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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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Detalles Bibliográficos
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
Descripción
Sumario: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.