In:
Clinical & Translational Immunology, Wiley, Vol. 10, No. 6 ( 2021-01)
Abstract:
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 n m , 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 n m 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 n m 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.
Type of Medium:
Online Resource
ISSN:
2050-0068
,
2050-0068
Language:
English
Publisher:
Wiley
Publication Date:
2021
detail.hit.zdb_id:
2694482-0
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