The Interleukin-1 Receptor-Associated Kinase 4 Inhibitor PF-06650833 Blocks Inflammation in Preclinical Models of Rheumatic Disease and in Humans Enrolled in a Randomized Clinical Trial.
Animals
Arthritis, Experimental
/ drug therapy
Dendritic Cells
/ drug effects
Disease Models, Animal
Humans
Inflammation
/ drug therapy
Interleukin-1 Receptor-Associated Kinases
/ antagonists & inhibitors
Isoquinolines
/ pharmacology
Lactams
/ pharmacology
Leukocytes, Mononuclear
/ immunology
Macrophages
/ drug effects
Mice
Rats
Rheumatic Diseases
/ drug therapy
Synoviocytes
/ drug effects
Journal
Arthritis & rheumatology (Hoboken, N.J.)
ISSN: 2326-5205
Titre abrégé: Arthritis Rheumatol
Pays: United States
ID NLM: 101623795
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
received:
25
01
2021
accepted:
17
08
2021
pubmed:
24
8
2021
medline:
19
1
2022
entrez:
23
8
2021
Statut:
ppublish
Résumé
To investigate the role of PF-06650833, a highly potent and selective small-molecule inhibitor of interleukin-1-associated kinase 4 (IRAK4), in autoimmune pathophysiology in vitro, in vivo, and in the clinical setting. Rheumatoid arthritis (RA) inflammatory pathophysiology was modeled in vitro through 1) stimulation of primary human macrophages with anti-citrullinated protein antibody immune complexes (ICs), 2) RA fibroblast-like synoviocyte (FLS) cultures stimulated with Toll-like receptor (TLR) ligands, as well as 3) additional human primary cell cocultures exposed to inflammatory stimuli. Systemic lupus erythematosus (SLE) pathophysiology was simulated in human neutrophils, dendritic cells, B cells, and peripheral blood mononuclear cells stimulated with TLR ligands and SLE patient ICs. PF-06650833 was evaluated in vivo in the rat collagen-induced arthritis (CIA) model and the mouse pristane-induced and MRL/lpr models of lupus. Finally, RNA sequencing data generated with whole blood samples from a phase I multiple-ascending-dose clinical trial of PF-06650833 were used to test in vivo human pharmacology. In vitro, PF-06650833 inhibited human primary cell inflammatory responses to physiologically relevant stimuli generated with RA and SLE patient plasma. In vivo, PF-06650833 reduced circulating autoantibody levels in the pristane-induced and MRL/lpr murine models of lupus and protected against CIA in rats. In a phase I clinical trial (NCT02485769), PF-06650833 demonstrated in vivo pharmacologic action pertinent to SLE by reducing whole blood interferon gene signature expression in healthy volunteers. These data demonstrate that inhibition of IRAK4 kinase activity can reduce levels of inflammation markers in humans and provide confidence in the rationale for clinical development of IRAK4 inhibitors for rheumatologic indications.
Identifiants
pubmed: 34423919
doi: 10.1002/art.41953
pmc: PMC8671219
mid: NIHMS1734746
doi:
Substances chimiques
Isoquinolines
0
Lactams
0
IRAK4 protein, human
EC 2.7.11.1
Interleukin-1 Receptor-Associated Kinases
EC 2.7.11.1
1-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-7-methoxyisoquinoline-6-carboxamide
S3F315JJXI
Banques de données
ClinicalTrials.gov
['NCT02485769']
Types de publication
Journal Article
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2206-2218Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR076242
Pays : United States
Organisme : NIAMS NIH HHS
ID : R21 AR065959
Pays : United States
Organisme : NIH HHS
ID : 1R21AR065959-01
Pays : United States
Organisme : Pfizer
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
© 2021 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.
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