Antibody Conjugation of a Chimeric BET Degrader Enables in vivo Activity
Abstract
The ability to selectively degrade proteins with bifunctional small molecules has the potential to fundamentally alter therapy in a variety of diseases. However, the relatively large size of these chimeric molecules often results in challenging physico‐chemical properties (e. g., low aqueous solubility) and poor pharmacokinetics which may complicate their in vivo applications. We recently discovered an exquisitely potent chimeric BET degrader (GNE‐987) which exhibited picomolar cell potencies but also demonstrated low in vivo exposures. In an effort to improve the pharmacokinetic properties of this molecule, we discovered the first degrader‐antibody conjugate by attaching GNE‐987 to an anti‐CLL1 antibody via a novel linker. A single IV dose of the conjugate afforded sustained in vivo exposures that resulted in antigen‐specific tumor regressions. Enhancement of a chimeric protein degrader with poor in vivo properties through antibody conjugation thereby expands the utility of directed protein degradation as both a biological tool and a therapeutic possibility.
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Dragovic et al. successfully demonstrated tumour-specific targeting in two different cancer types with antibody-drug conjugates involving VHL-BRD4 PROTACs.
“Dragovic et al.160–162 at Genentech have pushed this modality forward and successfully demonstrated tumour-specific targeting in two different cancer types with ADCs involving VHL–BRD4 PROTACs.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [160]
Antibody-PROTAC conjugates can selectively degrade proteins of interest in targeted cells or tissues.
“These Ab-PROTACs can selectively degrade POIs in targeted cells/tissues [38–40].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [39]
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A beginner’s guide to current synthetic linker strategies towards VHL-recruiting PROTACs
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Novel approaches to targeted protein degradation technologies in drug discovery
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Expanding the horizons of targeted protein degradation: A non-small molecule perspective
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Self-citationNon-small molecule PROTACs (NSM-PROTACs): Protein degradation kaleidoscope
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Discovery and Optimization of a STING Agonist Platform for Application in Antibody Drug Conjugates
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Antibody–drug conjugates: prospects for the next generation
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Enriching Proteolysis Targeting Chimeras with a Second Modality: When Two Are Better Than One
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The cyclimids: Degron-inspired cereblon binders for targeted protein degradation
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Site-Specific Antibody Conjugation with Payloads beyond Cytotoxins
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Antibody-drug conjugates for targeted cancer therapy: Recent advances in potential payloads
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Self-citationHomobivalent, Trivalent, and Covalent PROTACs: Emerging Strategies for Protein Degradation
Yan, J., Li, T., Miao, Z., Wang, P., Sheng, C., & Zhuang, C. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00728 · Cited by 44 · see citing works
Ligation to Scavenging Strategy Enables On-Demand Termination of Targeted Protein Degradation
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New Technologies Bloom Together for Bettering Cancer Drug Conjugates
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Folate‐PEG‐PROTAC Micelles for Enhancing Tumor‐Specific Targeting Proteolysis In Vivo
Ma, J., Fang, L., Sun, Z., Li, M., Fan, T., Xiang, G., & Ma, X. (2024) · Advanced Healthcare Materials · doi:10.1002/adhm.202400109 · Cited by 41 · see citing works
Native Mass Spectrometry for the Study of PROTAC GNE‐987‐Containing Ternary Complexes
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PROTACs in Epigenetic Cancer Therapy: Current Status and Future Opportunities
Liu, X., Wang, A., Shi, Y., Dai, M., Liu, M., & Cai, H. (2023) · Molecules · doi:10.3390/molecules28031217 · Cited by 38 · see citing works
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Light-Controllable PROTACs for Temporospatial Control of Protein Degradation
Liu, J., Peng, Y., & Wei, W. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.678077 · Cited by 38 · see citing works
Targeting BET Bromodomains in Cancer
Trojer, P. (2022) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-070120-103531 · Cited by 36 · see citing works
PROTACs: Current Trends in Protein Degradation by Proteolysis-Targeting Chimeras
Madan, J., Ahuja, V. K., Dua, K., Samajdar, S., Ramchandra, M., & Giri, S. (2022) · BioDrugs · doi:10.1007/s40259-022-00551-9 · Cited by 36 · see citing works
Targeting the tumour cell surface in advanced prostate cancer
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A comprehensive review of BET-targeting PROTACs for cancer therapy
Zhou, X., Zhao, F., Xu, Y.-T., Guan, Y., Yu, T., Zhang, Y., Duan, Y., & Zhao, Y. (2022) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2022.117033 · Cited by 35 · see citing works
What influences the activity of Degrader−Antibody conjugates (DACs)
Guo, Y., Li, X., Xie, Y., & Wang, D. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.116216 · Cited by 35 · see citing works
A novel ROR1-targeting antibody-PROTAC conjugate promotes BRD4 degradation for solid tumor treatment
Wang, L., Ke, Y., He, Q., Paerhati, P., Zhuang, W., Yue, Y., Liu, J., Zhang, J., Huang, L., Yin, Q., et al. (2024) · Theranostics · doi:10.7150/thno.102531 · Cited by 34 · see citing works
Targeted Protein Degradation: Clinical Advances in the Field of Oncology
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Biologics-based degraders — an expanding toolkit for targeted-protein degradation
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Antibody-drug conjugates in cancer therapy: innovations, challenges, and future directions
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T herapeutic targeting of chromatin: status and opportunities
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PROTAC-biomacromolecule conjugates for precise protein degradation in cancer therapy: A review
Wang, C., Zhang, Y., Yu, W., Xu, J., & Xing, D. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.129864 · Cited by 28 · see citing works
BRD4 inhibitor GNE987 exerts anti-cancer effects by targeting super-enhancers in neuroblastoma
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Central Nervous System Targeted Protein Degraders
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Tissue distribution and retention drives efficacy of rapidly clearing VHL-based PROTACs
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Self-citationA self-assembled affibody-PROTAC conjugate nanomedicine for targeted cancer therapy
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PROTAC delivery in tumor immunotherapy: Where are we and where are we going?
