Development of Antibody-Based PROTACs for the Degradation of the Cell-Surface Immune Checkpoint Protein PD-L1
Open accessAbstract
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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In MDA-MB-231 cells, AC-1 induced the degradation of PDL1 via an RNF43- and lysosomal-dependent mechanism.
“In MDA-MB-231 cells, AC-1 induced the degradation of PDL1 via an RNF43- and lysosomal-dependent mechanism.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [251]
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Tissue-based map of the human proteome
Uhlén, M., Fagerberg, L., Hallström, B. M., Lindskog, C., Oksvold, P., Mardinoglu, A., Sivertsson, Å., Kampf, C., Sjöstedt, E., Asplund, A., et al. (2015) · Science · doi:10.1126/science.1260419 · Cited by 15,286 · see citing works
Freeman, G. J., Long, A. J., Iwai, Y., Bourque, K., Chernova, T., Nishimura, H., Fitz, L. J., Malenkovich, N., Okazaki, T., Byrne, M. C., et al. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.7.1027 · Cited by 5,294 · see citing works
Sakamoto, K. M., Kim, K. B., Kumagai, A., Mercurio, F., Crews, C. M., & Deshaies, R. J. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.141230798 · Cited by 2,609 · see citing works
Engineered Luciferase Reporter from a Deep Sea Shrimp Utilizing a Novel Imidazopyrazinone Substrate
Hall, M. P., Unch, J., Binkowski, B. F., Valley, M. P., Butler, B. L., Wood, M. G., Otto, P., Zimmerman, K., Vidugiris, G. J. A., Machleidt, T., et al. (2012) · ACS Chemical Biology · doi:10.1021/cb3002478 · Cited by 1,588 · see citing works
Catalytic in vivo protein knockdown by small-molecule PROTACs
Bondeson, D. P., Mares, A., Smith, I. E. D., Ko, E., Campos, S., Miah, A. H., Mulholland, K. E., Routly, N., Buckley, D. L., Gustafson, J. L., et al. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1858 · Cited by 1,356 · see citing works
Lysosome-targeting chimaeras for degradation of extracellular proteins
Banik, S. M., Pedram, K., Wisnovsky, S., Ahn, G., Riley, N. M., & Bertozzi, C. R. (2020) · Nature · doi:10.1038/s41586-020-2545-9 · Cited by 1,199 · see citing works
Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4
Lu, J., Qian, Y., Altieri, M., Dong, H., Wang, J., Raina, K., Hines, J., Winkler, J. D., Crew, A. P., Coleman, K., et al. (2015) · Chemistry & Biology · doi:10.1016/j.chembiol.2015.05.009 · Cited by 1,140 · see citing works
The dTAG system for immediate and target-specific protein degradation
Nabet, B., Roberts, J. M., Buckley, D. L., Paulk, J., Dastjerdi, S., Yang, A., Leggett, A. L., Erb, M. A., Lawlor, M. A., Souza, A., et al. (2018) · Nature Chemical Biology · doi:10.1038/s41589-018-0021-8 · Cited by 1,118 · see citing works
Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity
Li, C., Lim, S., Xia, W., Lee, H., Chan, L.-C., Kuo, C., Khoo, K., Chang, S.-S., Cha, J., Kim, T., et al. (2016) · Nature Communications · doi:10.1038/ncomms12632 · Cited by 1,100 · see citing works
Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors
Koo, B., Spit, M., Jordens, I., Low, T. Y., Stange, D. E., van de Wetering, M., van Es, J. H., Mohammed, S., Heck, A. J. R., Maurice, M. M., et al. (2012) · Nature · doi:10.1038/nature11308 · Cited by 991 · see citing works
Antibody Pharmacokinetics and Pharmacodynamics
Lobo, E. D., Hansen, R. J., & Balthasar, J. P. (2004) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.20178 · Cited by 909 · see citing works
‘Knobs-into-holes’ engineering of antibody C H 3 domains for heavy chain heterodimerization
Ridgway, J. B., Presta, L. G., & Carter, P. M. (1996) · Protein Engineering Design and Selection · doi:10.1093/protein/9.7.617 · Cited by 816 · see citing works
The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study
Burslem, G. M., Smith, B. E., Lai, A. C., Jaime-Figueroa, S., McQuaid, D. C., Bondeson, D. P., Toure, M., Dong, H., Qian, Y., Wang, J., et al. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.09.009 · Cited by 686 · see citing works
LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation
Ahn, G., Banik, S. M., Miller, C. L., Riley, N. M., Cochran, J. R., & Bertozzi, C. R. (2021) · Nature Chemical Biology · doi:10.1038/s41589-021-00770-1 · Cited by 654 · see citing works
Eradication of Triple-Negative Breast Cancer Cells by Targeting Glycosylated PD-L1
Li, C., Lim, S., Chung, E. M., Kim, Y., Park, A. H., Yao, J., Cha, J., Xia, W., Chan, L.-C., Kim, T., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.01.009 · Cited by 611 · see citing works
A Method for the Acute and Rapid Degradation of Endogenous Proteins
Clift, D., McEwan, W. A., Labzin, L. I., Konieczny, V., Mogessie, B., James, L. C., & Schuh, M. (2017) · Cell · doi:10.1016/j.cell.2017.10.033 · Cited by 531 · see citing works
Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16
Zhang, X., Crowley, V. M., Wucherpfennig, T. G., Dix, M. M., & Cravatt, B. F. (2019) · Nature Chemical Biology · doi:10.1038/s41589-019-0279-5 · Cited by 487 · see citing works
RNF43 is frequently mutated in colorectal and endometrial cancers
Giannakis, M., Hodis, E., Mu, X. J., Yamauchi, M., Rosenbluh, J., Cibulskis, K., Saksena, G., Lawrence, M. S., Qian, Z. R., Nishihara, R., et al. (2014) · Nature Genetics · doi:10.1038/ng.3127 · Cited by 470 · see citing works
Dual targeting strategies with bispecific antibodies
Kontermann, R. E. (2012) · mAbs · doi:10.4161/mabs.4.2.19000 · Cited by 438 · see citing works
Harnessing the anti-cancer natural product nimbolide for targeted protein degradation
Spradlin, J. N., Hu, X., Ward, C. C., Brittain, S. M., Jones, M. D., Ou, L., To, M., Proudfoot, A., Ornelas, E., Woldegiorgis, M., et al. (2019) · Nature Chemical Biology · doi:10.1038/s41589-019-0304-8 · Cited by 432 · see citing works
Salami, J., Alabi, S., Willard, R. R., Vitale, N. J., Wang, J., Dong, H., Jin, M., McDonnell, D. P., Crew, A. P., Neklesa, T. K., et al. (2018) · Communications Biology · doi:10.1038/s42003-018-0105-8 · Cited by 349 · see citing works
Ward, C. C., Kleinman, J. I., Brittain, S. M., Lee, P. S., Chung, C. Y. S., Kim, K., Petri, Y., Thomas, J. R., Tallarico, J. A., McKenna, J. M., et al. (2019) · ACS Chemical Biology · doi:10.1021/acschembio.8b01083 · Cited by 336 · see citing works
Selecting high-affinity binding proteins by monovalent phage display
Lowman, H. B., Bass, S., Simpson, N., & Wells, J. A. (1991) · Biochemistry · doi:10.1021/bi00109a004 · Cited by 312 · see citing works
Self-citationLu, M., Liu, T., Jiao, Q., Ji, J., Tao, M., Liu, Y., You, Q., & Jiang, Z. (2018) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.01.063 · Cited by 310 · see citing works
Quantitative Live-Cell Kinetic Degradation and Mechanistic Profiling of PROTAC Mode of Action
Riching, K. M., Mahan, S. D., Corona, C. R., McDougall, M. G., Vasta, J. D., Robers, M. B., Urh, M., & Daniels, D. L. (2018) · ACS Chemical Biology · doi:10.1021/acschembio.8b00692 · Cited by 307 · see citing works
The intracellular signalosome of PD-L1 in cancer cells
Escors, D., Gato, M., Zuazo, M., Arasanz, H., García-Granda, M. J., Vera, R., & Kochan, G. T. (2018) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-018-0022-9 · Cited by 299 · see citing works
Zebisch, M., Xu, Y., Krastev, C., MacDonald, B. T., Chen, M., Gilbert, R. J. C., He, X., & Jones, E. Y. (2013) · Nature Communications · doi:10.1038/ncomms3787 · Cited by 220 · see citing works
Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer
Rodrı́guez-González, A., Cyrus, K., Salcius, M., Kim, K., Crews, C. M., Deshaies, R. J., & Sakamoto, K. M. (2008) · Oncogene · doi:10.1038/onc.2008.320 · Cited by 211 · see citing works
SNIPERs—Hijacking IAP activity to induce protein degradation
Naito, M., Ohoka, N., & Shibata, N. (2019) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2018.12.002 · Cited by 167 · see citing works
