Preclinical Efficacy and Anti-Inflammatory Mechanisms of Action of the Bruton Tyrosine Kinase Inhibitor Rilzabrutinib for Immune-Mediated Disease

Autor: J. Michael Bradshaw, Angelina Bisconte, Ken A. Brameld, Claire L. Langrish, Timothy D. Owens, David Michael Goldstein, Catherine A. Outerbridge, Philip A. Nunn, Ronald J. Hill, Jacob LaStant, Stephen D. White, Jin Shu, Michelle Francesco, Yan Xing
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Cell
Anti-Inflammatory Agents
Drug Evaluation
Preclinical
Autoimmunity
129 Strain
Kidney
Mice
0302 clinical medicine
Agammaglobulinaemia Tyrosine Kinase
Immunology and Allergy
Mast Cells
Nephritis
biology
Chemistry
Idiopathic
Preclinical
Basophils
medicine.anatomical_structure
5.1 Pharmaceuticals
Development of treatments and therapeutic interventions
Blood Platelets
Programmed cell death
Mice
129 Strain
Immunology
Autoimmune Disease
03 medical and health sciences
Immune system
Dogs
In vivo
medicine
Bruton's tyrosine kinase
Animals
Humans
Protein Kinase Inhibitors
Purpura
Purpura
Thrombocytopenic
Idiopathic
Innate immune system
Arthus reaction
Animal
Inflammatory and immune system
Immunoglobulin E
medicine.disease
In vitro
Thrombocytopenic
Disease Models
Animal
Disease Models
biology.protein
Cancer research
Drug Evaluation
Pemphigus
030215 immunology
Zdroj: J Immunol
Journal of immunology (Baltimore, Md. : 1950), vol 206, iss 7
Popis: Bruton tyrosine kinase (BTK) is expressed in B cells and innate immune cells, acting as an essential signaling element in multiple immune cell pathways. Selective BTK inhibition has the potential to target multiple immune-mediated disease pathways. Rilzabrutinib is an oral, reversible, covalent BTK inhibitor designed for immune-mediated diseases. We examined the pharmacodynamic profile of rilzabrutinib and its preclinical mechanisms of action. In addition to potent and selective BTK enzyme and cellular activity, rilzabrutinib inhibited activation and inflammatory activities of B cells and innate cells such as macrophages, basophils, mast cells, and neutrophils, without cell death (in human and rodent assay systems). Rilzabrutinib demonstrated dose-dependent improvement of clinical scores and joint pathology in a rat model of collagen-induced arthritis and demonstrated reductions in autoantibody-mediated FcγR signaling in vitro and in vivo, with blockade of rat Arthus reaction, kidney protection in mouse Ab-induced nephritis, and reduction in platelet loss in mouse immune thrombocytopenia. Additionally, rilzabrutinib inhibited IgE-mediated, FcεR-dependent immune mechanisms in human basophils and mast cell–dependent mouse models. In canines with naturally occurring pemphigus, rilzabrutinib treatment resulted in rapid clinical improvement demonstrated by anti-inflammatory effects visible within 2 wk and all animals proceeding to complete or substantial disease control. Rilzabrutinib is characterized by reversible covalent BTK binding, long BTK residence time with low systemic exposure, and multiple mechanistic and biological effects on immune cells. Rilzabrutinib’s unique characteristics and promising efficacy and safety profile support clinical development of rilzabrutinib for a broad array of immune-mediated diseases.
Databáze: OpenAIRE
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