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Conditional PROTAC: Recent Strategies for Modulating Targeted Protein Degradation
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Estimating the cooperativity of PROTAC-induced ternary complexes using 19 F NMR displacement assay
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Proteolysis-Targeting Chimera (PROTAC): Is the Technology Looking at the Treatment of Brain Tumors?
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Recent Advances in Optically Controlled PROTAC
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- Authors
- Pillow, T. H., Adhikari, P., Blake, R. A., Chen, J., Del Rosario, G., Deshmukh, G., Figueroa, I., Gascoigne, K. E., Kamath, A. V., Kaufman, S., Kleinheinz, T., Kozak, K. R., Latifi, B., Leipold, D. D., Sing Li, C., Li, R., Mulvihill, M. M., O'Donohue, A., Rowntree, R. K., Sadowsky, J. D., Wai, J., Wang, X., Wu, C., Xu, Z., Yao, H., Yu, S., Zhang, D., Zang, R., Zhang, H., Zhou, H., Zhu, X., & Dragovich, P. S.
- Affiliations
- Genentech (US)
- WuXi AppTec (China) (CN)
- Genentech Inc. 1 DNA Way South San Francisco CA 94080 USA
- Wuxi Apptec 288 Fute Zhong Road Waigaoqiao Free Trade Zone Shanghai 200131 China
- Corresponding author
- Dragovich, Peter S.
- ORCID
- Pillow, Thomas H.
- Adhikari, Pragya
- Chen, Jinhua
- Deshmukh, Gauri
- Figueroa, Isabel
- Gascoigne, Karen E.
- Kozak, Katherine R.
- Latifi, Brandon
- Leipold, Douglas D.
- Li, Ruina
- Mulvihill, Melinda M.
- Rowntree, Rebecca K.
- Sadowsky, Jack D.
- Wang, Xinxin
- Wu, Cong
- Xu, Zijin
- Yao, Hui
- Yu, Shang‐Fan
- Zhang, Donglu
- Zang, Richard
- Zhang, Hongyan
- Zhou, Hao
- Zhu, Xiaoyu
- Dragovich, Peter S.
- Venue
- ChemMedChem
- Publisher
- Wiley
- Published
- 2019-11-14
- Volume
- 15
- Issue
- 1
- Pages
- 17-25
- ISSN
- 1860-7179 (ISSN-L)
- 1860-7187
- OpenAlex
- W2987291349
- Cited by
- 216
- References
- 43
- Citations by year
- 2026: 39 · 2025: 36 · 2024: 41 · 2023: 36 · 2022: 34 · 2021: 15 · 2020: 14 · 2019: 1
- FWCI
- 5.29
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- ChemMedChem (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Keywords
- antibody conjugation, pharmacokinetics, water solubility, linker design, in vivo exposure, targeted protein degradation, tumor regression
- MeSH terms
- Bromodomain Containing Proteins, Animals, Antibodies, Monoclonal, Cell Survival, Drug Carriers, Female, Half-Life, Heterocyclic Compounds, 4 or More Rings, Humans, Protein Binding, Receptors, Mitogen, Transcription Factors, Leukemia, Myeloid, Acute, Proto-Oncogene Proteins c-myc, Mice, SCID, Immunoconjugates, Cell Cycle Proteins, Surface Plasmon Resonance, Xenograft Model Antitumor Assays, Lectins, C-Type, Cell Line, Tumor, Mice, Von Hippel-Lindau Tumor Suppressor Protein, Proteolysis
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