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. Borie^5*

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}groton.pfizer.com (P.S.C.); dborie{at}stanford.edu (D.C.B.)

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