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5. The trispecific DARPin ensovibep inhibits diverse SARS-CoV-2 variants

Author

Rothenberger, Sylvia, Hurdiss, Daniel L., Walser, Marcel, Malvezzi, Francesca, Mayor, Jennifer, Ryter, Sarah, Moreno, Hector, Liechti, Nicole, Bosshart, Andreas, Iss, Chloé, Calabro, Valérie, Cornelius, Andreas, Hospodarsch, Tanja, Neculcea, Alexandra, Looser, Thamar, Schlegel, Anja, Fontaine, Simon, Villemagne, Denis, Paladino, Maria, Schiegg, Dieter, Mangold, Susanne, Reichen, Christian, Radom, Filip, Kaufmann, Yvonne, Schaible, Doris, Schlegel, Iris, Zitt, Christof, Sigrist, Gabriel, Straumann, Marcel, Wolter, Julia, Comby, Marco, Sacarcelik, Feyza, Drulyte, Ieva, Lyoo, Heyrhyoung, Wang, Chunyan, Li, Wentao, Du, Wenjuan, Binz, H. Kaspar, Herrup, Rachel, Lusvarghi, Sabrina, Neerukonda, Sabari Nath, Vassell, Russell, Wang, Wei, Adler, Julia M., Eschke, Kathrin, Nascimento, Mariana, Abdelgawad, Azza, Gruber, Achim D., Bushe, Judith, Kershaw, Olivia, Knutson, Charles G., Balavenkatraman, Kamal K., Ramanathan, Krishnan, Wyler, Emanuel, Teixeira Alves, Luiz Gustavo, Lewis, Seth, Watson, Randall, Haeuptle, Micha A., Zürcher, Alexander, Dawson, Keith M., Steiner, Daniel, Weiss, Carol D., Amstutz, Patrick, van Kuppeveld, Frank J. M., Stumpp, Michael T., Bosch, Berend-Jan, Engler, Olivier, and Trimpert, Jakob

Published
2022
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6. Structural and functional studies of polyketide synthases

Author

Drulyte, Ieva and Berry, Alan

Subjects
570
Abstract

Polyketides, natural products produced by multi-domain polyketide synthases (PKSs), have proven to be excellent starting points for drug discovery. Rational engineering of PKSs holds much promise for the generation of novel polyketide pharmaceuticals, however to enable this we need to gain a better understanding of how the mature polyketides are generated and how individual modules within a polyketide synthase assemble and interact. Here, work was performed to investigate three polypeptides from natural product indanomycin and rhizoxin biosynthesis, including the candidate polyketide cyclase IdmH, the fourth subunit of the indanomycin megasynthase, IdmO, and the branching module from the rhizoxin PKS. Indanomycin needs to undergo several transformations by post-PKS tailoring enzymes. One such enzyme, IdmH, has been hypothesised to act as a cyclase and catalyse the formation of the indane ring via a Diels-Alder reaction. Crystal structure of the wild-type IdmH was determined to 2.7 Å resolution and the interactions between IdmH and its proposed product indanomycin were characterised using NMR spectroscopy and in silico methods. Fully-reducing IdmO module was successfully expressed and purified. Characterisation by negative-stain electron microscopy resulted in a low-resolution model of IdmO, while attempts to carry out cryo-electron microscopy (cryo-EM) analysis revealed a number of difficulties associated with the denaturation of this large complex during cryo-EM grid preparation. A similar cryo-EM approach was utilised to study the branching module from the rhizoxin PKS. A 3.7 Å resolution map was determined for this module containing the ketosynthase, branching and acyl carrier protein (ACP) domains. Two ACP binding sites were identified, which can help explain the unorthodox activity of this module. This research has provided valuable insights into different aspects of PKS biology ranging from polyketide tailoring and branching to the assembly of the intact modules and forms a solid basis for future studies of these fascinating biosynthetic machines.

Published
2018

8. Neutralizing Antibodies Reveal Cryptic Vulnerabilities and Interdomain Crosstalk in the Porcine Deltacoronavirus Spike

Author

Bosch, Berend-Jan, primary, Du, Wenjuan, additional, Debski-Antoniak, Oliver, additional, Drabek, Dubravka, additional, Haperen, Rien van, additional, Dortmondt, Melissa van, additional, Lee, Joline van der, additional, Drulyte, Ieva, additional, Kuppeveld, Frank van, additional, Grosveld, Frank, additional, and Hurdiss, Daniel, additional

Published
2024
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10. Tomo Live: an on‐the‐fly reconstruction pipeline to judge data quality for cryo‐electron tomography workflows.

Author

Comet, Maxime, Dijkman, Patricia M., Boer Iwema, Reint, Franke, Tilman, Masiulis, Simonas, Schampers, Ruud, Raschdorf, Oliver, Grollios, Fanis, Pryor, Edward E., and Drulyte, Ieva

Subjects
DATA quality, TOMOGRAPHY, MERGERS & acquisitions, WORKFLOW, CYTOLOGY, WORKFLOW software, ACQUISITION of data
Abstract

Data acquisition and processing for cryo‐electron tomography can be a significant bottleneck for users. To simplify and streamline the cryo‐ET workflow, Tomo Live, an on‐the‐fly solution that automates the alignment and reconstruction of tilt‐series data, enabling real‐time data‐quality assessment, has been developed. Through the integration of Tomo Live into the data‐acquisition workflow for cryo‐ET, motion correction is performed directly after each of the acquired tilt angles. Immediately after the tilt‐series acquisition has completed, an unattended tilt‐series alignment and reconstruction into a 3D volume is performed. The results are displayed in real time in a dedicated remote web platform that runs on the microscope hardware. Through this web platform, users can review the acquired data (aligned stack and 3D volume) and several quality metrics that are obtained during the alignment and reconstruction process. These quality metrics can be used for fast feedback for subsequent acquisitions to save time. Parameters such as Alignment Accuracy, Deleted Tilts and Tilt Axis Correction Angle are visualized as graphs and can be used as filters to export only the best tomograms (raw data, reconstruction and intermediate data) for further processing. Here, the Tomo Live algorithms and workflow are described and representative results on several biological samples are presented. The Tomo Live workflow is accessible to both expert and non‐expert users, making it a valuable tool for the continued advancement of structural biology, cell biology and histology. [ABSTRACT FROM AUTHOR]

