Investigational immunosuppressive drugs and approaches in clinical kidney transplantation
- John Vella, MD, FACP, FRCP, FASN, FAST
John Vella, MD, FACP, FRCP, FASN, FAST
- Associate Professor of Medicine
- Tufts University School of Medicine
- Section Editor
- Daniel C Brennan, MD, FACP
Daniel C Brennan, MD, FACP
- Editor-in-Chief — Nephrology
- Section Editor — Renal Transplantation
- Professor of Medicine
- Medical Director and Co-Director of the Comprehensive Transplant Center, Department of Internal Medicine, Division of Nephrology
- Johns Hopkins Medical School
The introduction of cyclosporine in the early 1980s improved renal allograft survival by approximately 15 percent at one year posttransplant . However, cyclosporine failed to enhance long-term graft survival because of the inability to suppress the chronic and progressive loss of functioning renal tissue arising from antigen-dependent and -independent immunologic factors [2-4]. (See "Chronic renal allograft nephropathy".)
The administration of cyclosporine or tacrolimus may also exacerbate this process because of direct nephrotoxicity [5,6]. In addition, renal transplant recipients are at risk for significant side effects due to immunosuppression, including infection, cardiovascular disease, hypertension, and malignancy. (See "Cyclosporine and tacrolimus nephrotoxicity".)
These limitations constitute the rationale for the continued development of new immunosuppressive agents [7-11]. This topic will review the status of some of the new drugs that are currently under evaluation for use in renal transplantation.
This section will review those drugs and/or approaches undergoing current investigation.
Eculizimab — Eculizimab is a complement-inhibitory monoclonal antibody that inhibits assembly of the membrane attack complex via C5. The drug is licensed for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. It has been used "off label" to treat refractory antibody-mediated rejection in a very limited number of patients, although with impressive efficacy. Additional study is required before even preliminary recommendations can be made about its administration to transplant recipients. Cost is a major limitation to the use of this agent as it is extraordinarily expensive.To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Cecka JM, Terasaki PI. The UNOS scientific renal transplant registry. United Network for Organ Sharing. Clin Transpl 1995; :1.
- Terasaki PI, McClelland JD, Yuge J, et al. Advances in kidney transplantation: 1985-1995. Clin Transpl 1995; :487.
- Carpenter CB. Long-term failure of renal transplants: adding insult to injury. Kidney Int Suppl 1995; 50:S40.
- Tullius SG, Tilney NL. Both alloantigen-dependent and -independent factors influence chronic allograft rejection. Transplantation 1995; 59:313.
- Vella JP, Sayegh MH. Current and future immunosuppressive therapies: impact on chronic allograft dysfunction. J Nephrol 1997; 10:229.
- Vella JP, Sayegh MH. Maintenance pharmacological immunosuppressive strategies in renal transplantation. Postgrad Med J 1997; 73:386.
- Denton MD, Magee CC, Sayegh MH. Immunosuppressive strategies in transplantation. Lancet 1999; 353:1083.
- Gummert JF, Ikonen T, Morris RE. Newer immunosuppressive drugs: a review. J Am Soc Nephrol 1999; 10:1366.
- Kanmaz T, Knechtle SJ. Novel agents or strategies for immunosuppression after renal transplantation. Curr Opin Organ Transplant 2003; 8:172.
- Kahan BD. Individuality: the barrier to optimal immunosuppression. Nat Rev Immunol 2003; 3:831.
- Tedesco Silva H Jr, Pinheiro Machado P, Rosso Felipe C, Medina Pestana JO. Immunotherapy for De Novo renal transplantation: what's in the pipeline? Drugs 2006; 66:1665.
- Weaver TA, Charafeddine AH, Agarwal A, et al. Alefacept promotes co-stimulation blockade based allograft survival in nonhuman primates. Nat Med 2009; 15:746.
- Bîrsan T, Dambrin C, Freitag DG, et al. The novel calcineurin inhibitor ISA247: a more potent immunosuppressant than cyclosporine in vitro. Transpl Int 2005; 17:767.
