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.
Changelian
Paul S
PS
Immunology Group, Department of Antibacterials and Immunology, Pfizer Global Researchand Development, Groton, CT 06340, USA. paul_s_changelian@groton.pfizer.com
Flanagan
Mark E
ME
Ball
Douglas J
DJ
Kent
Craig R
CR
Magnuson
Kelly S
KS
Martin
William H
WH
Rizzuti
Bonnie J
BJ
Sawyer
Perry S
PS
Perry
Bret D
BD
Brissette
William H
WH
McCurdy
Sandra P
SP
Kudlacz
Elizabeth M
EM
Conklyn
Maryrose J
MJ
Elliott
Eileen A
EA
Koslov
Erika R
ER
Fisher
Michael B
MB
Strelevitz
Timothy J
TJ
Yoon
Kwansik
K
Whipple
David A
DA
Sun
Jianmin
J
Munchhof
Michael J
MJ
Doty
John L
JL
Casavant
Jeffrey M
JM
Blumenkopf
Todd A
TA
Hines
Michael
M
Brown
Matthew F
MF
Lillie
Brett M
BM
Subramanyam
Chakrapani
C
Shang-Poa
Chang
C
Milici
Anthony J
AJ
Beckius
Gretchen E
GE
Moyer
James D
JD
Su
Chunyan
C
Woodworth
Thasia G
TG
Gaweco
Anderson S
AS
Beals
Chan R
CR
Littman
Bruce H
BH
Fisher
Douglas A
DA
Smith
James F
JF
Zagouras
Panayiotis
P
Magna
Holly A
HA
Saltarelli
Mary J
MJ
Johnson
Kimberly S
KS
Nelms
Linda F
LF
Des Etages
Shelley G
SG
Hayes
Lisa S
LS
Kawabata
Thomas T
TT
Finco-Kent
Deborah
D
Baker
Deanna L
DL
Larson
Michael
M
Si
Ming-Sing
MS
Paniagua
Ricardo
R
Higgins
John
J
Holm
Bari
B
Reitz
Bruce
B
Zhou
Yong-Jie
YJ
Morris
Randall E
RE
O'Shea
John J
JJ
Borie
Dominic C
DC
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