Peptibody Based on FGFR1-Binding Peptides From the FGF4 Sequence as a Cancer-Targeting Agent

Targeted therapies are a promising alternative to conventional chemotherapy, with an increasing number of therapeutics targeting specific molecular aberrancies in cancer cells. One of the emerging targets for directed cancer treatments is fibroblast growth factor receptors (FGFRs), which are known t...

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Autores principales:	Karolina Jendryczko, Jakub Rzeszotko, Mateusz Adam Krzyscik, Jakub Szymczyk, Jacek Otlewski, Anna Szlachcic
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	targeting peptides peptide Fc fusions peptibodies cytotoxic conjugates targeted therapies FGF4 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/916c9edb3c4d499ab88c5169dc5b691f
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spelling	oai:doaj.org-article:916c9edb3c4d499ab88c5169dc5b691f2021-11-12T05:33:34ZPeptibody Based on FGFR1-Binding Peptides From the FGF4 Sequence as a Cancer-Targeting Agent1663-981210.3389/fphar.2021.748936https://doaj.org/article/916c9edb3c4d499ab88c5169dc5b691f2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.748936/fullhttps://doaj.org/toc/1663-9812Targeted therapies are a promising alternative to conventional chemotherapy, with an increasing number of therapeutics targeting specific molecular aberrancies in cancer cells. One of the emerging targets for directed cancer treatments is fibroblast growth factor receptors (FGFRs), which are known to be involved in the pathogenesis and progression of multiple cancer types, specially in lung, bladder, and breast cancers. Here, we are demonstrating the development of the FGFR1-targeting agent based on the interactome screening approach, based on the isolation of binding regions from ligands interacting with the receptor. The parallel analysis by FGFR1 pull-down of chymotryptic peptides coupled with MS analysis, and PepSpot analysis yielded equivalent peptide sequences from FGF4, one of the FGFR1 ligands. Three sequences served as a basis for peptibody (Fc-fusion) generation, to overcome clinical limitations of peptidic agents, and two of them showed favorable FGFR1-binding in vitro and FGFR1-dependent internalization into cells. To validate if developed FGFR1-targeting peptibodies can be used for drug delivery, similar to the well-established concept of antibody–drug conjugates (ADCs), peptibodyF4_1 was successfully conjugated with monomethylauristatin E (MMAE), and has shown significant and specific toxicity toward FGFR1-expressing lung cancer cell lines, with nanomolar EC50 values. Essentially, the development of new effective FGFR1 binders that comprise the naturally occurring FGFR-recognition peptides and Fc region ensuring high plasma stability, and long bloodstream circulation is an interesting strategy expanding targeted anticancer agents’ portfolio. Furthermore, identifying peptides effectively binding the receptor from sequences of its ligands is not limited to FGFRs and is an approach versatile enough to be a basis for a new peptide/peptibodies development strategy.Karolina JendryczkoJakub RzeszotkoMateusz Adam KrzyscikJakub SzymczykJacek OtlewskiAnna SzlachcicFrontiers Media S.A.articletargeting peptidespeptide Fc fusionspeptibodiescytotoxic conjugatestargeted therapiesFGF4Therapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	targeting peptides peptide Fc fusions peptibodies cytotoxic conjugates targeted therapies FGF4 Therapeutics. Pharmacology RM1-950
spellingShingle	targeting peptides peptide Fc fusions peptibodies cytotoxic conjugates targeted therapies FGF4 Therapeutics. Pharmacology RM1-950 Karolina Jendryczko Jakub Rzeszotko Mateusz Adam Krzyscik Jakub Szymczyk Jacek Otlewski Anna Szlachcic Peptibody Based on FGFR1-Binding Peptides From the FGF4 Sequence as a Cancer-Targeting Agent
description	Targeted therapies are a promising alternative to conventional chemotherapy, with an increasing number of therapeutics targeting specific molecular aberrancies in cancer cells. One of the emerging targets for directed cancer treatments is fibroblast growth factor receptors (FGFRs), which are known to be involved in the pathogenesis and progression of multiple cancer types, specially in lung, bladder, and breast cancers. Here, we are demonstrating the development of the FGFR1-targeting agent based on the interactome screening approach, based on the isolation of binding regions from ligands interacting with the receptor. The parallel analysis by FGFR1 pull-down of chymotryptic peptides coupled with MS analysis, and PepSpot analysis yielded equivalent peptide sequences from FGF4, one of the FGFR1 ligands. Three sequences served as a basis for peptibody (Fc-fusion) generation, to overcome clinical limitations of peptidic agents, and two of them showed favorable FGFR1-binding in vitro and FGFR1-dependent internalization into cells. To validate if developed FGFR1-targeting peptibodies can be used for drug delivery, similar to the well-established concept of antibody–drug conjugates (ADCs), peptibodyF4_1 was successfully conjugated with monomethylauristatin E (MMAE), and has shown significant and specific toxicity toward FGFR1-expressing lung cancer cell lines, with nanomolar EC50 values. Essentially, the development of new effective FGFR1 binders that comprise the naturally occurring FGFR-recognition peptides and Fc region ensuring high plasma stability, and long bloodstream circulation is an interesting strategy expanding targeted anticancer agents’ portfolio. Furthermore, identifying peptides effectively binding the receptor from sequences of its ligands is not limited to FGFRs and is an approach versatile enough to be a basis for a new peptide/peptibodies development strategy.
format	article
author	Karolina Jendryczko Jakub Rzeszotko Mateusz Adam Krzyscik Jakub Szymczyk Jacek Otlewski Anna Szlachcic
author_facet	Karolina Jendryczko Jakub Rzeszotko Mateusz Adam Krzyscik Jakub Szymczyk Jacek Otlewski Anna Szlachcic
author_sort	Karolina Jendryczko
title	Peptibody Based on FGFR1-Binding Peptides From the FGF4 Sequence as a Cancer-Targeting Agent
title_short	Peptibody Based on FGFR1-Binding Peptides From the FGF4 Sequence as a Cancer-Targeting Agent
title_full	Peptibody Based on FGFR1-Binding Peptides From the FGF4 Sequence as a Cancer-Targeting Agent
title_fullStr	Peptibody Based on FGFR1-Binding Peptides From the FGF4 Sequence as a Cancer-Targeting Agent
title_full_unstemmed	Peptibody Based on FGFR1-Binding Peptides From the FGF4 Sequence as a Cancer-Targeting Agent
title_sort	peptibody based on fgfr1-binding peptides from the fgf4 sequence as a cancer-targeting agent
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/916c9edb3c4d499ab88c5169dc5b691f
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Peptibody Based on FGFR1-Binding Peptides From the FGF4 Sequence as a Cancer-Targeting Agent

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