| Autor: |
Eris Bame, Hao Tang, Jeremy C Burns, Million Arefayene, Klaus Michelsen, Bin Ma, Isaac Marx, Robin Prince, Allie M Roach, Urjana Poreci, Douglas Donaldson, Patrick Cullen, Fergal Casey, Jing Zhu, Thomas M Carlile, Dipen Sangurdekar, Baohong Zhang, Patrick Trapa, Joseph Santoro, Param Muragan, Alex Pellerin, Stephen Rubino, Davide Gianni, Bekim Bajrami, Xiaomei Peng, Alex Coppell, Katherine Riester, Shibeshih Belachew, Devangi Mehta, Mike Palte, Brian T Hopkins, Matthew Scaramozza, Nathalie Franchimont, Michael Mingueneau |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Předmět: |
|
| Zdroj: |
Clinical & Translational Immunology, Vol 10, Iss 6, Pp n/a-n/a (2021) |
| Druh dokumentu: |
article |
| ISSN: |
2050-0068 |
| DOI: |
10.1002/cti2.1295 |
| Popis: |
Abstract 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 IC50s 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 t1/2 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 IC50s 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 IC50 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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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