Biologics in Transplantation (Anti-thymocyte Globulin, Belatacept, Alemtuzumab): How Should We Use Them?

Abstract

Purpose of Review

The use of immunosuppressive agents for induction and maintenance therapies continues to vary widely among countries and transplant centers. This review will consolidate the published body of evidence addressing the effectiveness and safety of the use of three biological agents: anti-thymocyte globulin, alemtuzumab, and belatacept in adult kidney transplant recipients.

Recent Findings

Clinical evidence clearly supports the use of Thymoglobulin in high immunological risk patients, while its benefit in low immunological risk patients remains controversial. Alemtuzumab has the advantage of easy administration with comparable efficacy to Thymoglobulin but concerns regarding increased risk for late rejection. Belatacept is the newest biological agent. It is associated with higher glomerular filtration rates compared to cyclosporine. Belatacept has not been compared to tacrolimus or studied in high immunological risk patients in sufficiently large numbers.

Summary

Tailoring immunosuppressive therapy to patient’s characteristics and immunological risk is the key for successful transplantation.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.

    Kahan BD. Individuality: the barrier to optimal immunosuppression. Nat Rev Immunol. 2003;3(10):831–8.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Kasiske BL, Zeier MG, Chapman JR, et al. KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney Int. 2010;77(4):299–311.

    Article  PubMed  Google Scholar 

  3. 3.

    Ruzek MC, Neff KS, Luong M, et al. In vivo characterization of rabbit anti-mouse thymocyte globulin: a surrogate for rabbit anti-human thymocyte globulin. Transplantation. 2009;88(2):170–9.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Boenisch O, Lopez M, Elyaman W, Magee CN, Ahmad U, Najafian N. Ex vivo expansion of human Tregs by rabbit ATG is dependent on intact STAT3-signaling in CD4(+) T cells and requires the presence of monocytes. Am J Transplant. 2012;12(4):856–66.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Gurkan S, Luan Y, Dhillon N, et al. Immune reconstitution following rabbit antithymocyte globulin. Am J Transplant. 2010;10(9):2132–41.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    • Brennan DC, Flavin K, Lowell JA, et al. A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients. Transplantation. 1999;67(7):1011–8. This is one of the few randomized double-blinded trials in transplantation and was the first to show that an induction agent, Thymoglobulin, not only delayed but decreased the incidence of acut rejection to an unprecedented level of less than 5% at one year

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Gaber AO, First MR, Tesi RJ, et al. Results of the double-blind, randomized, multicenter, phase III clinical trial of Thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation. Transplantation. 1998;66(1):29–37.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Popow I, Leitner J, Grabmeier-Pfistershammer K, et al. A comprehensive and quantitative analysis of the major specificities in rabbit antithymocyte globulin preparations. Am J Transplant. 2013;13(12):3103–13.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Cicora F, Mos F, Paz M, Roberti J. Clinical experience with thymoglobulin and antithymocyte globulin-Fresenius as induction therapy in renal transplant patients: a retrospective study. Exp Clin Transplant. 2013;11(5):418–22.

    Article  PubMed  Google Scholar 

  10. 10.

    Chen GD, Lai XQ, Ko DS, et al. Comparison of efficacy and safety between rabbit anti-thymocyte globulin and anti-T lymphocyte globulin in kidney transplantation from donation after cardiac death: a retrospective cohort study. Nephrology (Carlton). 2015;20(8):539–43.

    CAS  Article  Google Scholar 

  11. 11.

    Klem P, Cooper JE, Weiss AS, et al. Reduced dose rabbit anti-thymocyte globulin induction for prevention of acute rejection in high-risk kidney transplant recipients. Transplantation. 2009;88(7):891–6.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Peddi VR, Bryant M, Roy-Chaudhury P, Woodle ES, First MR. Safety, efficacy, and cost analysis of thymoglobulin induction therapy with intermittent dosing based on CD3+ lymphocyte counts in kidney and kidney-pancreas transplant recipients. Transplantation. 2002;73(9):1514–8.

    Article  PubMed  Google Scholar 

  13. 13.

    Stevens RB, Foster KW, Miles CD, et al. A randomized 2x2 factorial trial, part 1: single-dose rabbit antithymocyte globulin induction may improve renal transplantation outcomes. Transplantation. 2015;99(1):197–209.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Charpentier B, Rostaing L, Berthoux F, et al. A three-arm study comparing immediate tacrolimus therapy with antithymocyte globulin induction therapy followed by tacrolimus or cyclosporine A in adult renal transplant recipients. Transplantation. 2003;75(6):844–51.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Mourad G, Garrigue V, Squifflet JP, et al. Induction versus noninduction in renal transplant recipients with tacrolimus-based immunosuppression. Transplantation. 2001;72(6):1050–5.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Webster AC, Ruster LP, McGee R, et al. Interleukin 2 receptor antagonists for kidney transplant recipients. Cochrane Database Syst Rev. 2010;1:CD003897.

