Monoclonal Antibody Targeting of the T Cell Receptor Complex

  • Lucienne Chatenoud


OKT3 was the first murine monoclonal antibody to be introduced in clinical practice for both the treatment and the prevention of acute renal allograft rejection [1–3]. The initial rationale for these studies was the capacity of OKT3 to stain all mature peripheral T cells and to completely abolish both T cell proliferation and the generation of cytotoxic T cell effectors in in vitro mixed lymphocyte cultures [4]. Interestingly enough, this occurred in 1981, few years before it could be firmly established that the specific molecular target of OKT3 was one of the polypeptide chains included within the major T cell recognition element namely, the T cell antigen receptor (TCR)/CD3 complex.


Acute Renal Allograft Rejection Antigenic Modulation OKT3 Monoclonal Antibody Orthoclone OKT3 Necrosis Factor Monoclonal Antibody 
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  1. 1.
    Cosimi AB, Colvin RB, Burton RC, et al. Use of monoclonal antibodies to T cell subsets for immunologic monitoring and treatment in recipients of renal allografts. N Engl J Med 1981;305:308–314.PubMedCrossRefGoogle Scholar
  2. 2.
    Cosimi AB, Burton RC, Colvin RB, et al. Treatment of acute renal allograft rejection with OKT3 monoclonal antibody. Transplantation 1981;32:535–539.PubMedCrossRefGoogle Scholar
  3. 3.
    Vigeral P, Chkoff N, Chatenoud L, et al. Prophylactic use of OKT3 monoclonal antibody in cadaver kidney recipients. Utilization of OKT3 as the sole immunosuppressive agent. Transplantation 1986;41:730–733.PubMedCrossRefGoogle Scholar
  4. 4.
    Kung P, Goldstein G, Reinherz EL, Schlossman SF. Monoclonal antibodies defining distinctive human T cell surface antigens. Science 1979;206:347–349.PubMedCrossRefGoogle Scholar
  5. 5.
    Clevers H, Alarcon B, Wileman T, Terhorst C. The T cell receptor/CD3 complex: a dynamic protein ensemble. Annu Rev Immunol 1988;6:629–662.PubMedCrossRefGoogle Scholar
  6. 6.
    Davis MM, Chien YH. T cell antigen receptors. In: Paul WE, editors. Fundamental Immunology. New York: Raven Press, 1999:341–366.Google Scholar
  7. 7.
    Ortho X. A randomized clinical trial of OKT3 monoclonal antibody for acute rejection of cadaveric renal transplants. Ortho Multicenter Transplant Study Group. N Engl J Med 1985;313:337–342.CrossRefGoogle Scholar
  8. 8.
    Goldstein G. Overview of the development of Orthoclone OKT3: monoclonal antibody for therapeutic use in transplantation. Transplant Proc 1987;19:1–6.PubMedGoogle Scholar
  9. 9.
    Hricik DE, Zarconi J, Schulak JA. Influence of low-dose cyclosporine on the outcome of treatment with OKT3 for acute renal allograft rejection. Transplantation 1989;47:272–277.PubMedCrossRefGoogle Scholar
  10. 10.
    Norman DJ, Barry JM, Bennett WM, et al. The use of OKT3 in cadaveric renal transplantation for rejection that is unresponsive to conventional anti-rejection therapy. Am J Kidney Dis 1988;11:90–93.PubMedGoogle Scholar
  11. 11.
    Colonna Jo 2D, Goldstein LI, Brems JJ, et al. A prospective study on the use of monoclonal anti-T3-cell antibody (OKT3) to treat steroid-resistant liver transplant rejection. Arch Surg 1987;122:1120–1123.PubMedCrossRefGoogle Scholar
  12. 12.
    Woodle ES, Thistlethwaite Jr JR, Emond JC, et al. OKT3 therapy for hepatic allograft rejection. Differential response in adults and children. Transplantation 1991;51:1207–1212.PubMedCrossRefGoogle Scholar
  13. 13.
    Goldstein G, Kremer AB, Barnes L, Hirsch RL. OKT3 monoclonal antibody reversal of renal and hepatic rejection in pediatric patients. J Pediatr 1987;111: 1046–1050.PubMedCrossRefGoogle Scholar
  14. 14.
    Gilbert EM, Dewitt CW, Eiswirth CC, et al. Treatment of refractory cardiac allograft rejection with OKT3 monoclonal antibody. Am J Med 1987;82:202–206.PubMedCrossRefGoogle Scholar
  15. 15.
    Frey DJ, Matas AJ, Gillingham KJ, et al. Sequential therapy-a prospective randomized trial of MALG versus OKT3 for prophylactic immunosuppression in cadaver renal allograft recipients. Transplantation 1992;54:50–56.PubMedCrossRefGoogle Scholar
  16. 16.