Published
2024
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11. A broad-spectrum macrocyclic peptide inhibitor of the SARS-CoV-2 spike protein

Author

Thijssen, Vito, primary, Hurdiss, Daniel L., additional, Debski-Antoniak, Oliver J., additional, Spence, Matthew A., additional, Franck, Charlotte, additional, Norman, Alexander, additional, Aggarwal, Anupriya, additional, Mokiem, Nadia J., additional, van Dongen, David A. A., additional, Vermeir, Stein W., additional, Liu, Minglong, additional, Li, Wentao, additional, Chatziandreou, Marianthi, additional, Donselaar, Tim, additional, Du, Wenjuan, additional, Drulyte, Ieva, additional, Bosch, Berend-Jan, additional, Snijder, Joost, additional, Turville, Stuart G., additional, Payne, Richard J., additional, Jackson, Colin J., additional, van Kuppeveld, Frank J. M., additional, and Jongkees, Seino A. K., additional

Published
2023
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12. An ACE2-blocking antibody confers broad neutralization and protection against Omicron and other SARS-CoV-2 variants of concern

Author

European Commission, German Research Foundation, Federal Ministry of Education and Research (Germany), Ministry for Science and Culture of Lower Saxony, Du, Wenjuan [0000-0002-0790-9546], Hurdiss, Daniel L. [0000-0003-3834-5808], Drabek, Dubravka [0000-0002-9781-1701], Mykytyn, Anna Z. [0000-0001-7188-6871], González-Hernandez, Mariana [0000-0001-7019-2165], Muñoz-Santos, Diego [0000-0003-0591-0874], Lamers, Mart M. [0000-0002-1431-4022], Haperen, Rien van [0000-0001-9649-011X], Li, Wentao [0000-0002-7114-762X], Drulyte, Ieva [0000-0003-1117-7699], Wang, Chunyan [0000-0002-4584-259X], Solá Gurpegui, Isabel [0000-0002-5704-1917], Armando, Federico [0000-0002-2578-4409], Beythien, Georg [0000-0002-2192-2413], Ciurkiewicz, Malgorzata [0000-0001-6277-7366], Baumgärtner, Wolfgang [0000-0001-8151-5644], Guilfoyle, Kate [0000-0001-7292-3021], Kuppeveld, Frank J. M. van [0000-0001-5800-749X], Amerongen, Geert van [0000-0002-5469-6029], Haagmans, Bart L. [0000-0001-6221-2015], Enjuanes Sánchez, Luis [0000-0002-0854-0226], Osterhaus, Albert D. M. E. [0000-0001-6535-3497], Grosveld, Frank [0000-0002-7051-4715], Du, Wenjuan, Hurdiss, Daniel L., Drabek, Dubravka, Mykytyn, Anna Z., Kaiser, Franziska K., González-Hernandez, Mariana, Muñoz-Santos, Diego, Lamers, Mart M., Haperen, Rien van, Li, Wentao, Drulyte, Ieva, Wang, Chunyan, Solá Gurpegui, Isabel, Armando, Federico, Beythien, Georg, Ciurkiewicz, Malgorzata, Baumgärtner, Wolfgang, Guilfoyle, Kate, Smits, Tony, Lee, Joline van der, Kuppeveld, Frank J. M. van, Amerongen, Geert van, Haagmans, Bart L., Enjuanes Sánchez, Luis, Osterhaus, Albert D. M. E., Grosveld, Frank, Bosch, Berend Jan, European Commission, German Research Foundation, Federal Ministry of Education and Research (Germany), Ministry for Science and Culture of Lower Saxony, Du, Wenjuan [0000-0002-0790-9546], Hurdiss, Daniel L. [0000-0003-3834-5808], Drabek, Dubravka [0000-0002-9781-1701], Mykytyn, Anna Z. [0000-0001-7188-6871], González-Hernandez, Mariana [0000-0001-7019-2165], Muñoz-Santos, Diego [0000-0003-0591-0874], Lamers, Mart M. [0000-0002-1431-4022], Haperen, Rien van [0000-0001-9649-011X], Li, Wentao [0000-0002-7114-762X], Drulyte, Ieva [0000-0003-1117-7699], Wang, Chunyan [0000-0002-4584-259X], Solá Gurpegui, Isabel [0000-0002-5704-1917], Armando, Federico [0000-0002-2578-4409], Beythien, Georg [0000-0002-2192-2413], Ciurkiewicz, Malgorzata [0000-0001-6277-7366], Baumgärtner, Wolfgang [0000-0001-8151-5644], Guilfoyle, Kate [0000-0001-7292-3021], Kuppeveld, Frank J. M. van [0000-0001-5800-749X], Amerongen, Geert van [0000-0002-5469-6029], Haagmans, Bart L. [0000-0001-6221-2015], Enjuanes Sánchez, Luis [0000-0002-0854-0226], Osterhaus, Albert D. M. E. [0000-0001-6535-3497], Grosveld, Frank [0000-0002-7051-4715], Du, Wenjuan, Hurdiss, Daniel L., Drabek, Dubravka, Mykytyn, Anna Z., Kaiser, Franziska K., González-Hernandez, Mariana, Muñoz-Santos, Diego, Lamers, Mart M., Haperen, Rien van, Li, Wentao, Drulyte, Ieva, Wang, Chunyan, Solá Gurpegui, Isabel, Armando, Federico, Beythien, Georg, Ciurkiewicz, Malgorzata, Baumgärtner, Wolfgang, Guilfoyle, Kate, Smits, Tony, Lee, Joline van der, Kuppeveld, Frank J. M. van, Amerongen, Geert van, Haagmans, Bart L., Enjuanes Sánchez, Luis, Osterhaus, Albert D. M. E., Grosveld, Frank, and Bosch, Berend Jan

Abstract

The ongoing evolution of SARS-CoV-2 has resulted in the emergence of Omicron, which displays striking immune escape potential through mutations at key antigenic sites on the spike protein. Many of these mutations localize to the spike protein ACE2 receptor-binding domain, annulling the neutralizing activity of therapeutic antibodies that were effective against other Variants of Concern (VOCs) earlier in the pandemic. Here, we identified a receptor-blocking human monoclonal antibody, 87G7, that retained potent in vitro neutralizing activity against SARS-CoV-2 variants including the Alpha, Beta, Gamma, Delta and Omicron (BA.1/BA.2) VOCs. Using cryo-electron microscopy and site-directed mutagenesis experiments, we showed that 87G7 targets a patch of hydrophobic residues in the ACE2-binding site that are highly conserved in SARS-CoV-2 variants, explaining its broad neutralization capacity. 87G7 protected mice and/or hamsters prophylactically against challenge with all current SARS-CoV-2 VOCs, and showed therapeutic activity against SARS-CoV-2 challenge in both animal models. Our findings demonstrate that 87G7 holds promise as a prophylactic or therapeutic agent for COVID-19 that is more resilient to SARS-CoV-2 antigenic diversity.