    Google Scholar 

  17. 17.

    Brennan DC, Daller JA, Lake KD, Cibrik D, Del Castillo D. Thymoglobulin induction study G. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med. 2006;355(19):1967–77.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Brennan DC, Schnitzler MA. Long-term results of rabbit antithymocyte globulin and basiliximab induction. N Engl J Med. 2008;359(16):1736–8.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Lentine KL, Schnitzler MA, Xiao H, Brennan DC. Long-term safety and efficacy of antithymocyte globulin induction: use of integrated national registry data to achieve ten-year follow-up of 10-10 Study participants. Trials. 2015;16:365.

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Noel C, Abramowicz D, Durand D, et al. Daclizumab versus antithymocyte globulin in high-immunological-risk renal transplant recipients. J Am Soc Nephrol. 2009;20(6):1385–92.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Hellemans R, Hazzan M, Durand D, et al. Daclizumab versus rabbit antithymocyte globulin in high-risk renal transplants: five-year follow-up of a randomized study. Am J Transplant. 2015;15(7):1923–32.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Schold J, Poggio E, Goldfarb D, Kayler L, Flechner S. Clinical outcomes associated with induction regimens among retransplant kidney recipients in the United States. Transplantation. 2015;99(6):1165–71.

    Article  PubMed  Google Scholar 

  23. 23.

    • Woodle ES, First MR, Pirsch J, et al. A prospective, randomized, double-blind, placebo-controlled multicenter trial comparing early (7 day) corticosteroid cessation versus long-term, low-dose corticosteroid therapy. Ann Surg. 2008;248(4):564–77. This randomized-double-blineded study of early steroid withdrawal was possible with Thymoglobulin but not basilixmab induction but there was an increased risk of acute and chronic rejection without significant benefit in steroid-induced side effects like weight gain, post transplant diabetes or fractures or cataracts

    PubMed  Google Scholar 

  24. 24.

    Tanriover B, Jaikaransingh V, MacConmara MP, et al. Acute rejection rates and graft outcomes according to induction regimen among recipients of kidneys from deceased donors treated with tacrolimus and mycophenolate. Clin J Am Soc Nephrol. 2016;11(9):1650–61.

    Article  PubMed  Google Scholar 

  25. 25.

    Tanriover B, Zhang S, MacConmara M, et al. Induction therapies in live donor kidney transplantation on tacrolimus and mycophenolate with or without steroid maintenance. Clin J Am Soc Nephrol. 2015;10(6):1041–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Thomusch O, Wiesener M, Opgenoorth M, et al. Rabbit-ATG or basiliximab induction for rapid steroid withdrawal after renal transplantation (Harmony): an open-label, multicentre, randomised controlled trial. Lancet. 2016.

  27. 27.

    Kliem V, Fricke L, Wollbrink T, Burg M, Radermacher J, Rohde F. Improvement in long-term renal graft survival due to CMV prophylaxis with oral ganciclovir: results of a randomized clinical trial. Am J Transplant. 2008;8(5):975–83.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Bustami RT, Ojo AO, Wolfe RA, et al. Immunosuppression and the risk of post-transplant malignancy among cadaveric first kidney transplant recipients. Am J Transplant. 2004;4(1):87–93.

    Article  PubMed  Google Scholar 

  29. 29.

    Opelz G, Naujokat C, Daniel V, Terness P, Dohler B. Disassociation between risk of graft loss and risk of non-Hodgkin lymphoma with induction agents in renal transplant recipients. Transplantation. 2006;81(9):1227–33.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    van Leeuwen MT, Grulich AE, Webster AC, et al. Immunosuppression and other risk factors for early and late non-Hodgkin lymphoma after kidney transplantation. Blood. 2009;114(3):630–7.

    Article  PubMed  Google Scholar 

  31. 31.

    Gaber AO, Matas AJ, Henry ML, et al. Antithymocyte globulin induction in living donor renal transplant recipients: final report of the TAILOR registry. Transplantation. 2012;94(4):331–7.

