Efficacy and Pharmacodynamic Modeling of the BTK Inhibitor Evobrutinib in Autoimmune Disease Models.

Autor:	Haselmayer P; Translational Innovation Platform Immunology, Merck KGaA, Darmstadt 64293, Germany., Camps M; Immunology, Merck Serono, 1201 Geneva, Switzerland., Liu-Bujalski L; Medicinal Chemistry, EMD Serono Research and Development Institute, Billerica, MA 01821., Nguyen N; Medicinal Chemistry, EMD Serono Research and Development Institute, Billerica, MA 01821., Morandi F; Molecular Pharmacology, EMD Serono Research and Development Institute, Billerica, MA 01821., Head J; Molecular Pharmacology, EMD Serono Research and Development Institute, Billerica, MA 01821., O'Mahony A; Eurofins DiscoverX Corporation, South San Francisco, CA 94080., Zimmerli SC; Translational Innovation Platform Immunology, EMD Serono Research and Development Institute, Billerica, MA 01821; and., Bruns L; Translational Innovation Platform Immunology, Merck KGaA, Darmstadt 64293, Germany., Bender AT; Translational Innovation Platform Immunology, EMD Serono Research and Development Institute, Billerica, MA 01821; and., Schroeder P; Translational Pharmacology, EMD Serono Research and Development Institute, Billerica, MA 01821., Grenningloh R; Translational Innovation Platform Immunology, EMD Serono Research and Development Institute, Billerica, MA 01821; and roland.grenningloh@emdserono.com.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2019 May 15; Vol. 202 (10), pp. 2888-2906. Date of Electronic Publication: 2019 Apr 15.
DOI:	10.4049/jimmunol.1800583
Abstrakt:	Because of its role in mediating both B cell and Fc receptor signaling, Bruton's tyrosine kinase (BTK) is a promising target for the treatment of autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Evobrutinib is a novel, highly selective, irreversible BTK inhibitor that potently inhibits BCR- and Fc receptor - mediated signaling and, thus, subsequent activation and function of human B cells and innate immune cells such as monocytes and basophils. We evaluated evobrutinib in preclinical models of RA and SLE and characterized the relationship between BTK occupancy and inhibition of disease activity. In mouse models of RA and SLE, orally administered evobrutinib displayed robust efficacy, as demonstrated by reduction of disease severity and histological damage. In the SLE model, evobrutinib inhibited B cell activation, reduced autoantibody production and plasma cell numbers, and normalized B and T cell subsets. In the RA model, efficacy was achieved despite failure to reduce autoantibodies. Pharmacokinetic/pharmacodynamic modeling showed that mean BTK occupancy in blood cells of 80% was linked to near-complete disease inhibition in both RA and SLE mouse models. In addition, evobrutinib inhibited mast cell activation in a passive cutaneous anaphylaxis model. Thus, evobrutinib achieves efficacy by acting both on B cells and innate immune cells. Taken together, our data show that evobrutinib is a promising molecule for the chronic treatment of B cell - driven autoimmune disorders. (Copyright © 2019 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
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