Preprint Review Version 1 Preserved in Portico This version is not peer-reviewed

The DARPin Encyclopedia: from Basic Research Towards Therapeutics

Version 1 : Received: 2 June 2022 / Approved: 10 June 2022 / Online: 10 June 2022 (04:20:57 CEST)
Version 2 : Received: 14 June 2022 / Approved: 15 June 2022 / Online: 15 June 2022 (02:54:19 CEST)
Version 3 : Received: 21 June 2022 / Approved: 21 June 2022 / Online: 21 June 2022 (10:21:27 CEST)

How to cite: Wild, P.; Eapen, R.; Forrer, P.; Jost, C. The DARPin Encyclopedia: from Basic Research Towards Therapeutics. Preprints 2022, 2022060147. Wild, P.; Eapen, R.; Forrer, P.; Jost, C. The DARPin Encyclopedia: from Basic Research Towards Therapeutics. Preprints 2022, 2022060147.


The adaptive immune system in vertebrates comes in two flavors. Historically, adaptive immunity focused on the study of immunoglobulins (also referred to as Ig-based antibodies herein); more recently, jawless vertebrates were found to use an entirely different class of proteins for their adaptive immunesystem. Specifically, these organisms express variable lymphocyte receptors (so called VLR antibodies) that create diversity based on the rearrangement of leucine-rich repeats. Meanwhile, various, naturally occurring repeat motifs have been used as building blocks for the design of artificial binding scaffolds which, among others, include designed ankyrin repeat proteins (DARPins). Such binding scaffolds are also referred to as non-Ig-based antibodies or non-Ig scaffolds herein). DARPins display several benefits such as a low molecular weight (~15 kDa), high thermal stability, high specificity and affinity, versatility (e.g., in terms of valency and multi-specificity), speedy preclinical development, low production costs and, thus, bear the potential to not only complement existing therapeutic Ig-based antibodies but also open up novel therapeutic strategies. The first generation DARPin therapeutic abicipar pegol has completed two Phase III studies in 2020 while several other DARPin drug candidates are currently undergoing clinical validation. Most recently, the rapid development of tri-specific SARSCoV-2 DARPin therapeutics showcases the immense potential of recombinant repeat proteins in adopting quickly e.g., new forms of target neutralization that a single Ig-based antibody cannot afford. Here, we highlight the design principles of repeat proteins in general and summarize in detail the continuous advancements of the DARPin scaffold that made it one of the most promising antibody mimetics to date. This review provides an overview of current and emerging applications of DARPins as both a research tool and therapeutic drug that can match or even surpass Ig-based antibody applications.


Designed Ankyrin Repeat protein; DARPin; drug development; ensovibep; abicipar pegol


Biology and Life Sciences, Biochemistry and Molecular Biology

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