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Marks WH, Ilsley JN, Dharnidharka VR. Posttransplantation lymphoproliferative disorder in kidney and heart transplant recipients receiving thymoglobulin: a systematic review. Transplant Proc. 2011;43(5):1395–404.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Kidney Disease: Improving Global Outcomes Transplant Work G. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009;9 Suppl 3:S1–155.

  34. 34.

    Lim WH, Chadban SJ, Campbell S, Dent H, Russ GR, McDonald SP. Interleukin-2 receptor antibody does not reduce rejection risk in low immunological risk or tacrolimus-treated intermediate immunological risk renal transplant recipients. Nephrology (Carlton). 2010;15(3):368–76.

    Article  Google Scholar 

  35. 35.

    Willoughby LM, Schnitzler MA, Brennan DC, et al. Early outcomes of thymoglobulin and basiliximab induction in kidney transplantation: application of statistical approaches to reduce bias in observational comparisons. Transplantation. 2009;87(10):1520–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Calne R, Moffatt SD, Friend PJ, et al. Campath IH allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients. Transplantation. 1999;68(10):1613–6.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Vo AA, Wechsler EA, Wang J, et al. Analysis of subcutaneous (SQ) alemtuzumab induction therapy in highly sensitized patients desensitized with IVIG and rituximab. Am J Transplant. 2008;8(1):144–9.

    CAS  PubMed  Google Scholar 

  38. 38.

    Hanaway MJ, Woodle ES, Mulgaonkar S, et al. Alemtuzumab induction in renal transplantation. N Engl J Med. 2011;364(20):1909–19.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Willicombe M, Brookes P, Santos-Nunez E, et al. Outcome of patients with preformed donor-specific antibodies following alemtuzumab induction and tacrolimus monotherapy. Am J Transplant. 2011;11(3):470–7.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Zachariah M, Nader ND, Brar J, et al. Alemtuzumab and minimization immunotherapy in kidney transplantation: long-term results of comparison with rabbit anti-thymocyte globulin and standard triple maintenance therapy. Transplant Proc. 2014;46(1):94–100.

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Farney AC, Doares W, Rogers J, et al. A randomized trial of alemtuzumab versus antithymocyte globulin induction in renal and pancreas transplantation. Transplantation. 2009;88(6):810–9.

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Morgan RD, O’Callaghan JM, Knight SR, Morris PJ. Alemtuzumab induction therapy in kidney transplantation: a systematic review and meta-analysis. Transplantation. 2012;93(12):1179–88.

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Zhang X, Huang H, Han S, Fu S, Wang L. Alemtuzumab induction in renal transplantation: a meta-analysis and systemic review. Transpl Immunol. 2012;27(2–3):63–8.

    Article  PubMed  Google Scholar 

  44. 44.

    Ciancio G, Gaynor JJ, Guerra G, et al. Randomized trial of three induction antibodies in kidney transplantation: long-term results. Transplantation. 2014;97(11):1128–38.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Group CSC, Haynes R, Harden P, et al. Alemtuzumab-based induction treatment versus basiliximab-based induction treatment in kidney transplantation (the 3C Study): a randomised trial. Lancet. 2014;384(9955):1684–90.

    Article  Google Scholar 

  46. 46.

    Saull HE, Enderby CY, Gonwa TA, Wadei HM. Comparison of alemtuzumab vs. antithymocyte globulin induction therapy in primary non-sensitized renal transplant patients treated with rapid steroid withdrawal. Clin Transpl. 2015;29(7):573–80.

    CAS  Article  Google Scholar 

  47. 47.

    Chan K, Taube D, Roufosse C, et al. Kidney transplantation with minimized maintenance: alemtuzumab induction with tacrolimus monotherapy—an open label, randomized trial. Transplantation. 2011;92(7):774–80.

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Cannon RM, Brock G, Marvin MR, Eng M, Buell JF. Analysis of BK viral infection after alemtuzumab induction for renal transplant. Transpl Infect Dis. 2012;14(4):374–9.

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Theodoropoulos N, Wang E, Penugonda S, et al. BK virus replication and nephropathy after alemtuzumab-induced kidney transplantation. Am J Transplant. 2013;13(1):197–206.

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    LaMattina JC, Mezrich JD, Hofmann RM, et al. Alemtuzumab as compared to alternative contemporary induction regimens. Transpl Int. 2012;25(5):518–26.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Margreiter R, Klempnauer J, Neuhaus P, Muehlbacher F, Boesmueller C, Calne RY. Alemtuzumab (Campath-1H) and tacrolimus monotherapy after renal transplantation: results of a prospective randomized trial. Am J Transplant. 2008;8(7):1480–5.

