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Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor |
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| Authors: | Changelian Paul S Flanagan Mark E Ball Douglas J Kent Craig R Magnuson Kelly S Martin William H Rizzuti Bonnie J Sawyer Perry S Perry Bret D Brissette William H McCurdy Sandra P Kudlacz Elizabeth M Conklyn Maryrose J Elliott Eileen A Koslov Erika R Fisher Michael B Strelevitz Timothy J Yoon Kwansik Whipple David A Sun Jianmin Munchhof Michael J Doty John L Casavant Jeffrey M Blumenkopf Todd A Hines Michael Brown Matthew F Lillie Brett M Subramanyam Chakrapani Shang-Poa Chang Milici Anthony J Beckius Gretchen E Moyer James D Su Chunyan Woodworth Thasia G Gaweco Anderson S Beals Chan R |
| Affiliation: | Immunology Group, Department of Antibacterials and Immunology, Pfizer Global Researchand Development, Groton, CT 06340, USA. paul_s_changelian@groton.pfizer.com |
| Abstract: | 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. |
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