Published
2022

13. Sialoglycan binding triggers spike opening in a human coronavirus

Author

Pronker, Matti F, Creutznacher, Robert, Drulyte, Ieva, Hulswit, Ruben J G, Li, Zeshi, van Kuppeveld, Frank J M, Snijder, Joost, Lang, Yifei, Bosch, Berend-Jan, Boons, Geert-Jan, Frank, Martin, de Groot, Raoul J, Hurdiss, Daniel L, Pronker, Matti F, Creutznacher, Robert, Drulyte, Ieva, Hulswit, Ruben J G, Li, Zeshi, van Kuppeveld, Frank J M, Snijder, Joost, Lang, Yifei, Bosch, Berend-Jan, Boons, Geert-Jan, Frank, Martin, de Groot, Raoul J, and Hurdiss, Daniel L

Abstract

Coronavirus spike proteins mediate receptor binding and membrane fusion, making them prime targets for neutralizing antibodies. In the cases of severe acute respiratory syndrome coronavirus, severe acute respiratory syndrome coronavirus 2 and Middle East respiratory syndrome coronavirus, spike proteins transition freely between open and closed conformations to balance host cell attachment and immune evasion 1-5. Spike opening exposes domain S1 B, allowing it to bind to proteinaceous receptors 6,7, and is also thought to enable protein refolding during membrane fusion 4,5. However, with a single exception, the pre-fusion spike proteins of all other coronaviruses studied so far have been observed exclusively in the closed state. This raises the possibility of regulation, with spike proteins more commonly transitioning to open states in response to specific cues, rather than spontaneously. Here, using cryogenic electron microscopy and molecular dynamics simulations, we show that the spike protein of the common cold human coronavirus HKU1 undergoes local and long-range conformational changes after binding a sialoglycan-based primary receptor to domain S1 A. This binding triggers the transition of S1 B domains to the open state through allosteric interdomain crosstalk. Our findings provide detailed insight into coronavirus attachment, with possibilities of dual receptor usage and priming of entry as a means of immune escape.

Published
2023

14. A broad-spectrum macrocyclic peptide inhibitor of the SARS-CoV-2 spike protein

Author

Thijssen, Vito, Hurdiss, Daniel L., Debski-Antoniak, Oliver J., Spence, Matthew A., Franck, Charlotte, Norman, Alexander, Aggarwal, Anupriya, Mokiem, Nadia J., Dongen, David A. A. van, Vermeir, Stein W., Liu, Minglong, Li, Wentao, Chatziandreou, Marianthi, Donselaar, Tim, Du, Wenjuan, Drulyte, Ieva, Bosch, Berend-Jan, Snijder, Joost, Turville, Stuart, Payne, Richard J., Jackson, Colin J., Kuppeveld, Frank J. M. van, Jongkees, Seino A. K., Thijssen, Vito, Hurdiss, Daniel L., Debski-Antoniak, Oliver J., Spence, Matthew A., Franck, Charlotte, Norman, Alexander, Aggarwal, Anupriya, Mokiem, Nadia J., Dongen, David A. A. van, Vermeir, Stein W., Liu, Minglong, Li, Wentao, Chatziandreou, Marianthi, Donselaar, Tim, Du, Wenjuan, Drulyte, Ieva, Bosch, Berend-Jan, Snijder, Joost, Turville, Stuart, Payne, Richard J., Jackson, Colin J., Kuppeveld, Frank J. M. van, and Jongkees, Seino A. K.

Abstract

The ongoing COVID-19 pandemic has had great societal and health consequences. Despite the availability of vaccines, infection rates remain high due to immune evasive Omicron sublineages. Broad-spectrum antivirals are needed to safeguard against emerging variants and future pandemics. We used mRNA display under a reprogrammed genetic code to find a spike-targeting macrocyclic peptide that inhibits SARS-CoV-2 Wuhan strain infection and pseudoviruses containing spike proteins of SARS-CoV-2 variants or related sarbecoviruses. Structural and bioinformatic analyses reveal a conserved binding pocket between the receptor binding domain, N-terminal domain and S2 region, distal to the ACE2 receptor-interaction site. Our data reveal a hitherto unexplored site of vulnerability in sarbecoviruses that peptides and potentially other drug-like molecules can target.

Published
2023

15. Sialoglycan binding triggers spike opening in a human coronavirus

Author

Sub Biomol.Mass Spectrometry & Proteom., Virologie, Afd Chemical Biology and Drug Discovery, Sub Chemical Biology and Drug Discovery, Infectious Diseases and Immunology - Virology, Pronker, Matti F, Creutznacher, Robert, Drulyte, Ieva, Hulswit, Ruben J G, Li, Zeshi, van Kuppeveld, Frank J M, Snijder, Joost, Lang, Yifei, Bosch, Berend-Jan, Boons, Geert-Jan, Frank, Martin, de Groot, Raoul J, Hurdiss, Daniel L, Sub Biomol.Mass Spectrometry & Proteom., Virologie, Afd Chemical Biology and Drug Discovery, Sub Chemical Biology and Drug Discovery, Infectious Diseases and Immunology - Virology, Pronker, Matti F, Creutznacher, Robert, Drulyte, Ieva, Hulswit, Ruben J G, Li, Zeshi, van Kuppeveld, Frank J M, Snijder, Joost, Lang, Yifei, Bosch, Berend-Jan, Boons, Geert-Jan, Frank, Martin, de Groot, Raoul J, and Hurdiss, Daniel L

