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Next‐generation Bruton's tyrosine kinase inhibitor BIIB091 selectively and potently inhibits B cell and Fc receptor signaling and downstream functions in B cells and myeloid cells
OBJECTIVES: Bruton's tyrosine kinase (BTK) plays a non‐redundant signaling role downstream of the B‐cell receptor (BCR) in B cells and the receptors for the Fc region of immunoglobulins (FcR) in myeloid cells. Here, we characterise BIIB091, a novel, potent, selective and reversible small‐molecu...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204096/ https://www.ncbi.nlm.nih.gov/pubmed/34141433 http://dx.doi.org/10.1002/cti2.1295 |
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author | Bame, Eris Tang, Hao Burns, Jeremy C Arefayene, Million Michelsen, Klaus Ma, Bin Marx, Isaac Prince, Robin Roach, Allie M Poreci, Urjana Donaldson, Douglas Cullen, Patrick Casey, Fergal Zhu, Jing Carlile, Thomas M Sangurdekar, Dipen Zhang, Baohong Trapa, Patrick Santoro, Joseph Muragan, Param Pellerin, Alex Rubino, Stephen Gianni, Davide Bajrami, Bekim Peng, Xiaomei Coppell, Alex Riester, Katherine Belachew, Shibeshih Mehta, Devangi Palte, Mike Hopkins, Brian T Scaramozza, Matthew Franchimont, Nathalie Mingueneau, Michael |
author_facet | Bame, Eris Tang, Hao Burns, Jeremy C Arefayene, Million Michelsen, Klaus Ma, Bin Marx, Isaac Prince, Robin Roach, Allie M Poreci, Urjana Donaldson, Douglas Cullen, Patrick Casey, Fergal Zhu, Jing Carlile, Thomas M Sangurdekar, Dipen Zhang, Baohong Trapa, Patrick Santoro, Joseph Muragan, Param Pellerin, Alex Rubino, Stephen Gianni, Davide Bajrami, Bekim Peng, Xiaomei Coppell, Alex Riester, Katherine Belachew, Shibeshih Mehta, Devangi Palte, Mike Hopkins, Brian T Scaramozza, Matthew Franchimont, Nathalie Mingueneau, Michael |
author_sort | Bame, Eris |
collection | PubMed |
description | OBJECTIVES: Bruton's tyrosine kinase (BTK) plays a non‐redundant signaling role downstream of the B‐cell receptor (BCR) in B cells and the receptors for the Fc region of immunoglobulins (FcR) in myeloid cells. Here, we characterise BIIB091, a novel, potent, selective and reversible small‐molecule inhibitor of BTK. METHODS: BIIB091 was evaluated in vitro and in vivo in preclinical models and in phase 1 clinical trial. RESULTS: In vitro, BIIB091 potently inhibited BTK‐dependent proximal signaling and distal functional responses in both B cells and myeloid cells with IC(50)s ranging from 3 to 106 nm, including antigen presentation to T cells, a key mechanism of action thought to be underlying the efficacy of B cell‐targeted therapeutics in multiple sclerosis. BIIB091 effectively sequestered tyrosine 551 in the kinase pocket by forming long‐lived complexes with BTK with t (1/2) of more than 40 min, thereby preventing its phosphorylation by upstream kinases. As a key differentiating feature of BIIB091, this property explains the very potent whole blood IC(50)s of 87 and 106 nm observed with stimulated B cells and myeloid cells, respectively. In vivo, BIIB091 blocked B‐cell activation, antibody production and germinal center differentiation. In phase 1 healthy volunteer trial, BIIB091 inhibited naïve and unswitched memory B‐cell activation, with an in vivo IC(50) of 55 nm and without significant impact on lymphoid or myeloid cell survival after 14 days of dosing. CONCLUSION: Pharmacodynamic results obtained in preclinical and early clinical settings support the advancement of BIIB091 in phase 2 clinical trials. |
format | Online Article Text |
