Development of Antibody-Based PROTACs for the Degradation of the Cell-Surface Immune Checkpoint Protein PD-L1

Overview

Journal J Am Chem Soc

Publisher American Chemical Society

Specialty Chemistry

Date 2021 Jan 4

PMID 33395526

Citations 136

Authors

Adam D Cotton

Duy P Nguyen

Josef A Gramespacher

Ian B Seiple

James A Wells

Affiliations

Soon will be listed here.

Abstract

Targeted protein degradation has emerged as a new paradigm to manipulate cellular proteostasis. Proteolysis-targeting chimeras (PROTACs) are bifunctional small molecules that recruit an E3 ligase to a target protein of interest, promoting its ubiquitination and subsequent degradation. Here, we report the development of antibody-based PROTACs (AbTACs), fully recombinant bispecific antibodies that recruit membrane-bound E3 ligases for the degradation of cell-surface proteins. We show that an AbTAC can induce the lysosomal degradation of programmed death-ligand 1 by recruitment of the membrane-bound E3 ligase RNF43. AbTACs represent a new archetype within the PROTAC field to target cell-surface proteins with fully recombinant biological molecules.

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References

Luca V, Miao Y, Li X, Hollander M, Kuo C, Garcia K . Surrogate R-spondins for tissue-specific potentiation of Wnt Signaling. PLoS One. 2020; 15(1):e0226928. PMC: 6949110. DOI: 10.1371/journal.pone.0226928. View

Burslem G, Smith B, Lai A, Jaime-Figueroa S, McQuaid D, Bondeson D . The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study. Cell Chem Biol. 2017; 25(1):67-77.e3. PMC: 5831399. DOI: 10.1016/j.chembiol.2017.09.009. View

Ward C, Kleinman J, Brittain S, Lee P, Chung C, Kim K . Covalent Ligand Screening Uncovers a RNF4 E3 Ligase Recruiter for Targeted Protein Degradation Applications. ACS Chem Biol. 2019; 14(11):2430-2440. PMC: 7422721. DOI: 10.1021/acschembio.8b01083. View

Freeman G, Long A, Iwai Y, Bourque K, Chernova T, Nishimura H . Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000; 192(7):1027-34. PMC: 2193311. DOI: 10.1084/jem.192.7.1027. View

Spradlin J, Hu X, Ward C, Brittain S, Jones M, Ou L . Harnessing the anti-cancer natural product nimbolide for targeted protein degradation. Nat Chem Biol. 2019; 15(7):747-755. PMC: 6592714. DOI: 10.1038/s41589-019-0304-8. View

Lowman H, Bass S, Simpson N, Wells J . Selecting high-affinity binding proteins by monovalent phage display. Biochemistry. 1991; 30(45):10832-8. DOI: 10.1021/bi00109a004. View

Tsukiyama T, Fukui A, Terai S, Fujioka Y, Shinada K, Takahashi H . Molecular Role of RNF43 in Canonical and Noncanonical Wnt Signaling. Mol Cell Biol. 2015; 35(11):2007-23. PMC: 4420922. DOI: 10.1128/MCB.00159-15. View

Li C, Lim S, Xia W, Lee H, Chan L, Kuo C . Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity. Nat Commun. 2016; 7:12632. PMC: 5013604. DOI: 10.1038/ncomms12632. View

Banik S, Pedram K, Wisnovsky S, Ahn G, Riley N, Bertozzi C . Lysosome-targeting chimaeras for degradation of extracellular proteins. Nature. 2020; 584(7820):291-297. PMC: 7727926. DOI: 10.1038/s41586-020-2545-9. View

10.

Hall M, Unch J, Binkowski B, Valley M, Butler B, Wood M . Engineered luciferase reporter from a deep sea shrimp utilizing a novel imidazopyrazinone substrate. ACS Chem Biol. 2012; 7(11):1848-57. PMC: 3501149. DOI: 10.1021/cb3002478. View

11.

Li C, Lim S, Chung E, Kim Y, Park A, Yao J . Eradication of Triple-Negative Breast Cancer Cells by Targeting Glycosylated PD-L1. Cancer Cell. 2018; 33(2):187-201.e10. PMC: 5824730. DOI: 10.1016/j.ccell.2018.01.009. View

12.

Koo B, Spit M, Jordens I, Low T, Stange D, van de Wetering M . Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature. 2012; 488(7413):665-9. DOI: 10.1038/nature11308. View

13.

Rodriguez-Gonzalez A, Cyrus K, Salcius M, Kim K, Crews C, Deshaies R . Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer. Oncogene. 2008; 27(57):7201-11. PMC: 5573236. DOI: 10.1038/onc.2008.320. View

14.

Zhang F, Qi X, Wang X, Wei D, Wu J, Feng L . Structural basis of the therapeutic anti-PD-L1 antibody atezolizumab. Oncotarget. 2017; 8(52):90215-90224. PMC: 5685743. DOI: 10.18632/oncotarget.21652. View

15.

Zebisch M, Xu Y, Krastev C, MacDonald B, Chen M, Gilbert R . Structural and molecular basis of ZNRF3/RNF43 transmembrane ubiquitin ligase inhibition by the Wnt agonist R-spondin. Nat Commun. 2013; 4:2787. PMC: 3905715. DOI: 10.1038/ncomms3787. View

16.

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View

17.

Hornsby M, Paduch M, Miersch S, Saaf A, Matsuguchi T, Lee B . A High Through-put Platform for Recombinant Antibodies to Folded Proteins. Mol Cell Proteomics. 2015; 14(10):2833-47. PMC: 4597156. DOI: 10.1074/mcp.O115.052209. View

18.

Koerber J, Hornsby M, Wells J . An improved single-chain Fab platform for efficient display and recombinant expression. J Mol Biol. 2014; 427(2):576-86. PMC: 4297586. DOI: 10.1016/j.jmb.2014.11.017. View

19.

Ahn G, Banik S, Miller C, Riley N, Cochran J, Bertozzi C . LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation. Nat Chem Biol. 2021; 17(9):937-946. PMC: 8387313. DOI: 10.1038/s41589-021-00770-1. View

20.

Clift D, McEwan W, Labzin L, Konieczny V, Mogessie B, James L . A Method for the Acute and Rapid Degradation of Endogenous Proteins. Cell. 2017; 171(7):1692-1706.e18. PMC: 5733393. DOI: 10.1016/j.cell.2017.10.033. View