Published
2023

16. A broad-spectrum macrocyclic peptide inhibitor of the SARS-CoV-2 spike protein

Author

Afd Chemical Biology and Drug Discovery, Virologie, Sub Biomol.Mass Spectrometry & Proteom., Infectious Diseases and Immunology - Virology, Thijssen, Vito, Hurdiss, Daniel L, Debski-Antoniak, Oliver J, Spence, Matthew A, Franck, Charlotte, Norman, Alexander, Aggarwal, Anupriya, Mokiem, Nadia J, van Dongen, David A A, Vermeir, Stein W, Liu, Minglong, Li, Wentao, Chatziandreou, Marianthi, Donselaar, Tim, Du, Wenjuan, Drulyte, Ieva, Bosch, Berend-Jan, Snijder, Joost, Turville, Stuart G, Payne, Richard J, Jackson, Colin J, van Kuppeveld, Frank J M, Jongkees, Seino A K, Afd Chemical Biology and Drug Discovery, Virologie, Sub Biomol.Mass Spectrometry & Proteom., Infectious Diseases and Immunology - Virology, Thijssen, Vito, Hurdiss, Daniel L, Debski-Antoniak, Oliver J, Spence, Matthew A, Franck, Charlotte, Norman, Alexander, Aggarwal, Anupriya, Mokiem, Nadia J, van Dongen, David A A, Vermeir, Stein W, Liu, Minglong, Li, Wentao, Chatziandreou, Marianthi, Donselaar, Tim, Du, Wenjuan, Drulyte, Ieva, Bosch, Berend-Jan, Snijder, Joost, Turville, Stuart G, Payne, Richard J, Jackson, Colin J, van Kuppeveld, Frank J M, and Jongkees, Seino A K

Published
2023

17. Sialoglycan binding triggers spike opening in a human coronavirus

Author

Pronker, Matti F., primary, Creutznacher, Robert, additional, Drulyte, Ieva, additional, Hulswit, Ruben J.G., additional, Li, Zeshi, additional, van Kuppeveld, Frank J.M., additional, Snijder, Joost, additional, Lang, Yifei, additional, Bosch, Berend-Jan, additional, Boons, Geert-Jan, additional, Frank, Martin, additional, de Groot, Raoul J., additional, and Hurdiss, Daniel L., additional

Published
2023
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18. A broad-spectrum macrocyclic peptide inhibitor of the SARS-CoV-2 spike protein

Author

Thijssen, Vito, primary, Hurdiss, Daniel L., additional, Debski-Antoniak, Oliver J., additional, Spence, Matthew A., additional, Franck, Charlotte, additional, Norman, Alexander, additional, Aggarwal, Anupriya, additional, Mokiem, Nadia J., additional, van Dongen, David A. A., additional, Vermeir, Stein W., additional, Liu, Minglong, additional, Chatziandreou, Marianthi, additional, Donselaar, Tim, additional, Du, Wenjuan, additional, Drulyte, Ieva, additional, Bosch, Berend-Jan, additional, Snijder, Joost, additional, Turville, Stuart, additional, Payne, Richard J., additional, Jackson, Colin J., additional, van Kuppeveld, Frank J. M., additional, and Jongkees, Seino A. K., additional

Published
2022
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19. An ACE2-blocking antibody confers broad neutralization and protection against Omicron and other SARS-CoV-2 variants of concern

Author

Du, Wenjuan, Hurdiss, Daniel L, Drabek, Dubravka, Mykytyn, Anna Z, Kaiser, Franziska K, González-Hernández, Mariana, Muñoz-Santos, Diego, Lamers, Mart M, van Haperen, Rien, Li, Wentao, Drulyte, Ieva, Wang, Chunyan, Sola, Isabel, Armando, Federico, Beythien, Georg, Ciurkiewicz, Malgorzata, Baumgärtner, Wolfgang, Guilfoyle, Kate, Smits, Tony, van der Lee, Joline, van Kuppeveld, Frank J M, van Amerongen, Geert, Haagmans, Bart L, Enjuanes, Luis, Osterhaus, Albert D M E, Grosveld, Frank, Bosch, Berend-Jan, Virologie, dI&I I&I-1, Bedrijfsvoering, European Commission, German Research Foundation, Federal Ministry of Education and Research (Germany), Ministry for Science and Culture of Lower Saxony, Du, Wenjuan [0000-0002-0790-9546], Hurdiss, Daniel L. [0000-0003-3834-5808], Drabek, Dubravka [0000-0002-9781-1701], Mykytyn, Anna Z. [0000-0001-7188-6871], González-Hernandez, Mariana [0000-0001-7019-2165], Muñoz-Santos, Diego [0000-0003-0591-0874], Lamers, Mart M. [0000-0002-1431-4022], Haperen, Rien van [0000-0001-9649-011X], Li, Wentao [0000-0002-7114-762X], Drulyte, Ieva [0000-0003-1117-7699], Wang, Chunyan [0000-0002-4584-259X], Solá Gurpegui, Isabel [0000-0002-5704-1917], Armando, Federico [0000-0002-2578-4409], Beythien, Georg [0000-0002-2192-2413], Ciurkiewicz, Malgorzata [0000-0001-6277-7366], Baumgärtner, Wolfgang [0000-0001-8151-5644], Guilfoyle, Kate [0000-0001-7292-3021], Kuppeveld, Frank J. M. van [0000-0001-5800-749X], Amerongen, Geert van [0000-0002-5469-6029], Haagmans, Bart L. [0000-0001-6221-2015], Enjuanes Sánchez, Luis [0000-0002-0854-0226], Osterhaus, Albert D. M. E. [0000-0001-6535-3497], Grosveld, Frank [0000-0002-7051-4715], Virologie, dI&I I&I-1, Bedrijfsvoering, Cell biology, Virology, Du, Wenjuan, Hurdiss, Daniel L., Drabek, Dubravka, Mykytyn, Anna Z., González-Hernandez, Mariana, Muñoz-Santos, Diego, Lamers, Mart M., Haperen, Rien van, Li, Wentao, Drulyte, Ieva, Wang, Chunyan, Solá Gurpegui, Isabel, Armando, Federico, Beythien, Georg, Ciurkiewicz, Malgorzata, Baumgärtner, Wolfgang, Guilfoyle, Kate, Kuppeveld, Frank J. M. van, Amerongen, Geert van, Haagmans, Bart L., Enjuanes Sánchez, Luis, Osterhaus, Albert D. M. E., and Grosveld, Frank