id | pubmed-8204096 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82040962021-06-16 Next‐generation Bruton's tyrosine kinase inhibitor BIIB091 selectively and potently inhibits B cell and Fc receptor signaling and downstream functions in B cells and myeloid cells Bame, Eris Tang, Hao Burns, Jeremy C Arefayene, Million Michelsen, Klaus Ma, Bin Marx, Isaac Prince, Robin Roach, Allie M Poreci, Urjana Donaldson, Douglas Cullen, Patrick Casey, Fergal Zhu, Jing Carlile, Thomas M Sangurdekar, Dipen Zhang, Baohong Trapa, Patrick Santoro, Joseph Muragan, Param Pellerin, Alex Rubino, Stephen Gianni, Davide Bajrami, Bekim Peng, Xiaomei Coppell, Alex Riester, Katherine Belachew, Shibeshih Mehta, Devangi Palte, Mike Hopkins, Brian T Scaramozza, Matthew Franchimont, Nathalie Mingueneau, Michael Clin Transl Immunology Original Articles OBJECTIVES: Bruton's tyrosine kinase (BTK) plays a non‐redundant signaling role downstream of the B‐cell receptor (BCR) in B cells and the receptors for the Fc region of immunoglobulins (FcR) in myeloid cells. Here, we characterise BIIB091, a novel, potent, selective and reversible small‐molecule inhibitor of BTK. METHODS: BIIB091 was evaluated in vitro and in vivo in preclinical models and in phase 1 clinical trial. RESULTS: In vitro, BIIB091 potently inhibited BTK‐dependent proximal signaling and distal functional responses in both B cells and myeloid cells with IC(50)s ranging from 3 to 106 nm, including antigen presentation to T cells, a key mechanism of action thought to be underlying the efficacy of B cell‐targeted therapeutics in multiple sclerosis. BIIB091 effectively sequestered tyrosine 551 in the kinase pocket by forming long‐lived complexes with BTK with t (1/2) of more than 40 min, thereby preventing its phosphorylation by upstream kinases. As a key differentiating feature of BIIB091, this property explains the very potent whole blood IC(50)s of 87 and 106 nm observed with stimulated B cells and myeloid cells, respectively. In vivo, BIIB091 blocked B‐cell activation, antibody production and germinal center differentiation. In phase 1 healthy volunteer trial, BIIB091 inhibited naïve and unswitched memory B‐cell activation, with an in vivo IC(50) of 55 nm and without significant impact on lymphoid or myeloid cell survival after 14 days of dosing. CONCLUSION: Pharmacodynamic results obtained in preclinical and early clinical settings support the advancement of BIIB091 in phase 2 clinical trials. John Wiley and Sons Inc. 2021-06-14 /pmc/articles/PMC8204096/ /pubmed/34141433 http://dx.doi.org/10.1002/cti2.1295 Text en © 2021 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Articles Bame, Eris Tang, Hao Burns, Jeremy C Arefayene, Million Michelsen, Klaus Ma, Bin Marx, Isaac Prince, Robin Roach, Allie M Poreci, Urjana Donaldson, Douglas Cullen, Patrick Casey, Fergal Zhu, Jing Carlile, Thomas M Sangurdekar, Dipen Zhang, Baohong Trapa, Patrick Santoro, Joseph Muragan, Param Pellerin, Alex Rubino, Stephen Gianni, Davide Bajrami, Bekim Peng, Xiaomei Coppell, Alex Riester, Katherine Belachew, Shibeshih Mehta, Devangi Palte, Mike Hopkins, Brian T Scaramozza, Matthew Franchimont, Nathalie Mingueneau, Michael Next‐generation Bruton's tyrosine kinase inhibitor BIIB091 selectively and potently inhibits B cell and Fc receptor signaling and downstream functions in B cells and myeloid cells |
title | Next‐generation Bruton's tyrosine kinase inhibitor BIIB091 selectively and potently inhibits B cell and Fc receptor signaling and downstream functions in B cells and myeloid cells |
title_full | Next‐generation Bruton's tyrosine kinase inhibitor BIIB091 selectively and potently inhibits B cell and Fc receptor signaling and downstream functions in B cells and myeloid cells |
title_fullStr | Next‐generation Bruton's tyrosine kinase inhibitor BIIB091 selectively and potently inhibits B cell and Fc receptor signaling and downstream functions in B cells and myeloid cells |
title_full_unstemmed | Next‐generation Bruton's tyrosine kinase inhibitor BIIB091 selectively and potently inhibits B cell and Fc receptor signaling and downstream functions in B cells and myeloid cells |
title_short | Next‐generation Bruton's tyrosine kinase inhibitor BIIB091 selectively and potently inhibits B cell and Fc receptor signaling and downstream functions in B cells and myeloid cells |
title_sort | next‐generation bruton's tyrosine kinase inhibitor biib091 selectively and potently inhibits b cell and fc receptor signaling and downstream functions in b cells and myeloid cells |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204096/ https://www.ncbi.nlm.nih.gov/pubmed/34141433 http://dx.doi.org/10.1002/cti2.1295 |
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