    Debure A, Chkoff N, Chatenoud L, et al. One-month prophylactic use of OKT3 in cadaver kidney transplant recipients. Transplantation 1988;45:546–553.PubMedCrossRefGoogle Scholar
  17. 17.
    Abramowicz D, Goldman M, de Pauw L, Vanherweghem JL, Kinnaert P, Vereerstraeten P. The long-term effects of prophylactic OKT3 monoclonal antibody in cadaver kidney transplantation-a single-center, prospective, randomized study. Transplantation 1992;54:433–437.PubMedCrossRefGoogle Scholar
  18. 18.
    Opelz G. Efficacy of rejection prophylaxis with OKT3 in renal transplantation. Collaborative Transplant Study. Transplantation 1995;60:1220–1224.PubMedGoogle Scholar
  19. 19.
    Farges O, Ericzon BG, Bresson-Hadni S, et al. A randomized trial of OKT3-based versus cyclosporine-based immunoprophylaxis after liver transplantation. Long-term results of a European and Australian multicenter study. Tansplantation 1994;58:891–898.CrossRefGoogle Scholar
  20. 20.
    Miilis JM, McDiarmid SV, Hiatt JR, et al. Randomized prospective trial of OKT3 for early prophylaxis of rejection after liver transplantation. Transplantation 1989;47:82–88.CrossRefGoogle Scholar
  21. 21.
    Eason JD, Cosimi AB. Biologic immunosuppressive agents. In: Ginns LC, Cosimi AB, Morris PJ, editors. Transplantation. Maiden, USA: Blackwell Science, 1999:196–224.Google Scholar
  22. 22.
    Robbins RC, Oyer PE, Stinson EB, Starnes VA. The use of monoclonal antibodies after heart transplantation. Transplantation Science 1992;2:22–27.Google Scholar
  23. 23.
    Farges 0, Samuel D, Bismuth H. Orthocione OKT3 in liver transplantation. Transplant Sci 1992;2:16–21.Google Scholar
  24. 24.
    Ericzon BG, Salmela K, Barkholt L, Hockerstedt K. OKT3 prophylaxis in liver transplantation: the Scandinavian experience. Transplant Proc 1990;22:223–224.PubMedGoogle Scholar
  25. 25.
    Cosimi AB. Clinical development of Orthoclone OKT3. Transplant Proc 1987;19:7–16.PubMedGoogle Scholar
  26. 26.
    Chatenoud L, Legendre C, Ferran C, Bach JF, Kreis H. Corticosteroid inhibition of the OKT3-induced cytokine-related syndrome-dosage and kinetics prerequisites Transplantation 1991;51:334–338.PubMedCrossRefGoogle Scholar
  27. 27.
    Abramowicz D, Schandene L, Goldman M, et al. Release of tumor necrosis factor, interleukin-2, and gam mainterferon in serum after injection of OKT3 monoclonal antibody in kidney transplant recipients. Transplantation 1989;47:606–608.PubMedCrossRefGoogle Scholar
  28. 28.
    Schutt HJ, Kurrle R, Wonigeit K. T cell activation by monoclonal antibodies directed to different epitopes on the human T cell receptor/CD3 complex: evidence for two different modes of activation. Eur J Immunol 1989; 19:1649–1655.CrossRefGoogle Scholar
  29. 29.
    Land W, Hillebrand G, Illner WD, et al. First clinical experience with a new TCR/CD3-monoclonal antibody (BMA 031) in kidney transplant patients. Transpl Int 1988;1:116–117.PubMedGoogle Scholar
  30. 30.
    Smely S, Weschka M, Hillebrand G, et al. Prophylactic use of the new monoclonal antibody BMA 031 in clinical kidney transplantation. Transplant Proc 1990;22:1785–1786.PubMedGoogle Scholar
  31. 31.
    Chatenoud L, Legendre C, Kurrle R, Kreis H, Bach JF. Absence of clinical symptoms following the first injection of anti-T cell receptor monoclonal antibody (BMA 031) despite isolated TNF release. Transplantation 1993;55:443–445.PubMedCrossRefGoogle Scholar
  32. 32.
    Waid TH, Lucas BA, Thompson JS, et al. Treatment of acute cellular rejection with T10B9.1A-31 or OKT3 in renal allograft recipients. Transplantation 1992;53:80–86.PubMedCrossRefGoogle Scholar
  33. 33.
    Chatenoud L, Baudrihaye MF, Chkoff N, Kreis H, Goldstein G, Bach JF. Restriction of the human in vivo immune response against the mouse monoclonal antibody OKT3. J Immunol 1986;137:830–838.PubMedGoogle Scholar
  34. 34.