Subjects
Membrane Glycoproteins, SARS-CoV-2, Cryoelectron Microscopy, Immunology, General Medicine, Refinement, Antibodies, Neutralizing, COVID-19 Drug Treatment, Mice, Viral Envelope Proteins, Neutralization Tests, Spike Glycoprotein, Coronavirus, Validation, Animals, Humans, Immunology and Allergy, Angiotensin-Converting Enzyme 2, Model, Visualization
Abstract

The ongoing evolution of SARS-CoV-2 has resulted in the emergence of Omicron, which displays striking immune escape potential through mutations at key antigenic sites on the spike protein. Many of these mutations localize to the spike protein ACE2 receptor-binding domain, annulling the neutralizing activity of therapeutic antibodies that were effective against other Variants of Concern (VOCs) earlier in the pandemic. Here, we identified a receptor-blocking human monoclonal antibody, 87G7, that retained potent in vitro neutralizing activity against SARS-CoV-2 variants including the Alpha, Beta, Gamma, Delta and Omicron (BA.1/BA.2) VOCs. Using cryo-electron microscopy and site-directed mutagenesis experiments, we showed that 87G7 targets a patch of hydrophobic residues in the ACE2-binding site that are highly conserved in SARS-CoV-2 variants, explaining its broad neutralization capacity. 87G7 protected mice and/or hamsters prophylactically against challenge with all current SARS-CoV-2 VOCs, and showed therapeutic activity against SARS-CoV-2 challenge in both animal models. Our findings demonstrate that 87G7 holds promise as a prophylactic or therapeutic agent for COVID-19 that is more resilient to SARS-CoV-2 antigenic diversity., The MANCO project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 101003651). This work made use of the Dutch national e-infrastructure with the support of the SURF Cooperative using grant no. EINF-2453. This research was funded by the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) -398066876/GRK 2485/1; BMBF (Federal Ministry of Education and Research) project entitled RAPID (Risk assessment in re-pandemic respiratory infectious diseases), 01KI1723G, Ministry of Science and Culture of Lower Saxony in Germany (14 - 76103-184 CORONA-15/20)

Published
2022
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21. An ACE2-blocking antibody confers broad neutralization and protection against Omicron and other SARS-CoV-2 variants of concern

Author

Virologie, dI&I I&I-1, Bedrijfsvoering, Du, Wenjuan, Hurdiss, Daniel L, Drabek, Dubravka, Mykytyn, Anna Z, Kaiser, Franziska K, González-Hernández, Mariana, Muñoz-Santos, Diego, Lamers, Mart M, van Haperen, Rien, Li, Wentao, Drulyte, Ieva, Wang, Chunyan, Sola, Isabel, Armando, Federico, Beythien, Georg, Ciurkiewicz, Malgorzata, Baumgärtner, Wolfgang, Guilfoyle, Kate, Smits, Tony, van der Lee, Joline, van Kuppeveld, Frank J M, van Amerongen, Geert, Haagmans, Bart L, Enjuanes, Luis, Osterhaus, Albert D M E, Grosveld, Frank, Bosch, Berend-Jan, Virologie, dI&I I&I-1, Bedrijfsvoering, Du, Wenjuan, Hurdiss, Daniel L, Drabek, Dubravka, Mykytyn, Anna Z, Kaiser, Franziska K, González-Hernández, Mariana, Muñoz-Santos, Diego, Lamers, Mart M, van Haperen, Rien, Li, Wentao, Drulyte, Ieva, Wang, Chunyan, Sola, Isabel, Armando, Federico, Beythien, Georg, Ciurkiewicz, Malgorzata, Baumgärtner, Wolfgang, Guilfoyle, Kate, Smits, Tony, van der Lee, Joline, van Kuppeveld, Frank J M, van Amerongen, Geert, Haagmans, Bart L, Enjuanes, Luis, Osterhaus, Albert D M E, Grosveld, Frank, and Bosch, Berend-Jan

Published
2022

22. The trispecific DARPin ensovibep inhibits diverse SARS-CoV-2 variants

Author

Virologie, Rothenberger, Sylvia, Hurdiss, Daniel L, Walser, Marcel, Malvezzi, Francesca, Mayor, Jennifer, Ryter, Sarah, Moreno, Hector, Liechti, Nicole, Bosshart, Andreas, Iss, Chloé, Calabro, Valérie, Cornelius, Andreas, Hospodarsch, Tanja, Neculcea, Alexandra, Looser, Thamar, Schlegel, Anja, Fontaine, Simon, Villemagne, Denis, Paladino, Maria, Schiegg, Dieter, Mangold, Susanne, Reichen, Christian, Radom, Filip, Kaufmann, Yvonne, Schaible, Doris, Schlegel, Iris, Zitt, Christof, Sigrist, Gabriel, Straumann, Marcel, Wolter, Julia, Comby, Marco, Sacarcelik, Feyza, Drulyte, Ieva, Lyoo, Heyrhyoung, Wang, Chunyan, Li, Wentao, Du, Wenjuan, Binz, H Kaspar, Herrup, Rachel, Lusvarghi, Sabrina, Neerukonda, Sabari Nath, Vassell, Russell, Wang, Wei, Adler, Julia M, Eschke, Kathrin, Nascimento, Mariana, Abdelgawad, Azza, Gruber, Achim D, Bushe, Judith, Kershaw, Olivia, Knutson, Charles G, Balavenkatraman, Kamal K, Ramanathan, Krishnan, Wyler, Emanuel, Teixeira Alves, Luiz Gustavo, Lewis, Seth, Watson, Randall, Haeuptle, Micha A, Zürcher, Alexander, Dawson, Keith M, Steiner, Daniel, Weiss, Carol D, Amstutz, Patrick, van Kuppeveld, Frank J M, Stumpp, Michael T, Bosch, Berend-Jan, Engler, Olivier, Trimpert, Jakob, Virologie, Rothenberger, Sylvia, Hurdiss, Daniel L, Walser, Marcel, Malvezzi, Francesca, Mayor, Jennifer, Ryter, Sarah, Moreno, Hector, Liechti, Nicole, Bosshart, Andreas, Iss, Chloé, Calabro, Valérie, Cornelius, Andreas, Hospodarsch, Tanja, Neculcea, Alexandra, Looser, Thamar, Schlegel, Anja, Fontaine, Simon, Villemagne, Denis, Paladino, Maria, Schiegg, Dieter, Mangold, Susanne, Reichen, Christian, Radom, Filip, Kaufmann, Yvonne, Schaible, Doris, Schlegel, Iris, Zitt, Christof, Sigrist, Gabriel, Straumann, Marcel, Wolter, Julia, Comby, Marco, Sacarcelik, Feyza, Drulyte, Ieva, Lyoo, Heyrhyoung, Wang, Chunyan, Li, Wentao, Du, Wenjuan, Binz, H Kaspar, Herrup, Rachel, Lusvarghi, Sabrina, Neerukonda, Sabari Nath, Vassell, Russell, Wang, Wei, Adler, Julia M, Eschke, Kathrin, Nascimento, Mariana, Abdelgawad, Azza, Gruber, Achim D, Bushe, Judith, Kershaw, Olivia, Knutson, Charles G, Balavenkatraman, Kamal K, Ramanathan, Krishnan, Wyler, Emanuel, Teixeira Alves, Luiz Gustavo, Lewis, Seth, Watson, Randall, Haeuptle, Micha A, Zürcher, Alexander, Dawson, Keith M, Steiner, Daniel, Weiss, Carol D, Amstutz, Patrick, van Kuppeveld, Frank J M, Stumpp, Michael T, Bosch, Berend-Jan, Engler, Olivier, and Trimpert, Jakob

