MassIVE MSV000089542

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Repurposing E3 ubiquitin ligases as cell surface protein degraders using Proteolysis Targeting Antibodies

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Description

The majority of current therapeutics targeting plasma membrane receptors function by antagonizing ligand binding or enzymatic activities. Typical mammalian proteins, however, consist of multiple domains executing discrete but coordinated activities, and saturating inhibition of one functional domain often incompletely suppresses the totality of the protein's function. Recent work on targeted protein degradation technologies including Proteolysis Targeting Chimeras (PROTACs) has highlighted clinically important distinctions between target inhibition and target degradation. However, the generation of heterobifunctional compounds requiring linkage of two small molecules, each with high affinity for their targets, is highly complex, particularly with respect to achieving oral bioavailability. Here we describe the development of Proteolysis Targeting Antibodies (PROTABs) that tether cell-surface E3 ubiquitin ligases to transmembrane proteins, resulting in target ubiquitination and subsequent degradation. PROTAB-mediated degradation drives deeper pathway inhibition than inhibitory antibodies and is functional in vivo. The scope of this technology is also demonstrated through the identification of additional cell surface E3 ubiquitin ligases that can function as on demand degraders of various cell surface proteins. The generality of this approach enables tissue-selective degradation, as suggested by the Wnt-responsive ligases RNF43 and ZNRF3. Furthermore, through engineering of various optimized antibody formats, we offer insights on the ground rules governing optimal target degradation. Taken together, this work describes a strategy for the rapid development of potent, bioavailable and tissue selective degradation of cell surface proteins. [doi:10.25345/C5W669C8F] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: TMT ; Global proteome profiling ; ZNRF3 ; E3 ubiquitin ligases

Contact

Principal Investigators:
(in alphabetical order) 		Felipe de Sousa e Melo, Genentech, Inc., USA
Submitting User: mnchoi

Publications

Marei H, Tsai WK, Kee YS, Ruiz K, He J, Cox C, Sun T, Penikalapati S, Dwivedi P, Choi M, Kan D, Saenz-Lopez P, Dorighi K, Zhang P, Kschonsak YT, Kljavin N, Amin D, Kim I, Mancini AG, Nguyen T, Wang C, Janezic E, Doan A, Mai E, Xi H, Gu C, Heinlein M, Biehs B, Wu J, Lehoux I, Harris S, Comps-Agrar L, Seshasayee D, de Sauvage FJ, Grimmer M, Li J, Agard NJ, de Sousa E Melo F.
Antibody targeting of E3 ubiquitin ligases for receptor degradation.
Nature. 2022 Oct;610(7930):182-189. Epub 2022 Sep 21.

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