Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor.
Because of its requirement for signaling by multiple cytokines, Janus kinase 3 (JAK3) is an excellent target for clinical immunosuppression. We report the development of a specific, orally active inhibitor of JAK3, CP-690,550, that significantly prolonged survival in a murine model of heart transplantation and in cynomolgus monkeys receiving kidney transplants. CP-690,550 treatment was not associated with hypertension, hyperlipidemia, or lymphoproliferative disease. On the basis of these preclinical results, we believe JAK3 blockade by CP-690,550 has potential for therapeutically desirable immunosuppression in human organ transplantation and in other clinical settings.
Immunology Group, Department of Antibacterials and Immunology, Pfizer Global Researchand Development, Groton, CT 06340, USA. paul_s_changelian@groton.pfizer.com
Paul S
PS
Changelian
Mark E
ME
Flanagan
Douglas J
DJ
Ball
Craig R
CR
Kent
Kelly S
KS
Magnuson
William H
WH
Martin
Bonnie J
BJ
Rizzuti
Perry S
PS
Sawyer
Bret D
BD
Perry
William H
WH
Brissette
Sandra P
SP
McCurdy
Elizabeth M
EM
Kudlacz
Maryrose J
MJ
Conklyn
Eileen A
EA
Elliott
Erika R
ER
Koslov
Michael B
MB
Fisher
Timothy J
TJ
Strelevitz
Kwansik
K
Yoon
David A
DA
Whipple
Jianmin
J
Sun
Michael J
MJ
Munchhof
John L
JL
Doty
Jeffrey M
JM
Casavant
Todd A
TA
Blumenkopf
Michael
M
Hines
Matthew F
MF
Brown
Brett M
BM
Lillie
Chakrapani
C
Subramanyam
Chang
C
Shang-Poa
Anthony J
AJ
Milici
Gretchen E
GE
Beckius
James D
JD
Moyer
Chunyan
C
Su
Thasia G
TG
Woodworth
Anderson S
AS
Gaweco
Chan R
CR
Beals
Bruce H
BH
Littman
Douglas A
DA
Fisher
James F
JF
Smith
Panayiotis
P
Zagouras
Holly A
HA
Magna
Mary J
MJ
Saltarelli
Kimberly S
KS
Johnson
Linda F
LF
Nelms
Shelley G
SG
Des Etages
Lisa S
LS
Hayes
Thomas T
TT
Kawabata
Deborah
D
Finco-Kent
Deanna L
DL
Baker
Michael
M
Larson
Ming-Sing
MS
Si
Ricardo
R
Paniagua
John
J
Higgins
Bari
B
Holm
Bruce
B
Reitz
Yong-Jie
YJ
Zhou
Randall E
RE
Morris
John J
JJ
O'Shea
Dominic C
DC
Borie
D000818:Animals; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D007376:Interleukin-2 / Q000276:immunology; D053616:Janus Kinase 3; D016030:Kidney Transplantation; D008213:Lymphocyte Activation / Q000187:drug effects; D018655:Lymphocyte Count; D007959:Lymphocyte Culture Test, Mixed; D016131:Lymphocyte Subsets / Q000187:drug effects; D008252:Macaca fascicularis; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009206:Myocardium / Q000378:metabolism; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3