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Design and characteristics of cytotoxic fibroblast growth factor 1 conjugate for fibroblast growth factor receptor-targeted cancer therapy

Authors Szlachcic A, Zakrzewska M, Lobocki M, Jakimowicz P, Otlewski J

Received 5 February 2016

Accepted for publication 31 March 2016

Published 9 August 2016 Volume 2016:10 Pages 2547—2560

DOI https://doi.org/10.2147/DDDT.S105896

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Venkateshwar Madka

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Wei Duan


Anna Szlachcic, Malgorzata Zakrzewska, Michal Lobocki, Piotr Jakimowicz, Jacek Otlewski

Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland

Abstract: Fibroblast growth factor receptors (FGFRs) are attractive candidate cancer therapy targets as they are overexpressed in multiple types of tumors, such as breast, prostate, bladder, and lung cancer. In this study, a natural ligand of FGFR, an engineered variant of fibroblast growth factor 1 (FGF1V), was conjugated to a potent cytotoxic drug, monomethyl auristatin E (MMAE), and used as a targeting agent for cancer cells overexpressing FGFRs, similar to antibodies in antibody–drug conjugates. The FGF1V–valine–citrulline–MMAE conjugate showed a favorable stability profile, bound FGFRs on the cell surface specifically, and efficiently released the drug (MMAE) upon cleavage by the lysosomal protease cathepsin B. Importantly, the conjugate showed a prominent cytotoxic effect toward cell lines expressing FGFR. FGF1V–vcMMAE was highly cytotoxic at concentrations even an order of magnitude lower than those found for free MMAE. This effect was FGFR-specific as cells lacking FGFR did not show any increased mortality.

Keywords: fibroblast growth factor 1, FGF receptor, targeted cancer therapy, cytotoxic conjugates, FGFR-dependent cancer, MMAE, auristatin

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