- Bissonnette R, Papp K, Poulin Y, et al. A randomized, multicenter, double-blind, placebo-controlled phase 2 trial of ISA247 in patients with chronic plaque psoriasis. J Am Acad Dermatol 2006; 54:472.
- The first-in-class oral protein kinase C (pkc) inhibitor nvp-aeb071 (aeb) prolongs renal allograft survival in non-human primates (nhp) and suppresses lymphocyte proliferation at safe exposures in human proof-of-concept studies (abstract). Transplantation 2006; 82(Suppl2):86.
- Budde K, Sommerer C, Becker T, et al. Sotrastaurin, a novel small molecule inhibiting protein kinase C: first clinical results in renal-transplant recipients. Am J Transplant 2010; 10:571.
- Kudlacz E, Perry B, Sawyer P, et al. The novel JAK-3 inhibitor CP-690550 is a potent immunosuppressive agent in various murine models. Am J Transplant 2004; 4:51.
- Busque S, Leventhal J, Brennan DC, et al. Calcineurin-inhibitor-free immunosuppression based on the JAK inhibitor CP-690,550: a pilot study in de novo kidney allograft recipients. Am J Transplant 2009; 9:1936.
- Dall'Amico R, Livi U, Milano A, et al. Extracorporeal photochemotherapy as adjuvant treatment of heart transplant recipients with recurrent rejection. Transplantation 1995; 60:45.
- Costanzo-Nordin MR, McManus BM, Wilson JE, et al. Efficacy of photopheresis in the rescue therapy of acute cellular rejection in human heart allografts: a preliminary clinical and immunopathologic report. Transplant Proc 1993; 25:881.
- Dall'Amico R, Murer L, Montini G, et al. Successful treatment of recurrent rejection in renal transplant patients with photopheresis. J Am Soc Nephrol 1998; 9:121.
- Kawai T, Cosimi AB, Spitzer TR, et al. HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med 2008; 358:353.
- Scandling JD, Busque S, Dejbakhsh-Jones S, et al. Tolerance and chimerism after renal and hematopoietic-cell transplantation. N Engl J Med 2008; 358:362.
- Starzl TE. Immunosuppressive therapy and tolerance of organ allografts. N Engl J Med 2008; 358:407.
- Kuypers DR, Vanrenterghem YF. Monoclonal antibodies in renal transplantation: old and new. Nephrol Dial Transplant 2004; 19:297.
- Abramowicz D, Schandene L, Goldman M, et al. Release of tumor necrosis factor, interleukin-2, and gamma-interferon in serum after injection of OKT3 monoclonal antibody in kidney transplant recipients. Transplantation 1989; 47:606.
- Woodle ES, Thistlethwaite JR, Jolliffe LK, et al. Humanized OKT3 antibodies: successful transfer of immune modulating properties and idiotype expression. J Immunol 1992; 148:2756.
- Alegre ML, Peterson LJ, Xu D, et al. A non-activating "humanized" anti-CD3 monoclonal antibody retains immunosuppressive properties in vivo. Transplantation 1994; 57:1537.
- Woodle ES, Xu D, Zivin RA, et al. Phase I trial of a humanized, Fc receptor nonbinding OKT3 antibody, huOKT3gamma1(Ala-Ala) in the treatment of acute renal allograft rejection. Transplantation 1999; 68:608.
- Friend PJ, Hale G, Chatenoud L, et al. Phase I study of an engineered aglycosylated humanized CD3 antibody in renal transplant rejection. Transplantation 1999; 68:1632.
- Waid TH, Lucas BA, Amlot P, et al. T10B9.1A-31 anti-T-cell monoclonal antibody: preclinical studies and clinical treatment of solid organ allograft rejection. Am J Kidney Dis 1989; 14:61.
- Brown SA, Lucas BA, Waid TH, et al. T10B9 (MEDI-500) mediated immunosuppression: studies on the mechanism of action. Clin Transplant 1996; 10:607.
