Preprint Review Version 1 Preserved in Portico This version is not peer-reviewed

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

Version 1 : Received: 18 January 2020 / Approved: 19 January 2020 / Online: 19 January 2020 (03:25:24 CET)

A peer-reviewed article of this Preprint also exists.

Chandler, P.G.; Buckle, A.M. Development and Differentiation in Monobodies Based on the Fibronectin Type 3 Domain. Cells 2020, 9, 610. Chandler, P.G.; Buckle, A.M. Development and Differentiation in Monobodies Based on the Fibronectin Type 3 Domain. Cells 2020, 9, 610.

Journal reference: Cells 2020, 9, 610
DOI: 10.3390/cells9030610

Abstract

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 design of new therapeutics. In response, clinical 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 of chains, 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.

Subject Areas

adnectin; biosensor; Fibronectin; monobody; non-antibody scaffold; therapeutic

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