An Overview on GPCRs and Drug Discovery: Structure-Based Drug Design and Structural Biology on GPCRs
Lundstrom, K. (2009) · Methods in Molecular Biology · doi:10.1007/978-1-60327-317-6_4 · Cited by 137 · see citing works
A High Through-put Platform for Recombinant Antibodies to Folded Proteins
Hornsby, M. J., Paduch, M., Miersch, S., Sääf, A. M., Matsuguchi, T., Lee, B. H., Wypisniak, K., Doak, A. K., King, D., Usatyuk, S., et al. (2015) · Molecular & Cellular Proteomics · doi:10.1074/mcp.o115.052209 · Cited by 106 · see citing works
Self-citationMolecular Role of RNF43 in Canonical and Noncanonical Wnt Signaling
Tsukiyama, T., Fukui, A., Terai, S., Fujioka, Y., Shinada, K., Takahashi, H., Yamaguchi, T. P., Ohba, Y., & Hatakeyama, S. (2015) · Molecular and Cellular Biology · doi:10.1128/mcb.00159-15 · Cited by 101 · see citing works
Structural basis of the therapeutic anti-PD-L1 antibody atezolizumab
Zhang, F., Qi, X., Wang, X., Wei, D., Wu, J., Feng, L., Cai, H., Wang, Y., Zeng, N., Xu, T., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.21652 · Cited by 82 · see citing works
An Improved Single-Chain Fab Platform for Efficient Display and Recombinant Expression
Koerber, J. T., Hornsby, M. J., & Wells, J. A. (2014) · Journal of Molecular Biology · doi:10.1016/j.jmb.2014.11.017 · Cited by 53 · see citing works
Self-citationSurrogate R-spondins for tissue-specific potentiation of Wnt Signaling
Luca, V. C., Miao, Y., Li, X., Hollander, M. J., Kuo, C. J., & García, K. C. (2020) · PLoS ONE · doi:10.1371/journal.pone.0226928 · Cited by 24 · see citing works
Ovacik, A. M., Li, J., Lemper, M., Danilenko, D. M., Stagg, N. J., Mathieu, M. A., Ellerman, D. A., Gupta, V., Kalia, N., Nguy, T., et al. (2018) · mAbs · doi:10.1080/19420862.2018.1551676 · Cited by 16 · see citing works
Ahn, G., Banik, S. M., Miller, C. L., et al. (2020) · ChemRxiv · doi:10.26434/chemrxiv.12736778.v1 · Cited by 13 · see citing works
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Marei, H., Tsai, W.-T. K., Kee, Y.-S., Ruiz, K., He, J., Cox, C., Sun, T., Penikalapati, S., Dwivedi, P., Choi, M., et al. (2022) · Nature · doi:10.1038/s41586-022-05235-6 · Cited by 273 · see citing works
Pance, K., Gramespacher, J. A., Byrnes, J. R., Salangsang, F., Serrano, J.-A. C., Cotton, A. D., Steri, V., & Wells, J. A. (2023) · Nature Biotechnology · doi:10.1038/s41587-022-01456-2 · Cited by 265 · see citing works
Self-citationBifunctional small molecules that mediate the degradation of extracellular proteins
Caianiello, D. F., Zhang, M., Ray, J. D., Howell, R. A., Swartzel, J. C., Branham, E. M. J., Chirkin, E., Sabbasani, V. R., Gong, A. Z., McDonald, D. M., et al. (2021) · Nature Chemical Biology · doi:10.1038/s41589-021-00851-1 · Cited by 244 · see citing works
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- Authors
- Cotton, A. D., Nguyen, D. P., Gramespacher, J. A., Seiple, I. B., & Wells, J. A.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Wells, James A.
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2021-01-04
- Volume
- 143
- Issue
- 2
- Pages
- 593-598
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- PMC
- PMC8154509
- OpenAlex
- W3120553915
- Cited by
- 551
- References
- 37
- Citations by year
- 2026: 118 · 2025: 119 · 2024: 122 · 2023: 103 · 2022: 63 · 2021: 24 · 2020: 1 · 2014: 1
- FWCI
- 24.72
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of the American Chemical Society (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- National Cancer Institute (P41CA196276)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- PROTACs, PD-L1, targeted protein degradation, RNF43, lysosomal degradation, cell surface proteins, bispecific antibodies, immune checkpoint molecules, ubiquitination
- MeSH terms
- Antibodies, Humans, Proteolysis, B7-H1 Antigen
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