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Monoclonal Antibody Targeting of the Il-2R Complex

  • Flavio G. Vincenti

Abstract

Biologie agents have been used for induction therapy in renal transplantation since the 1970s. The primary objective of induction therapy has been to block T cell responses at the time of antigen presentation following allograft transplantation in an effort to reorient the host immune response toward accommodation rather than rejection. The first biologic agents that were used for induction were polyclonal antilymphocyte preparations obtained from horses or rabbits. The polyclonal antibodies result in T cell depletion thus depriving the host of immune reactive cells. However these polyclonal preparations are raised against antigens of whle cells and thus they target a variety of antigens including the costimulatory molecules, adhesion molecules and CD25. Cross-reactive antibodies also target neutrophils, red blood cells and platelets resulting in a number of hematologic abnormalities. OKT3, a murine anti-CD3 monoclonal antibody, was introduced in 1986. The mechanism of action of OKT3 consists of T cell depletion and CD3 modulation. While the polyclonal agents and OKT3 induce effective immunosuppression, they are also associated with opportunistic infections and post transplant lymphoproliferative disorders. In the latter part of the 1990s, humanized (fully humanized and chimeric) monoclonal antibodies targeting the interleukin 2 α receptor (IL-2R α) were introduced with the intent of inducing selective rather than broad immunosuppression.

