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.

Autor: Bame E; Clinical Sciences Biogen Cambridge MA USA., Tang H; Biogen Research Biogen Cambridge MA USA., Burns JC; Biogen Research Biogen Cambridge MA USA., Arefayene M; Clinical Sciences Biogen Cambridge MA USA., Michelsen K; Biotherapeutics and Medicinal Sciences Biogen Cambridge MA USA.; Present address: Relay Therapeutics Cambridge MA USA., Ma B; Biotherapeutics and Medicinal Sciences Biogen Cambridge MA USA., Marx I; Biotherapeutics and Medicinal Sciences Biogen Cambridge MA USA., Prince R; Biotherapeutics and Medicinal Sciences Biogen Cambridge MA USA., Roach AM; Biogen Research Biogen Cambridge MA USA.; Present address: Gilead Sciences Seattle WA USA., Poreci U; Clinical Sciences Biogen Cambridge MA USA.; Present address: Pandion Therapeutics Watertown MA USA., Donaldson D; Clinical Sciences Biogen Cambridge MA USA.; Present address: Giner Labs Newton MA USA., Cullen P; Biogen Research Biogen Cambridge MA USA., Casey F; Biogen Research Biogen Cambridge MA USA., Zhu J; Biogen Research Biogen Cambridge MA USA., Carlile TM; Biogen Research Biogen Cambridge MA USA., Sangurdekar D; Biogen Research Biogen Cambridge MA USA.; Present address: Takeda Cambridge MA USA., Zhang B; Biogen Research Biogen Cambridge MA USA., Trapa P; Biotherapeutics and Medicinal Sciences Biogen Cambridge MA USA., Santoro J; Biotherapeutics and Medicinal Sciences Biogen Cambridge MA USA., Muragan P; Biotherapeutics and Medicinal Sciences Biogen Cambridge MA USA., Pellerin A; Biogen Research Biogen Cambridge MA USA., Rubino S; Biogen Research Biogen Cambridge MA USA., Gianni D; Biotherapeutics and Medicinal Sciences Biogen Cambridge MA USA., Bajrami B; Biotherapeutics and Medicinal Sciences Biogen Cambridge MA USA., Peng X; Global Safety and Regulatory Sciences Biogen Cambridge MA USA., Coppell A; Clinical Operations Biogen Maidenhead UK., Riester K; Clinical Sciences Biogen Cambridge MA USA., Belachew S; Personalized Health Research Biogen Baar Switzerland., Mehta D; Clinical Sciences Biogen Cambridge MA USA.; Present address: Immunologix Laboratories Cambridge MA USA., Palte M; MS Development Unit Biogen Cambridge MA USA., Hopkins BT; Biotherapeutics and Medicinal Sciences Biogen Cambridge MA USA., Scaramozza M; MS Development Unit Biogen Cambridge MA USA., Franchimont N; MS Development Unit Biogen Cambridge MA USA., Mingueneau M; Biogen Research Biogen Cambridge MA USA.
Jazyk: angličtina
Zdroj: Clinical & translational immunology [Clin Transl Immunology] 2021 Jun 14; Vol. 10 (6), pp. e1295. Date of Electronic Publication: 2021 Jun 14 (Print Publication: 2021).
DOI: 10.1002/cti2.1295
Abstrakt: 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.
Competing Interests: The authors declare no conflict of interest.
(© 2021 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)
Databáze: MEDLINE
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