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Engineering novel binding proteins from nonimmunoglobulin domains

Abstract

Not all adaptive immune systems use the immunoglobulin fold as the basis for specific recognition molecules: sea lampreys, for example, have evolved an adaptive immune system that is based on leucine-rich repeat proteins. Additionally, many other proteins, not necessarily involved in adaptive immunity, mediate specific high-affinity interactions. Such alternatives to immunoglobulins represent attractive starting points for the design of novel binding molecules for research and clinical applications. Indeed, through progress and increased experience in library design and selection technologies, gained not least from working with synthetic antibody libraries, researchers have now exploited many of these novel scaffolds as tailor-made affinity reagents. Significant progress has been made not only in the basic science of generating specific binding molecules, but also in applications of the selected binders in laboratory procedures, proteomics, diagnostics and therapy. Challenges ahead include identifying applications where these novel proteins can not only be an alternative, but can enable approaches so far deemed technically impossible, and delineate those therapeutic applications commensurate with the molecular properties of the respective proteins.

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Figure 1: Binding-site engineering strategies used with different alternative scaffolds.
Figure 2: Structures of affinity-selected binding molecules interacting with their protein or small molecule targets.
Figure 3: The generation of diversity in nature and in the test tube.

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Acknowledgements

The authors would like to thank Patrik Forrer, Michael Stumpp and Christian Zahnd for useful comments and discussions.

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Correspondence to Andreas Plückthun.

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H.K.B. and P.A. are affiliated with the University of ZŸrich and Molecular Partners AG. A.P. is shareholder in Molecular Partners AG. Molecular Partners AG is developing designed repeat proteins as binding agents for research, diagnostics and therapy.

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Binz, H., Amstutz, P. & Plückthun, A. Engineering novel binding proteins from nonimmunoglobulin domains. Nat Biotechnol 23, 1257–1268 (2005). https://doi.org/10.1038/nbt1127

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