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

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

doi:10.1126/science.1087061

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

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

Dermatology

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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.

Original language	English (US)
Pages (from-to)	875-878
Number of pages	4
Journal	Science
Volume	302
Issue number	5646
DOIs	https://doi.org/10.1126/science.1087061
State	Published - Oct 31 2003

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Changelian, P. S., Flanagan, M. E., Ball, D. J., Kent, C. R., Magnuson, K. S., Martin, W. H., Rizzuti, B. J., Sawyer, P. S., Perry, B. D., Brissette, W. H., McCurdy, S. P., Kudlacz, E. M., Conklyn, M. J., Elliott, E. A., Koslov, E. R., Fisher, M. B., Strelevitz, T. J., Yoon, K., Whipple, D. A., ... Borie, D. C. (2003). Prevention of Organ Allograft Rejection by a Specific Janus Kinase 3 Inhibitor. Science, 302(5646), 875-878. https://doi.org/10.1126/science.1087061

Changelian, PS, Flanagan, ME, Ball, DJ, Kent, CR, Magnuson, KS, Martin, WH, Rizzuti, BJ, Sawyer, PS, Perry, BD, Brissette, WH, McCurdy, SP, Kudlacz, EM, Conklyn, MJ, Elliott, EA, Koslov, ER, Fisher, MB, Strelevitz, TJ, Yoon, K, Whipple, DA, Sun, J, Munchhof, MJ, Doty, JL, Casavant, JM, Blumenkopf, TA, Hines, M, Brown, MF, Lillie, BM, Subramanyam, C, Shang-Poa, C, Milici, AJ, Beckius, GE, Moyer, JD, Su, C, Woodworth, TG, Gaweco, AS, Beals, CR, Littman, BH, Fisher, DA, Smith, JF, Zagouras, P, Magna, HA, Saltarelli, MJ, Johnson, KS, Nelms, LF, Des Etages, SG, Hayes, LS, Kawabata, TT, Finco-Kent, D, Baker, DL, Larson, M, Si, MS, Paniagua, R, Higgins, J, Holm, B, Reitz, B, Zhou, YJ, Morris, RE, O'Shea, JJ & Borie, DC 2003, 'Prevention of Organ Allograft Rejection by a Specific Janus Kinase 3 Inhibitor', Science, vol. 302, no. 5646, pp. 875-878. https://doi.org/10.1126/science.1087061

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title = "Prevention of Organ Allograft Rejection by a Specific Janus Kinase 3 Inhibitor",

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.",

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

year = "2003",

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doi = "10.1126/science.1087061",

language = "English (US)",

volume = "302",

pages = "875--878",

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T1 - Prevention of Organ Allograft Rejection by a Specific Janus Kinase 3 Inhibitor

AU - Changelian, Paul S.

AU - Flanagan, Mark E.

AU - Ball, Douglas J.

AU - Kent, Craig R.

AU - Magnuson, Kelly S.

AU - Martin, William H.

AU - Rizzuti, Bonnie J.

AU - Sawyer, Perry S.

AU - Perry, Bret D.

AU - Brissette, William H.

AU - McCurdy, Sandra P.

AU - Kudlacz, Elizabeth M.

AU - Conklyn, Maryrose J.

AU - Elliott, Eileen A.

AU - Koslov, Erika R.

AU - Fisher, Michael B.

AU - Strelevitz, Timothy J.

AU - Yoon, Kwansik

AU - Whipple, David A.

AU - Sun, Jianmin

AU - Munchhof, Michael J.

AU - Doty, John L.

AU - Casavant, Jeffrey M.

AU - Blumenkopf, Todd A.

AU - Hines, Michael

AU - Brown, Matthew F.

AU - Lillie, Brett M.

AU - Subramanyam, Chakrapani

AU - Shang-Poa, Chang

AU - Milici, Anthony J.

AU - Beckius, Gretchen E.

AU - Moyer, James D.

AU - Su, Chunyan

AU - Woodworth, Thasia G.

AU - Gaweco, Anderson S.

AU - Beals, Chan R.

AU - Littman, Bruce H.

AU - Fisher, Douglas A.

AU - Smith, James F.

AU - Zagouras, Panayiotis

AU - Magna, Holly A.

AU - Saltarelli, Mary J.

AU - Johnson, Kimberly S.

AU - Nelms, Linda F.

AU - Des Etages, Shelley G.

AU - Hayes, Lisa S.

AU - Kawabata, Thomas T.

AU - Finco-Kent, Deborah

AU - Baker, Deanna L.

AU - Larson, Michael

AU - Si, Ming Sing

AU - Paniagua, Ricardo

AU - Higgins, John

AU - Holm, Bari

AU - Reitz, Bruce

AU - Zhou, Yong Jie

AU - Morris, Randall E.

AU - O'Shea, John J.

AU - Borie, Dominic C.

PY - 2003/10/31

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N2 - 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.

AB - 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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DO - 10.1126/science.1087061

M3 - Article

C2 - 14593182

AN - SCOPUS:0242332186

SN - 0036-8075

VL - 302

SP - 875

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JO - Science

JF - Science

IS - 5646

ER -

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

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