Keywords

Renal Transplantation Acute Rejection Graft Survival Calcineurin Inhibitor Mycophenolate Mofetil 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Nashan B, Moor R, Amlot P, et al. Randomised trial of bsiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. Lancet 1997;350:1193–1198.PubMedCrossRefGoogle Scholar
  2. 2.
    Vincenti F, Kirkman R, Light S, et al. Interleukin-2-receptor blockade with daclizumab to prevent acure rejection in renal transplantation. N Engl J Med 1998;338:161–165.PubMedCrossRefGoogle Scholar
  3. 3.
    Nashan B, Light S, Hardie IR, et al. Reduction of acute renal allograft rejection by daclizumab. Transplantation 1999;67:110–115.PubMedCrossRefGoogle Scholar
  4. 4.
    Kahan BD, Rajagopalan PR, Hall M. Reduction of the occurrence of acute cellular rejection among renal allograft recipients treated with basiliximab, a chimeric anti-interleukin-2-receptor monoclonal antibody. Transplantation 1999;67:276–284.PubMedCrossRefGoogle Scholar
  5. 5.
    Boelaars-van Haperen MJAM, Baan CC, van Riemsdijk IC, et al: Treatment with the chimeric anti-IL2Ra antibody basiliximab prevents the development of renal rejection by affecting the IL-2 and IL-15 pathway. XVIII International Congress of the Transplantation Society (Abstract OAP17) pg. 28, Aurg. 27–Sept. 1, 2000.Google Scholar
  6. 6.
    Goebel J, Stevens E, Forrest K, et al: Daclizumab (dac) blocks early interleukin (IL)-2 receptor ® signaling. XVII International Congress of the Transplantation Society (Abstract #P0528), pg. 316, Aug. 27–Sept. 1, 2000.Google Scholar
  7. 7.
    Souillou JP, Cantarovich D, LeMauff B, et al. Randomized controlled trial of monoclonal antibody against rejection of renal allografts. N Eng J Med 1990;322:1175.CrossRefGoogle Scholar
  8. 8.
    Krikman RL, Shapiro ME, Carpenter DB, et al. A randomized prospective trial of anti-Tac monoclonal antibody in human renal transplantation. Transplantation 1991; 51:107–113.CrossRefGoogle Scholar
  9. 9.
    Kriaa F, Hiesse C, Alard P, et al. Prophylactic use of the anti-IL-2-receptor monoclonal antibody LO-Tact-I in cadaveric renal transplantation: results of a randomized study. Transplant Proc 1993;25:817–819.PubMedGoogle Scholar
  10. 10.
    van Gelder T, Zietse R, Mulder AH, et al. A double-blind, placebo-controlled study of monoclonal anti-interleukin-2 receptor antibody (BT563) administration to prevent acute rejection after kidney transplantation. Transplantation 1995;60:248–252.PubMedCrossRefGoogle Scholar
  11. 11.
    Vincenti F, Lantz M, Birnbaum J, et al. A phase I tirla of humanized anti-interleukin 2 receptor antibody in renal transplantation. Transplantation 1997;63:33–38.PubMedCrossRefGoogle Scholar
  12. 12.
    Amlot PL, Rawlings E, Fernando ON, et al. Prolonged action of chiameric IL-2 receptor (CD25) monoclonal antibody used in cadaveric renal transplantation. Transplantation, 1995;60:748–756.PubMedCrossRefGoogle Scholar
  13. 13.
    Kirkman RL, Bumgardner G, Gaston RS, et al. Addition of daclizumab to mycophenolate mofetil, cyclosporine, and steroids in renal transplantation: pharmacokinetics, safety and efficacy. (Submitted for publication, Clinical Transplantation).Google Scholar
  14. 14.
    Davies E, Lawen J, Mourad G, et al. Basiliximab (Simulect®) is safe and effective in combination with Neoral®, steroids, and CellCept® for the prevention of acute rejection episodes in renal transplantation. Interim results of a double-blind, randomized clinical trial. (Abstract #A3672) Amer. Soc Nephrology 32nd annual meeting, Nov. 1–8, 1999.Google Scholar
  15. 15.
    Ciancio G, Miller A, Cespedes M, et al: Daclizumab induction for primary kidney transplant recipients using tacrolimus, mycophenolate mofetil and steroids as maintenance immunosuppression. XVIII International Congress of the Transplantation Society. (Abstract OAP27), pg. 46, Aug. 27–Sept. 1, 2000.Google Scholar
  16. 16.
    Deierhoi MH, Hudson SL, Gaston RS: Clinical experience with a two dose regimen of daclizumab in cadaveric renal transplantation. (Abstract #574) pg. S75, AST Transplant 2000.Google Scholar
  17. 17.
    Lebranchu Y, Hurault de Ligny B, Toupance O, et al. A multicenter randomized trial of Simulect® versus Thymoglobuline® in renal transplantation, (Abstract #567) pg. S74, AST Transplant 2000.Google Scholar
  18. 18.
    Sollinger H, Kaplan B, Pewscovitz M, et al: A multicenter, randomized trial of Simulect® with early Neoral® vs. ATGAM® with delayed Neoral in renal transplantation,. XVIII International Congress of the Transplantation Soceity (Abstract #0113) pg. 29, Aug. 27–Sept 1, 2000.Google Scholar
  19. 19.
    Hong JC, Kahan BD. Interleukin-2 receptor monoclonal antibodies and sirolimus: a novel induction immunosuppression strategy. Transplantation & Immunology Letter XVI:7–9, 2000.Google Scholar
  20. 20.
    Landsberg DN, Cole EH, Russell D, et al. Renal transplantation without steroids — one year results of a multicentre Canadian pilot study. (Abstract #86), pg. S49, AST Transplant 2000.Google Scholar
  21. 21.
    Vincenti F, Monaco A, Grinyo J, et al. Rapid steroid withdrawal versus standard steroid treatment in patients treated with Simulect®, Neoral®, and Cellcept® for the prevention of acute rejection in renal transplantation: a multicenter, randomized trial. (Abstract #83) pg. S49, AST Transplant 2000.Google Scholar
  22. 22.
    Vincenti F, Ramos E, Brattstrom C, Cho S, Ekberg H, Grinyo J, Johnson R, Kuypers D, Stuart F, Khanna A, Navarro M, Nashan B. Multicenter trial exploring calcineurin inhibitors avoidance in renal transplantation. In Press, Transplantation, 2000.Google Scholar
  23. 23.
    Kreis H, Cisterne J-M, Land @, et al. Sirolimus inassociation with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients. Transplantation 69:1252–1260.Google Scholar
  24. 24.
    Tellides G, Dallman MJ, Morris PJ. Synergistic interaction of cyclosporine A with interleukin 2 receptor monoclonal antibody therapy. Transplantation Proc 1988;20(Suppl 2):202–206.Google Scholar
  25. 25.
    Baan CC, Knoop CJ, van Gelder T, et al. Anti-CD25 therapy reveals the redundancy of the intragraft cytokine network after clinical heart transplantation. Transplantation 1999;67:870–876.PubMedCrossRefGoogle Scholar
  26. 26.
    Chang, GJ, Harish H, Mahanty, Vincenti F, et al. A calcineurin inhibitor-sparing regimen with sirolimus, mycophenolate mofetil, and anti-CD25 mAb provides effective immunosuppression in kidney transplant recipients with delayed or impaired graft function. Clinical Transplantation 2000; 14:545–549.CrossRefGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2001

Authors and Affiliations

  • Flavio G. Vincenti

There are no affiliations available

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