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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.
Winkler, Aaron; Sun, Weiyong; De, Saurav; Jiao, Aiping; Sharif, M Nusrat; Symanowicz, Peter T; Athale, Shruti; Shin, Julia H; Wang, Ju; Jacobson, Bruce A; Ramsey, Simeon J; Dower, Ken; Andreyeva, Tatyana; Liu, Heng; Hegen, Martin; Homer, Bruce L; Brodfuehrer, Joanne; Tilley, Mera; Gilbert, Steven A; Danto, Spencer I; Beebe, Jean J; Barnes, Betsy J; Pascual, Virginia; Lin, Lih-Ling; Kilty, Iain; Fleming, Margaret; Rao, Vikram R.
Afiliação
  • Winkler A; Pfizer, Cambridge, Massachusetts.
  • Sun W; Pfizer, Cambridge, Massachusetts.
  • De S; The Feinstein Institute, Manhasset, New York.
  • Jiao A; Pfizer, Cambridge, Massachusetts.
  • Sharif MN; Pfizer, Cambridge, Massachusetts.
  • Symanowicz PT; Pfizer, Cambridge, Massachusetts.
  • Athale S; Baylor Institute for Immunology Research, Dallas, Texas.
  • Shin JH; Pfizer, Cambridge, Massachusetts.
  • Wang J; Pfizer, Cambridge, Massachusetts.
  • Jacobson BA; Pfizer, Cambridge, Massachusetts.
  • Ramsey SJ; Pfizer, Cambridge, Massachusetts.
  • Dower K; Pfizer, Cambridge, Massachusetts.
  • Andreyeva T; Pfizer, Cambridge, Massachusetts.
  • Liu H; Pfizer, Cambridge, Massachusetts.
  • Hegen M; Pfizer, Cambridge, Massachusetts.
  • Homer BL; Pfizer, Cambridge, Massachusetts.
  • Brodfuehrer J; Pfizer, Cambridge, Massachusetts.
  • Tilley M; Pfizer, Cambridge, Massachusetts.
  • Gilbert SA; Pfizer, Cambridge, Massachusetts.
  • Danto SI; Pfizer, Cambridge, Massachusetts.
  • Beebe JJ; Pfizer, Cambridge, Massachusetts.
  • Barnes BJ; The Feinstein Institute, Manhasset, New York.
  • Pascual V; Baylor Institute for Immunology Research, Dallas, Texas.
  • Lin LL; Pfizer, Cambridge, Massachusetts.
  • Kilty I; Pfizer, Cambridge, Massachusetts.
  • Fleming M; Pfizer, Cambridge, Massachusetts.
  • Rao VR; Pfizer, Cambridge, Massachusetts.
Arthritis Rheumatol ; 73(12): 2206-2218, 2021 12.
Article em En | MEDLINE | ID: mdl-34423919
ABSTRACT

OBJECTIVE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Artrite Experimental / Doenças Reumáticas / Quinases Associadas a Receptores de Interleucina-1 / Sinoviócitos / Isoquinolinas / Lactamas / Macrófagos Tipo de estudo: Clinical_trials / Risk_factors_studies Limite: Animals / Humans Idioma: En Revista: Arthritis Rheumatol Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Artrite Experimental / Doenças Reumáticas / Quinases Associadas a Receptores de Interleucina-1 / Sinoviócitos / Isoquinolinas / Lactamas / Macrófagos Tipo de estudo: Clinical_trials / Risk_factors_studies Limite: Animals / Humans Idioma: En Revista: Arthritis Rheumatol Ano de publicação: 2021 Tipo de documento: Article