Published
2022

23. An ACE2-blocking antibody confers broad neutralization and protection against Omicron and other SARS-CoV-2 variants

Author

European Commission, German Research Foundation, Federal Ministry of Education and Research (Germany), Ministry for Science and Culture of Lower Saxony, Du, Wenjuan, Hurdiss, Daniel L., Drabek, Dubravka, Mykytyn, Anna Z., Kaiser, Franziska K., González-Hernandez, Mariana, Muñoz-Santos, Diego, Lamers, Mart M., Haperen, Rien van, Li, Wentao, Drulyte, Ieva, Wang, Chunyan, Solá Gurpegui, Isabel, Armando, Federico, Beythien, Georg, Ciurkiewicz, Malgorzata, Baumgärtner, Wolfgang, Guilfoyle, Kate, Smits, Tony, Lee, Joline van der, Kuppeveld, Frank J. M. van, Amerongen, Geert van, Haagmans, Bart L., Enjuanes Sánchez, Luis, Osterhaus, Albert D. M. E., Grosveld, Frank, Bosch, Berend Jan, European Commission, German Research Foundation, Federal Ministry of Education and Research (Germany), Ministry for Science and Culture of Lower Saxony, Du, Wenjuan, Hurdiss, Daniel L., Drabek, Dubravka, Mykytyn, Anna Z., Kaiser, Franziska K., González-Hernandez, Mariana, Muñoz-Santos, Diego, Lamers, Mart M., Haperen, Rien van, Li, Wentao, Drulyte, Ieva, Wang, Chunyan, Solá Gurpegui, Isabel, Armando, Federico, Beythien, Georg, Ciurkiewicz, Malgorzata, Baumgärtner, Wolfgang, Guilfoyle, Kate, Smits, Tony, Lee, Joline van der, Kuppeveld, Frank J. M. van, Amerongen, Geert van, Haagmans, Bart L., Enjuanes Sánchez, Luis, Osterhaus, Albert D. M. E., Grosveld, Frank, and Bosch, Berend Jan

Abstract

The ongoing evolution of SARS-CoV-2 has resulted in the emergence of Omicron, which displays striking immune escape potential. Many of its mutations localize to the spike protein ACE2 receptor-binding domain, annulling the neutralizing activity of most therapeutic monoclonal antibodies. Here we describe a receptor-blocking human monoclonal antibody, 87G7, that retains ultrapotent neutralization against SARS-CoV-2 variants including the Alpha, Beta, Gamma, Delta and Omicron (BA.1/BA.2) Variants-of-Concern (VOCs). Structural analysis reveals that 87G7 targets a patch of hydrophobic residues in the ACE2-binding site that are highly conserved in SARS-CoV-2 variants, explaining its broad neutralization capacity. 87G7 protects mice and/or hamsters against challenge with all current SARS-CoV-2 VOCs. Our findings may aid the development of sustainable antibody-based strategies against COVID-19 that are more resilient to SARS-CoV-2 antigenic diversity.

Published
2022

24. An ACE2-blocking antibody confers broad neutralization and protection against Omicron and other SARS-CoV-2 variants

Author

Du, Wenjuan, primary, Hurdiss, Daniel L., additional, Drabek, Dubravka, additional, Mykytyn, Anna Z, additional, Kaiser, Franziska, additional, Gonzalez-Hernandez, Mariana, additional, Munoz-Santos, Diego, additional, Lamers, Mart M., additional, van Haperen, Rien, additional, Li, Wentao, additional, Drulyte, Ieva, additional, Wang, Chunyan, additional, Sola, Isabel, additional, Armando, Federico, additional, Beythien, Georg, additional, Ciurkiewicz, Malgorzata, additional, Baumgartner, Wolfgang, additional, Guilfoyle, Kate, additional, Smits, Tony, additional, van der Lee, Joline, additional, van Kuppeveld, Frank J.M., additional, van Amerongen, Geert, additional, Haagmans, Bart L., additional, Enjuanes, Luis, additional, Osterhaus, Albert DME, additional, Grosveld, Frank, additional, and Bosch, Berend Jan, additional

Published
2022
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27. Structural insights into the cross-neutralization of SARS-CoV and SARS-CoV-2 by the human monoclonal antibody 47D11

Author

Fedry, Juliette, Hurdiss, Daniel L, Wang, Chunyan, Li, Wentao, Obal, Gonzalo, Drulyte, Ieva, Du, Wenjuan, Howes, Stuart C, van Kuppeveld, Frank J M, Förster, Friedrich, Bosch, Berend-Jan, Fedry, Juliette, Hurdiss, Daniel L, Wang, Chunyan, Li, Wentao, Obal, Gonzalo, Drulyte, Ieva, Du, Wenjuan, Howes, Stuart C, van Kuppeveld, Frank J M, Förster, Friedrich, and Bosch, Berend-Jan

