title: The JAK3 inhibitor CP-690550 selectively reduces NK and CD8+ cell numbers in cynomolgus monkey blood following chronic oral dosing.
abstract: Janus kinase 3 (JAK3) is a cytoplasmic tyrosine kinase associated with the common gamma chain, an integral component of cytokine receptors of the interleukin (IL)-2 family, including IL-4, -7, -9, -15, and -21. CP-690550 is a JAK3 inhibitor with immunosuppressive properties under development for transplantation. We evaluated alterations in circulating lymphocyte subsets in cynomolgus monkey blood following chronic (3-week), oral CP-690550 administration. Natural killer (NK) and CD8+ T cell numbers were reduced in a dose- and time-dependent manner; the latter was a primary effect on memory subsets. CD4+ T and B cell numbers were unaffected or slightly increased, respectively. NK cell numbers were reduced approximately 80% (vs. 35% in vehicle-treated animals) and returned to baseline levels within 3 weeks following treatment cessation. CD8+ T cells declined by a maximum 43% (vs. 25% for vehicle-treated animals) but rebounded significantly (300%) within 2 weeks after the last dose. Although CP-690550 did not result in reduction of CD4+ T cell number, these cells also increased (225%) within 2 weeks of treatment cessation. IL-15 is important for maintaining homeostasis of these cell types, and CP-690550 inhibited IL-15-induced CD69 expression in NK cells [inhibitory concentration 50% (IC50)=48.0+/-8.4 nM] and CD8+ T cells (IC50=16.2+/-1.5 nM).
authors.affiliation: Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. maryrose_j_conklyn@groton.pfizer.com
authors.forename: Maryrose
authors.initials: M
authors.lastname: Conklyn
authors.forename: Catharine
authors.initials: C
authors.lastname: Andresen
authors.forename: Paul
authors.initials: P
authors.lastname: Changelian
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kudlacz
mesh_terms: D000284:Administration, Oral; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002452:Cell Count; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D007165:Immunosuppression Therapy / Q000379:methods*; D019409:Interleukin-15 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D053616:Janus Kinase 3; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D037181:Lectins, C-Type; D008252:Macaca fascicularis; D008297:Male; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D004791:Enzyme Inhibitors; D019409:Interleukin-15; D053616:Janus Kinase 3; D037181:Lectins, C-Type; D010880:Piperidines; D011505:Protein-Tyrosine Kinases; D011743:Pyrimidines; D011758:Pyrroles; D000099192:CD69 Antigens; C479163:tofacitinib; C507933:JAK3 protein, human