Combined use of the JAK3 inhibitor CP-690,550 with mycophenolate mofetil to prevent kidney allograft rejection in nonhuman primates.
BACKGROUND
Immunosuppression via Janus kinase (JAK) 3 inhibition affords significant prolongation of allograft survival. We investigated the effects of an immunosuppressive regimen combining the JAK3 inhibitor CP-690,550 with mycophenolate mofetil (MMF) in nonhuman primates (NHPs).


METHODS
Life-supporting kidney transplantations were performed between ABO-compatible, MLR-mismatched NHPs. Animals were treated orally twice a day with CP-690,550 and MMF (n=8) or MMF alone (n=2) and were euthanized at day 90 or earlier due to allograft rejection.


RESULTS
Mean survival time (+/-SEM) in animals treated with MMF alone (23+/-1 days) was significantly extended in animals that concurrently received CP-690,550 (59.5+/-9.8 days, P=0.02). Combination animals exposed to higher levels of CP-690,550 had a significantly better survival (75.2+/-8.7 days) than animals that received less CP-690,550 (33.3+/-12.6 days, P=0.02). Three combination therapy animals were euthanized at day 90 with a subnormal renal function and early-stage acute graft rejection. Rejection, delayed by treatment, ultimately developed in other animals. Anemia and gastrointestinal intolerance was seen in combination therapy animals that otherwise did not show evidence of viral or bacterial infection besides signs consistent with subclinical pyelonephritis (n=3). One incidental lymphosarcoma was noted.


CONCLUSIONS
Addition of CP-690,550 to MMF significantly improved allograft survival. The observed side effects appear amenable to improvements upon alteration of dosing strategies. Efficacy of this combination regimen suggests that it could become the backbone of calcineurin inhibitor-free regimens.
Borie
Dominic C
DC
Transplantation Immunology Laboratory, Department of Cardiothoracic Surgery, Falk Cardiovascular Research Center, Stanford University School of Medicine, Stanford, CA 94305-5407, USA. dborie@stanford.edu
Larson
Michael J
MJ
Flores
Mona G
MG
Campbell
Andrew
A
Rousvoal
Geraldine
G
Zhang
Sally
S
Higgins
John P
JP
Ball
Douglas J
DJ
Kudlacz
Elizabeth M
EM
Brissette
William H
WH
Elliott
Eileen A
EA
Reitz
Bruce A
BA
Changelian
Paul S
PS
D000818:Animals; D006085:Graft Survival / Q000187:drug effects*; D053616:Janus Kinase 3; D016030:Kidney Transplantation / Q000276:immunology*; D008252:Macaca fascicularis; D023421:Models, Animal; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use*; D011758:Pyrroles / Q000627:therapeutic use*
D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; D011505:Protein-Tyrosine Kinases; D053616:Janus Kinase 3; D009173:Mycophenolic Acid