Abstract

The emergence of SARS-CoV-2 antibody escape mutations highlights the urgent need for broadly neutralizing therapeutics. We previously identified a human monoclonal antibody, 47D11, capable of cross-neutralizing SARS-CoV-2 and SARS-CoV and protecting against the associated respiratory disease in an animal model. Here, we report cryo-EM structures of both trimeric spike ectodomains in complex with the 47D11 Fab. 47D11 binds to the closed receptor-binding domain, distal to the ACE2 binding site. The CDRL3 stabilizes the N343 glycan in an upright conformation, exposing a mutationally constrained hydrophobic pocket, into which the CDRH3 loop inserts two aromatic residues. 47D11 stabilizes a partially open conformation of the SARS-CoV-2 spike, suggesting that it could be used effectively in combination with other antibodies targeting the exposed receptor-binding motif. Together, these results reveal a cross-protective epitope on the SARS-CoV-2 spike and provide a structural roadmap for the development of 47D11 as a prophylactic or postexposure therapy for COVID-19.

Published
2021

28. Structural insights into the cross-neutralization of SARS-CoV and SARS-CoV-2 by the human monoclonal antibody 47D11

Author

Sub Structural Biochemistry, Virologie, dI&I I&I-1, Fedry, Juliette, Hurdiss, Daniel L, Wang, Chunyan, Li, Wentao, Obal, Gonzalo, Drulyte, Ieva, Du, Wenjuan, Howes, Stuart C, van Kuppeveld, Frank J M, Förster, Friedrich, Bosch, Berend-Jan, Sub Structural Biochemistry, Virologie, dI&I I&I-1, Fedry, Juliette, Hurdiss, Daniel L, Wang, Chunyan, Li, Wentao, Obal, Gonzalo, Drulyte, Ieva, Du, Wenjuan, Howes, Stuart C, van Kuppeveld, Frank J M, Förster, Friedrich, and Bosch, Berend-Jan

Published
2021

29. Ensovibep, a novel trispecific DARPin candidate that protects against SARS-CoV-2 variants

Author

Rothenberger, Sylvia, primary, Hurdiss, Daniel L., additional, Walser, Marcel, additional, Malvezzi, Francesca, additional, Mayor, Jennifer, additional, Ryter, Sarah, additional, Moreno, Hector, additional, Liechti, Nicole, additional, Bosshart, Andreas, additional, Iss, Chloe, additional, Calabro, Valérie, additional, Cornelius, Andreas, additional, Hospodarsch, Tanja, additional, Neculcea, Alexandra, additional, Looser, Thamar, additional, Schlegel, Anja, additional, Fontaine, Simon, additional, Villemagne, Denis, additional, Paladino, Maria, additional, Kaufmann, Yvonne, additional, Schaible, Doris, additional, Schlegel, Iris, additional, Schiegg, Dieter, additional, Zitt, Christof, additional, Sigrist, Gabriel, additional, Straumann, Marcel, additional, Sacarcelik, Feyza, additional, Wolter, Julia, additional, Comby, Marco, additional, Adler, Julia M., additional, Eschke, Kathrin, additional, Nascimento, Mariana, additional, Abdelgawad, Azza, additional, Gruber, Achim D., additional, Bushe, Judith, additional, Kershaw, Olivia, additional, Lyoo, Heyrhyoung, additional, Wang, Chunyan, additional, Li, Wentao, additional, Drulyte, Ieva, additional, Du, Wenjuan, additional, Binz, H. Kaspar, additional, Herrup, Rachel, additional, Lusvarghi, Sabrina, additional, Neerukonda, Sabari Nath, additional, Vassell, Russell, additional, Wang, Wei, additional, Mangold, Susanne, additional, Reichen, Christian, additional, Radom, Filip, additional, Knutson, Charles G., additional, Balavenkatraman, Kamal K., additional, Ramanathan, Krishnan, additional, Lewis, Seth, additional, Watson, Randall, additional, Haeuptle, Micha A., additional, Zürcher, Alexander, additional, Dawson, Keith M., additional, Steiner, Daniel, additional, Weiss, Carol D., additional, Amstutz, Patrick, additional, van Kuppeveld, Frank J.M., additional, Stumpp, Michael T., additional, Bosch, Berend-Jan, additional, Engler, Olivier, additional, and Trimpert, Jakob, additional

Published
2021
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32. Highly potent anti-SARS-CoV-2 multivalent DARPin therapeutic candidates

Author

Walser, Marcel, primary, Rothenberger, Sylvia, additional, Hurdiss, Daniel L., additional, Schlegel, Anja, additional, Calabro, Valérie, additional, Fontaine, Simon, additional, Villemagne, Denis, additional, Paladino, Maria, additional, Hospodarsch, Tanja, additional, Neculcea, Alexandra, additional, Cornelius, Andreas, additional, Schildknecht, Patricia, additional, Matzner, Mirela, additional, Hänggi, Martin, additional, Franchini, Marco, additional, Kaufmann, Yvonne, additional, Schaible, Doris, additional, Schlegel, Iris, additional, Iss, Chloe, additional, Looser, Thamar, additional, Mangold, Susanne, additional, Herzog, Christel, additional, Schiegg, Dieter, additional, Reichen, Christian, additional, Radom, Filip, additional, Bosshart, Andreas, additional, Lehmann, Andreas, additional, Haeuptle, Micha A., additional, Zürcher, Alexander, additional, Vagt, Toni, additional, Sigrist, Gabriel, additional, Straumann, Marcel, additional, Proba, Karl, additional, Veitonmäki, Niina, additional, Dawson, Keith M., additional, Zitt, Christof, additional, Mayor, Jennifer, additional, Ryter, Sarah, additional, Lyoo, Heyrhyoung, additional, Wang, Chunyan, additional, Li, Wentao, additional, Drulyte, Ieva, additional, Du, Wenjuan, additional, Binz, H. Kaspar, additional, de Waal, Leon, additional, Stittelaar, Koert J., additional, Taplin, Sarah, additional, Lewis, Seth, additional, Steiner, Daniel, additional, van Kuppeveld, Frank J.M., additional, Engler, Olivier, additional, Bosch, Berend-Jan, additional, Stumpp, Michael T., additional, and Amstutz, Patrick, additional