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Schadde E, D’Alessandro AM, Knechtle SJ, et al. Alemtuzumab induction and triple maintenance immunotherapy in kidney transplantation from donors after cardiac death. Transpl Int. 2008;21(7):625–36.

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Ciancio G, Burke GW, Gaynor JJ, et al. A randomized trial of three renal transplant induction antibodies: early comparison of tacrolimus, mycophenolate mofetil, and steroid dosing, and newer immune-monitoring. Transplantation. 2005;80(4):457–65.

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Hall EC, Engels EA, Pfeiffer RM, Segev DL. Association of antibody induction immunosuppression with cancer after kidney transplantation. Transplantation. 2015;99(5):1051–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Puttarajappa C, Yabes J, Bei L, et al. Cancer risk with alemtuzumab following kidney transplantation. Clin Transpl. 2013;27(3):E264–71.

    CAS  Article  Google Scholar 

  56. 56.

    Vincenti F, Larsen C, Durrbach A, et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med. 2005;353(8):770–81.

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    • Vincenti F, Charpentier B, Vanrenterghem Y, et al. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant. 2010;10(3):535–46. This randomized open label study of two different regimens of belatacept used in place of cyclosporine at relatively high doses and levels was associated with more rejection but a better estimated glomerular filtration rate

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Durrbach A, Pestana JM, Pearson T, et al. A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study). Am J Transplant. 2010;10(3):547–57.

    CAS  Article  PubMed  Google Scholar 

  59. 59.

    Vincenti F, Larsen CP, Alberu J, et al. Three-year outcomes from BENEFIT, a randomized, active-controlled, parallel-group study in adult kidney transplant recipients. Am J Transplant. 2012;12(1):210–7.

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Pestana JO, Grinyo JM, Vanrenterghem Y, et al. Three-year outcomes from BENEFIT-EXT: a phase III study of belatacept versus cyclosporine in recipients of extended criteria donor kidneys. Am J Transplant. 2012;12(3):630–9.

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    Vincenti F, Rostaing L, Grinyo J, et al. Belatacept and long-term outcomes in kidney transplantation. N Engl J Med. 2016;374(4):333–43.

    CAS  Article  PubMed  Google Scholar 

  62. 62.

    Durrbach A, Pestana JM, Florman S, et al. Long-term outcomes in Belatacept- versus cyclosporine-treated recipients of extended criteria donor kidneys: final results from BENEFIT-EXT, a phase III randomized study. Am J Transplant. 2016;16(11):3192–201.

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007;357(25):2562–75.

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Ferguson R, Grinyo J, Vincenti F, et al. Immunosuppression with belatacept-based, corticosteroid-avoiding regimens in de novo kidney transplant recipients. Am J Transplant. 2011;11(1):66–76.

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Gupta G, Regmi A, Kumar D, et al. Safe conversion from tacrolimus to belatacept in high immunologic risk kidney transplant recipients with allograft dysfunction. Am J Transplant. 2015;15(10):2726–31.

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    Rostaing L, Massari P, Garcia VD, et al. Switching from calcineurin inhibitor-based regimens to a belatacept-based regimen in renal transplant recipients: a randomized phase II study. Clin J Am Soc Nephrol. 2011;6(2):430–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Brakemeier S, Kannenkeril D, Durr M, et al. Experience with belatacept rescue therapy in kidney transplant recipients. Transpl Int. 2016;29(11):1184–95.

    CAS  Article  PubMed  Google Scholar 

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Correspondence to Reem Daloul.

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The primary author and all involved coauthors of this article have no financial or non-financial conflict of interest to declare. The manuscript is original and is currently not under consideration by any other journal and has not been published before.

Sagar Gupta and Reem Daloul declare no conflict of interest.

Daniel Brennan reports grants from Alexion, Astellas, Bristol-Meyer Squib, Shire, Pfizer, and Veloxi and personal fees from Alexion, Astellas, Novartis, Sanofi, and Veloxis, outside the submitted work.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Kidney Transplantation

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Daloul, R., Gupta, S. & Brennan, D.C. Biologics in Transplantation (Anti-thymocyte Globulin, Belatacept, Alemtuzumab): How Should We Use Them?. Curr Transpl Rep 4, 82–90 (2017). https://doi.org/10.1007/s40472-017-0147-8

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Keywords

  • Thymoglobulin
  • Alemtuzumab
  • Belatacept
  • Induction
  • Immunotherapy
  • Kidney transplant
  • Maintenance therapy