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Gaurav Article

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Novel immunosuppressive agents in kidney transplantation J.E. Cooper and A.C. Wiseman University of Colorado – Denver and Health Sciences Center, Transplant Center,  Aurora, CO, USA  Novel immunosuppressive agents Abstract. The last several decades have seen a substantial decrease in the prevalence of acut e all ogr aft reje ction in kidn ey tra nsp lant recipi ents, while equivale nt impro vements in long-term graft function have not been real- iz ed .Asa re su lt , th e pr imar y focus of ne w im- munosuppressive drug development has ex-  panded to include ease of use, improved side effect profiles, and reduced nephrotoxicity in addition to the more traditional goal of im-  proved short-term outcomes. A number of novel drugs are currently under investigation in Phase I, II, or III clinical trials primarily to replace the nephrotoxic but highly effective calcineurin inhibitors. ISA247 (voclosporine) is a cyclosporine (CsA) analog with reduced neph rot oxic ity in Pha se III stu dy . AEB071 (so tra sta uri n), a pro tei n kinase C inhi bit or , and CP-69 0550, a JAK3 inhibito r, are small mole - cul es in Pha se II stud ies . Eve rol imu s is der ived from the mTOR inhibitor sirolimus and is in Phase III study. Belatacept is a humanized an- tibo dy that inhibits T -cell costimulation and has shown encou ragin g resu lts in multi ple Phas e II and III trials. Ale fac ept and Efa - luzimab are humanized antibodies that inhibit T -c ell ad hes ion and are in Ph as eI and II cli nic al trials. This article reviews the mechanisms of action as well as published and preliminary re- su lts of th e Ph ase I III cl in ic al trials in vo lv in g these novel immunosuppressive agents. Introduction The introduction of the calcineurin inhibi- tors (CNIs) cyclosporine (CsA) and tacrolim us together with the development of antiprolifer- ative agents such as mycophenolate mofetil (MMF) and antibody induction agents, has resulted in vast improvements in acute rejec - tion (AR) rates and short-term graft survival over the last three decades in patients receiv- ing kidney transplants [10]. While this prog- res s initi ally was predicte d to lea d to a corr e- sponding improvement in long- term graf t function from the late 1980’s to the mid 1990’s [23], a mo re re ce nt anal ys is ha s shown a lack of improvement in the relative risk of gra ft failure for those transplanted in 1995 through 2000 despite a reduction in acute re-  jection rates of nearly 50% during that time [35] . One potential explana tion for this lack of improve ment in long-ter m graf t survival is the nephrotoxicity imparted by CNIs over time. This hypothesis is supported by histo- logical data obtai ned from protoco l biops ies of kidney-pancreas recipients over 10 years that identified chronic CNI nephrotoxicity in 50%of gr af ts at 2 ye ars and in 100% of gr aft s at 10 years post-transplant [41]. Despite the overt nephrotoxicity of CNIs, these agents remain the cornerstone of main- tenance immunosuppression regimens due to their efficacy in preventing acute rejection. Acc ord ing to the Sci ent ifi c Reg ist ry of Trans-  plant Recipients, CNIs are used in 95% of immunosuppression protocols at the time of hospital discharge after kidney transplanta- tion in the United States. However, as the fo- cus of immunosuppression has shifted away fro m fur the r red uct ion in the inc ide nce of AR and towards preservation of long-term func- tion, a significant number of novel immuno- suppressive agents are undergoing develop- men t as a re pla cement forCNIs. In thi s article we review the mechanisms of action, pre- clinical, and Phase I – III completed or ongo- ing clinical tri als of 7 novel immunosup -  pressive agents. While not comprehensive of all dru gs cur ren tly in develo pme nt [64 ], the se agents were selected for review based upon their common features of a similar immune cell target (the T-lymphocyte) and a similar focusin drug devel opmen t (CNIminim iza tio n or elimination). Key words kidney transplant – immunosuppres sion clinical trials-revi ew Received May 29, 2009; accepted in revised form November 6, 2009 Correspondenc e to  A.C. Wiseman, MD University of Colorado – Denver and Health Sciences Center, Transplant Center, 1635 N Aurora Court,  AOP 7089, MS F749,  Aurora, CO 80045, USA  Alexander.wiseman@ ucdenver.edu Review ©2010 Dustri-Verlag Dr. K. Feistle ISSN 0301-0430 Clinical Nephrology, Vol. 73 – No. 5/2010 (333-343)
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