Research : MCR, vol. 15, no. 8, 2017, pp. 1040-1050.
Sokolowska-Wedzina A, Chodaczek G, Chudzian J, et al. High-Affinity Internalizing Human scFv-Fc Antibody for Targeting FGFR1-Overexpressing Lung Cancer. Mol Cancer Res. 2017;15(8):1040-1050.
Sokolowska-Wedzina, A., Chodaczek, G., Chudzian, J., Borek, A., Zakrzewska, M., & Otlewski, J. (2017). High-Affinity Internalizing Human scFv-Fc Antibody for Targeting FGFR1-Overexpressing Lung Cancer. Molecular Cancer Research : MCR, 15(8), pp. 1040-1050. doi:10.1158/1541-7786.MCR-16-0136.
Sokolowska-Wedzina A, et al. High-Affinity Internalizing Human scFv-Fc Antibody for Targeting FGFR1-Overexpressing Lung Cancer. Mol Cancer Res. 2017;15(8):1040-1050. PubMed PMID: 28483948.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - High-Affinity Internalizing Human scFv-Fc Antibody for Targeting FGFR1-Overexpressing Lung Cancer. AU - Sokolowska-Wedzina,Aleksandra, AU - Chodaczek,Grzegorz, AU - Chudzian,Julia, AU - Borek,Aleksandra, AU - Zakrzewska,Malgorzata, AU - Otlewski,Jacek, Y1 - 2017/05/08/ PY - 2016/04/20/received PY - 2016/12/27/revised PY - 2017/05/02/accepted PY - 2017/5/10/pubmed PY - 2018/4/18/medline PY - 2017/5/10/entrez SP - 1040 EP - 1050 JF - Molecular cancer research : MCR JO - Mol. Cancer Res. VL - 15 IS - 8 N2 - Targeted delivery of anticancer drugs using antibodies specific for tumor-associated antigens represents one of the most important approaches in current immuno-oncology research. Fibroblast growth factor receptor 1 (FGFR1) has been demonstrated to be a high-frequency targetable oncogene specific for smoking-associated lung cancers, present in over 20% of lung squamous cell carcinoma cases. This report describes the generation of a potent, fully human antibody fragment in scFv-Fc format efficiently targeting FGFR1. Antibody phage display was used to select high-affinity scFv antibody fragments against the extracellular domain of FGFR1(IIIc). Enzyme immunoassay (ELISA) and surface plasmon resonance (SPR) analysis were used for antibody screening and characterization. The best binder (named D2) was cloned to diabody and Fc fusion formats. All D2 antibodies demonstrated high affinity for FGFR1 with dissociation constants of 18 nmol/L (scFvD2), 0.82 nmol/L (scFvD2 diabody), and 0.59 nmol/L (scFvD2-Fc). scFvD2 was found to be exquisitely selective for FGFR1 versus other FGFR family members and bound FGFR1 even in the presence of its natural ligand FGF2, as shown by competitive analysis. Confocal microscopy revealed that scFvD2-Fc was specifically and rapidly internalized by a panel of cell lines overexpressing FGFR1. Finally, it was demonstrated that scFvD2-Fc mediated specific delivery of a cytotoxic payload into lung cancer cells harboring oncogenic FGFR1 gene amplifications.Implications: This study reports a highly specific internalizing antibody fragment that can serve as a therapeutic targeting agent for efficient delivery of cytotoxic drugs into FGFR1-positive lung cancer cells. Mol Cancer Res; 15(8); 1040-50. ©2017 AACR. SN - 1557-3125 UR - https://www.unboundmedicine.com/medline/citation/28483948/High_Affinity_Internalizing_Human_scFv_Fc_Antibody_for_Targeting_FGFR1_Overexpressing_Lung_Cancer_ L2 - http://mcr.aacrjournals.org/cgi/pmidlookup?view=long&pmid=28483948 DB - PRIME DP - Unbound Medicine ER -