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Science 302 (5646): 875-878

Copyright © 2003 by the American Association for the Advancement of Science

Prevention of Organ Allograft Rejection by a Specific Janus Kinase 3 Inhibitor

Paul S. Changelian,1* Mark E. Flanagan,1 Douglas J. Ball,2 Craig R. Kent,1 Kelly S. Magnuson,1 William H. Martin,1 Bonnie J. Rizzuti,1 Perry S. Sawyer,1 Bret D. Perry,1 William H. Brissette,1 Sandra P. McCurdy,1 Elizabeth M. Kudlacz,1 Maryrose J. Conklyn,1 Eileen A. Elliott,1 Erika R. Koslov,1 Michael B. Fisher,3 Timothy J. Strelevitz,3 Kwansik Yoon,3 David A. Whipple,1 Jianmin Sun,1 Michael J. Munchhof,1 John L. Doty,1 Jeffrey M. Casavant,1 Todd A. Blumenkopf,1 Michael Hines,1 Matthew F. Brown,1 Brett M. Lillie,1 Chakrapani Subramanyam,1 Chang Shang-Poa,1 Anthony J. Milici,1 Gretchen E. Beckius,1 James D. Moyer,1 Chunyan Su,1 Thasia G. Woodworth,1 Anderson S. Gaweco,1 Chan R. Beals,1 Bruce H. Littman,1 Douglas A. Fisher,1 James F. Smith,1 Panayiotis Zagouras,4 Holly A. Magna,4 Mary J. Saltarelli,4 Kimberly S. Johnson,4 Linda F. Nelms,2 Shelley G. Des Etages,4 Lisa S. Hayes,4 Thomas T. Kawabata,2 Deborah Finco-Kent,2 Deanna L. Baker,2 Michael Larson,5 Ming-Sing Si,5 Ricardo Paniagua,5 John Higgins,6 Bari Holm,5 Bruce Reitz,5 Yong-Jie Zhou,7 Randall E. Morris,5 John J. O'Shea,7 Dominic C. Borie5*

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 prolongedsurvival in a murine model of heart transplantation and in cynomolgus monkeys receiving kidney transplants. CP-690,550 treatment was not associatedwith 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 andin other clinical settings.

1 Immunology Group, Department of Antibacterials and Immunology, Pfizer Global Researchand Development, Groton, CT 06340, USA.
2 Department of Drug Safety Evaluation, Pfizer Global Researchand Development, Groton, CT 06340, USA.
3 Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Researchand Development, Groton, CT 06340, USA.
4 Department of Genomic and Proteomic Sciences, Pfizer Global Researchand Development, Groton, CT 06340, USA.
5 Transplantation Immunology Laboratory, Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
6 Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
7 Molecular Immunology and Inflammation Branch, National Institutes of Health, Bethesda, MD 20892, USA.

* To whom correspondence should be addressed. E-mail: paul_s_changelian{at} (P.S.C.); dborie{at} (D.C.B.)

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