Published
2020
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34. Cryo-EM structure of coronavirus-HKU1 haemagglutinin esterase reveals architectural changes arising from prolonged circulation in humans

Author

Hurdiss, Daniel L, Drulyte, Ieva, Lang, Yifei, Shamorkina, Tatiana M, Pronker, Matti F, van Kuppeveld, Frank J M, Snijder, Joost, de Groot, Raoul J, Hurdiss, Daniel L, Drulyte, Ieva, Lang, Yifei, Shamorkina, Tatiana M, Pronker, Matti F, van Kuppeveld, Frank J M, Snijder, Joost, and de Groot, Raoul J

Abstract

The human betacoronaviruses HKU1 and OC43 (subgenus Embecovirus) arose from separate zoonotic introductions, OC43 relatively recently and HKU1 apparently much longer ago. Embecovirus particles contain two surface projections called spike (S) and haemagglutinin-esterase (HE), with S mediating receptor binding and membrane fusion, and HE acting as a receptor-destroying enzyme. Together, they promote dynamic virion attachment to glycan-based receptors, specifically 9-O-acetylated sialic acid. Here we present the cryo-EM structure of the ~80 kDa, heavily glycosylated HKU1 HE at 3.4 Å resolution. Comparison with existing HE structures reveals a drastically truncated lectin domain, incompatible with sialic acid binding, but with the structure and function of the esterase domain left intact. Cryo-EM and mass spectrometry analysis reveals a putative glycan shield on the now redundant lectin domain. The findings further our insight into the evolution and host adaptation of human embecoviruses, and demonstrate the utility of cryo-EM for studying small, heavily glycosylated proteins.

Published
2020

35. Cryo-EM structure of coronavirus-HKU1 haemagglutinin esterase reveals architectural changes arising from prolonged circulation in humans

Author

Virologie, dI&I I&I-1, Sub Biomol.Mass Spectrometry & Proteom., Biomolecular Mass Spectrometry and Proteomics, Hurdiss, Daniel L, Drulyte, Ieva, Lang, Yifei, Shamorkina, Tatiana M, Pronker, Matti F, van Kuppeveld, Frank J M, Snijder, Joost, de Groot, Raoul J, Virologie, dI&I I&I-1, Sub Biomol.Mass Spectrometry & Proteom., Biomolecular Mass Spectrometry and Proteomics, Hurdiss, Daniel L, Drulyte, Ieva, Lang, Yifei, Shamorkina, Tatiana M, Pronker, Matti F, van Kuppeveld, Frank J M, Snijder, Joost, and de Groot, Raoul J

Published
2020

38. Oral Estrogen Receptor PROTAC Vepdegestrant (ARV-471) Is Highly Efficacious as Monotherapy and in Combination with CDK4/6 or PI3K/mTOR Pathway Inhibitors in Preclinical ER+ Breast Cancer Models.

Author

Gough SM, Flanagan JJ, Teh J, Andreoli M, Rousseau E, Pannone M, Bookbinder M, Willard R, Davenport K, Bortolon E, Cadelina G, Gordon D, Pizzano J, Macaluso J, Soto L, Corradi J, Digianantonio K, Drulyte I, Morgan A, Quinn C, Békés M, Ferraro C, Chen X, Wang G, Dong H, Wang J, Langley DR, Houston J, Gedrich R, and Taylor IC

Subjects
Humans, Female, Animals, Mice, Cell Line, Tumor, Estrogen Receptor alpha metabolism, Estrogen Receptor alpha genetics, Estrogen Receptor alpha antagonists & inhibitors, Piperazines pharmacology, Piperazines administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols pharmacology, Phosphoinositide-3 Kinase Inhibitors pharmacology, Phosphoinositide-3 Kinase Inhibitors administration & dosage, Receptors, Estrogen metabolism, Pyridines administration & dosage, Pyridines pharmacology, Protein Kinase Inhibitors pharmacology, Cell Proliferation drug effects, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Breast Neoplasms metabolism, Cyclin-Dependent Kinase 6 antagonists & inhibitors, Cyclin-Dependent Kinase 4 antagonists & inhibitors, Xenograft Model Antitumor Assays, TOR Serine-Threonine Kinases metabolism, TOR Serine-Threonine Kinases antagonists & inhibitors, Signal Transduction drug effects
Abstract

Purpose: Estrogen receptor (ER) alpha signaling is a known driver of ER-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Combining endocrine therapy (ET) such as fulvestrant with CDK4/6, mTOR, or PI3K inhibitors has become a central strategy in the treatment of ER+ advanced breast cancer. However, suboptimal ER inhibition and resistance resulting from the ESR1 mutation dictates that new therapies are needed., Experimental Design: A medicinal chemistry campaign identified vepdegestrant (ARV-471), a selective, orally bioavailable, and potent small molecule PROteolysis-TArgeting Chimera (PROTAC) degrader of ER. We used biochemical and intracellular target engagement assays to demonstrate the mechanism of action of vepdegestrant, and ESR1 wild-type (WT) and mutant ER+ preclinical breast cancer models to demonstrate ER degradation-mediated tumor growth inhibition (TGI)., Results: Vepdegestrant induced ≥90% degradation of wild-type and mutant ER, inhibited ER-dependent breast cancer cell line proliferation in vitro, and achieved substantial TGI (87%-123%) in MCF7 orthotopic xenograft models, better than those of the ET agent fulvestrant (31%-80% TGI). In the hormone independent (HI) mutant ER Y537S patient-derived xenograft (PDX) breast cancer model ST941/HI, vepdegestrant achieved tumor regression and was similarly efficacious in the ST941/HI/PBR palbociclib-resistant model (102% TGI). Vepdegestrant-induced robust tumor regressions in combination with each of the CDK4/6 inhibitors palbociclib, abemaciclib, and ribociclib; the mTOR inhibitor everolimus; and the PI3K inhibitors alpelisib and inavolisib., Conclusions: Vepdegestrant achieved greater ER degradation in vivo compared with fulvestrant, which correlated with improved TGI, suggesting vepdegestrant could be a more effective backbone ET for patients with ER+/HER2- breast cancer., (©2024 The Authors; Published by the American Association for Cancer Research.)

Published
2024
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