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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
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.
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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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