- Waid TH, Lucas BA, Thompson JS, et al. Treatment of renal allograft rejection with T10B9.1A31 or OKT3: final analysis of a phase II clinical trial. Transplantation 1997; 64:274.
- Rabb H, Bonventre JV. Leukocyte adhesion molecules in transplantation. Am J Med 1999; 107:157.
- Cosimi AB, Conti D, Delmonico FL, et al. In vivo effects of monoclonal antibody to ICAM-1 (CD54) in nonhuman primates with renal allografts. J Immunol 1990; 144:4604.
- Haug CE, Colvin RB, Delmonico FL, et al. A phase I trial of immunosuppression with anti-ICAM-1 (CD54) mAb in renal allograft recipients. Transplantation 1993; 55:766.
- Salmela K, Wramner L, Ekberg H, et al. A randomized multicenter trial of the anti-ICAM-1 monoclonal antibody (enlimomab) for the prevention of acute rejection and delayed onset of graft function in cadaveric renal transplantation: a report of the European Anti-ICAM-1 Renal Transplant Study Group. Transplantation 1999; 67:729.
- Nicolls MR, Gill RG. LFA-1 (CD11a) as a therapeutic target. Am J Transplant 2006; 6:27.
- Hourmant M, Bedrossian J, Durand D, et al. A randomized multicenter trial comparing leukocyte function-associated antigen-1 monoclonal antibody with rabbit antithymocyte globulin as induction treatment in first kidney transplantations. Transplantation 1996; 62:1565.
- Vincenti F, Mendez R, Pescovitz M, et al. A phase I/II randomized open-label multicenter trial of efalizumab, a humanized anti-CD11a, anti-LFA-1 in renal transplantation. Am J Transplant 2007; 7:1770.
- Kunzendorf U, Ziegler E, Kabelitz D. FTY720--the first compound of a new promising class of immunosuppressive drugs. Nephrol Dial Transplant 2004; 19:1677.
- Guba M, Graeb C, Jauch KW, Geissler EK. Pro- and anti-cancer effects of immunosuppressive agents used in organ transplantation. Transplantation 2004; 77:1777.
- Guasch A, Roy-Chaudhury P, Woodle ES, et al. Assessment of efficacy and safety of FK778 in comparison with standard care in renal transplant recipients with untreated BK nephropathy. Transplantation 2010; 90:891.
- Tedesco-Silva H, Mourad G, Kahan BD, et al. FTY720, a novel immunomodulator: efficacy and safety results from the first phase 2A study in de novo renal transplantation. Transplantation 2004; 77:1826.
- Mulgaonkar S, Tedesco H, Oppenheimer F, et al. FTY720/cyclosporine regimens in de novo renal transplantation: a 1-year dose-finding study. Am J Transplant 2006; 6:1848.
- Salvadori M, Budde K, Charpentier B, et al. FTY720 versus MMF with cyclosporine in de novo renal transplantation: a 1-year, randomized controlled trial in Europe and Australasia. Am J Transplant 2006; 6:2912.
- Saab G, Almony A, Blinder KJ, et al. Reversible cystoid macular edema secondary to fingolimod in a renal transplant recipient. Arch Ophthalmol 2008; 126:140.
- Vanrenterghem Y, van Hooff JP, Klinger M, et al. The effects of FK778 in combination with tacrolimus and steroids: a phase II multicenter study in renal transplant patients. Transplantation 2004; 78:9.
- UNDER DEVELOPMENT
- Voclosporine (ISA247)
- Sotrastaurin (AEB071)
- Tofacitinib (formerly Tasocitinib [CP690550]) Jak 3 inhibitor
- No maintenance immunosuppression
- STALLED DEVELOPMENT
- Humanized OKT3
- T10B9.1A monoclonal antibody
- Anti-ICAM-1 antibodies
- Anti-LFA-1 antibodies
- Fingolimod (FTY720)
- FK778, metabolite of leflunomide
- SUMMARY AND RECOMMENDATIONS