Development and Differentiation in Monobodies Based on the Fibronectin Type 3 Domain

As a non-antibody scaffold, monobodies based on the fibronectin type III (FN3) domain overcome antibody size and complexity while maintaining analogous binding loops. However, antibodies and their derivatives remain the gold standard for the design of new therapeutics. In response, clinical-stage th...

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Autores principales: Chandler, Peter G., Buckle, Ashley M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140400/
https://www.ncbi.nlm.nih.gov/pubmed/32143310
http://dx.doi.org/10.3390/cells9030610
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author Chandler, Peter G.
Buckle, Ashley M.
author_facet Chandler, Peter G.
Buckle, Ashley M.
author_sort Chandler, Peter G.
collection PubMed
description As a non-antibody scaffold, monobodies based on the fibronectin type III (FN3) domain overcome antibody size and complexity while maintaining analogous binding loops. However, antibodies and their derivatives remain the gold standard for the design of new therapeutics. In response, clinical-stage therapeutic proteins based on the FN3 domain are beginning to use native fibronectin function as a point of differentiation. The small and simple structure of monomeric monobodies confers increased tissue distribution and reduced half-life, whilst the absence of disulphide bonds improves stability in cytosolic environments. Where multi-specificity is challenging with an antibody format that is prone to mis-pairing between chains, multiple FN3 domains in the fibronectin assembly already interact with a large number of molecules. As such, multiple monobodies engineered for interaction with therapeutic targets are being combined in a similar beads-on-a-string assembly which improves both efficacy and pharmacokinetics. Furthermore, full length fibronectin is able to fold into multiple conformations as part of its natural function and a greater understanding of how mechanical forces allow for the transition between states will lead to advanced applications that truly differentiate the FN3 domain as a therapeutic scaffold.
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spelling pubmed-71404002020-04-13 Development and Differentiation in Monobodies Based on the Fibronectin Type 3 Domain Chandler, Peter G. Buckle, Ashley M. Cells Review As a non-antibody scaffold, monobodies based on the fibronectin type III (FN3) domain overcome antibody size and complexity while maintaining analogous binding loops. However, antibodies and their derivatives remain the gold standard for the design of new therapeutics. In response, clinical-stage therapeutic proteins based on the FN3 domain are beginning to use native fibronectin function as a point of differentiation. The small and simple structure of monomeric monobodies confers increased tissue distribution and reduced half-life, whilst the absence of disulphide bonds improves stability in cytosolic environments. Where multi-specificity is challenging with an antibody format that is prone to mis-pairing between chains, multiple FN3 domains in the fibronectin assembly already interact with a large number of molecules. As such, multiple monobodies engineered for interaction with therapeutic targets are being combined in a similar beads-on-a-string assembly which improves both efficacy and pharmacokinetics. Furthermore, full length fibronectin is able to fold into multiple conformations as part of its natural function and a greater understanding of how mechanical forces allow for the transition between states will lead to advanced applications that truly differentiate the FN3 domain as a therapeutic scaffold. MDPI 2020-03-04 /pmc/articles/PMC7140400/ /pubmed/32143310 http://dx.doi.org/10.3390/cells9030610 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Chandler, Peter G.
Buckle, Ashley M.
Development and Differentiation in Monobodies Based on the Fibronectin Type 3 Domain
title Development and Differentiation in Monobodies Based on the Fibronectin Type 3 Domain
title_full Development and Differentiation in Monobodies Based on the Fibronectin Type 3 Domain
title_fullStr Development and Differentiation in Monobodies Based on the Fibronectin Type 3 Domain
title_full_unstemmed Development and Differentiation in Monobodies Based on the Fibronectin Type 3 Domain
title_short Development and Differentiation in Monobodies Based on the Fibronectin Type 3 Domain
title_sort development and differentiation in monobodies based on the fibronectin type 3 domain
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140400/
https://www.ncbi.nlm.nih.gov/pubmed/32143310
http://dx.doi.org/10.3390/cells9030610
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