Immunosuppression by the JAK3 inhibitor CP-690,550 delays rejection and significantly prolongs kidney allograft survival in nonhuman primates.
BACKGROUND
Janus kinase 3 (JAK3) mediates signal transduction from cytokine receptors using the common chain (gammac). Because mutations in genes encoding gammac or JAK3 result in immunodeficiency, we investigated the potential of a rationally designed inhibitor of JAK3, CP-690,550, to prevent renal allograft rejection in nonhuman primates.


METHODS
Life-supporting kidney transplantations were performed between mixed leukocyte reaction-mismatched, ABO blood group-matched cynomolgus monkeys. Animals were treated with CP-690,550 (n = 18) or its vehicle (controls, n = 3) and were euthanized at day 90 or earlier if there was allograft rejection.


RESULTS
Mean survival time (+/- standard error of mean) in animals treated with CP-690,550 (53 +/- 7 days) was significantly longer than in control animals (7 +/- 1 days, P=0.0003) and was positively correlated with exposure to the drug (r = 0.79, P < 0.01). Four treated animals were euthanized at 90 days with a normal renal function and low-grade rejection at final pathology. Occurrence of rejection was significantly delayed in treated animals (46 +/- 7 days from transplantation vs. 7 +/- 1 days in controls, P = 0.0003). Persistent anemia, polyoma virus-like nephritis (n = 2), and urinary calcium carbonate accretions (n = 3) were seen in animals with high exposure. Natural killer cell and CD4 and CD8 T-cell numbers were significantly reduced in treated animals. Blood glucose, serum lipid levels, and arterial blood pressure were within normal range in treated animals, and no cancers were demonstrated.


CONCLUSIONS
CP-690,550 is the first reported JAK3 inhibitor combining efficacy and good tolerability in a preclinical model of allotransplantation in nonhuman primates and thus has interesting potential for immunosuppression in humans.
Borie
Dominic C
DC
Transplantation Immunology Laboratory, Department of Cardiothoracic Surgery, Falk Cardiovascular Research Center, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA. dborie@stanford.edu
Changelian
Paul S
PS
Larson
Michael J
MJ
Si
Ming-Sing
MS
Paniagua
Ricardo
R
Higgins
John P
JP
Holm
Bari
B
Campbell
Andrew
A
Lau
Macy
M
Zhang
Sally
S
Flores
Mona G
MG
Rousvoal
Geraldine
G
Hawkins
Jennifer
J
Ball
Douglas A
DA
Kudlacz
Elizabeth M
EM
Brissette
William H
WH
Elliott
Eileen A
EA
Reitz
Bruce A
BA
Morris
Randall E
RE
D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005434:Flow Cytometry; D006084:Graft Rejection / Q000188:drug therapy* / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D053616:Janus Kinase 3; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D016030:Kidney Transplantation / Q000276:immunology*; D007958:Leukocyte Count; D008214:Lymphocytes / Q000276:immunology; D008252:Macaca fascicularis; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011758:Pyrroles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; C015482:protein kinase modulator; C479163:tofacitinib; D011505:Protein-Tyrosine Kinases; D053616:Janus Kinase 3