    Baudrihaye MF, Chatenoud L, Kreis H, Goldstein G, Bach JF. Unusually restricted anti-isotype human immune response to OKT3 monoclonal antibody. Eur J Immunol 1984;14:686–691.PubMedCrossRefGoogle Scholar
  35. 35.
    Chatenoud L, Jonker M, Villemain F, Goldstein G, Bach JF. The human immune response to the OKT3 monoclonal antibody is oligoclonal. Science 1986;232:1406–1408.PubMedCrossRefGoogle Scholar
  36. 36.
    Abramowicz D, Crusiaux A, Goldman M. Anaphylactic shock after retreatment with OKT3 monoclonal antibody. N Engl J Med 1992;327:736.PubMedCrossRefGoogle Scholar
  37. 37.
    Hricik DE, Mayes JT, Schulak JA. Inhibition of anti-OKT3 antibody generation by cyclosporine-results of a prospective randomized trial. Transplantation 1990;50:237–240.PubMedCrossRefGoogle Scholar
  38. 38.
    Bolt S, Routledge E, Lloyd I, et al. The generation of a humanized, non-mitogenic CD3 monoclonal antibody which retains in vitro immunosuppressive properties. Eur J Immunol 1993;23:403–411.PubMedCrossRefGoogle Scholar
  39. 39.
    Routledge EG, Falconer ME, Pope H, Lloyd IS, Waldmann H. The effect of aglycosylation on the immunogenicity of a humanized therapeutic CD3 monoclonal antibody. Tansplantation 1995;60:847–853.Google Scholar
  40. 40.
    Alegre ML, Peterson U, Xu D, et al. A non-activating “humanized” anti-CD3 monoclonal antibody retains immunosuppressive properties in vivo. Tansplantation 1994;57:1537–1543.Google Scholar
  41. 41.
    Hirsch R, Gress RE, Pluznik DH, Eckhaus M, Bluestone JA. Effects of in vivo administration of anti-CD3 monoclonal antibody on T cell function in mice. II. In vivo activation of T cells. J Immunol 1989;142:737–743.PubMedGoogle Scholar
  42. 42.
    Ferran C, Sheehan K, Dy M, et al. Cytokine-related syndrome following injection of anti-CD3 monoclonal antibody: further evidence for transient in vivo T cell activation. Eur J Immunol 1990;20:509–515.PubMedCrossRefGoogle Scholar
  43. 43.
    Alegre M, Vandenabeele P, Flamand V, et al. Hypothermia and hypoglycemia induced by anti-CD3 monoclonal antibody in mice: role of tumor necrosis factor. Eur J Immunol 1990;20:707–710.PubMedCrossRefGoogle Scholar
  44. 44.
    Durez P, Abramowicz D, Gerard C, et al. In vivo induction of interleukin 10 by anti-CD3 monoclonal antibody or bacterial lipopolysaccharide: differential modulation by cyclosporin A. J Exp Med 1993;177:551–555.PubMedCrossRefGoogle Scholar
  45. 45.
    Yoshimoto T, Paul WE. CD4pos, NKl.lpos T cells promptly produce interleukin 4 in response to in vivo challenge with anti-CD3. J Exp Med 1994;179:1285–1295.PubMedCrossRefGoogle Scholar
  46. 46.
    Flamand V, Abramowicz D, Goldman M, et al. Anti-CD3 antibodies induce T cells from unprimed animals to secrete IL-4 both in vitro and in vivo. J Immunol 1990;144:2875–2882.PubMedGoogle Scholar
  47. 47.
    Ferran C, Dy M, Sheehan K, et al. Cascade modulation by anti-tumor necrosis factor monoclonal antibody of interferon-gamma, interleukin 3 and interleukin 6 release after triggering of the CD3/T cell receptor activation pathway. Eur J Immunol 1991;21:2349–2353.PubMedCrossRefGoogle Scholar
  48. 48.
    Charpentier B, Hiesse C, Lantz O, et al. Evidence that antihuman tumor necrosis factor monoclonal antibody prevents OKT3-induced acute syndrome. Transplantation 1992;54:997–1002.PubMedCrossRefGoogle Scholar
  49. 49.
    Van Lier RA, Boot JH, de Groot ER, Aarden LA. Induction of T cell proliferation with anti-CD3 switch-variant monoclonal antibodies: effects of heavy chain isotype in monocyte-dependent systems. Eur J Immunol 1987;17:1599–1604.PubMedCrossRefGoogle Scholar
  50. 50.
    Hirsch R, Bluestone JA, de Nenno L, Gress RE. Anti-CD3 F(ab’)2 fragments are immunosuppressive in vivo without evoking either the strong humoral response or morbidity associated with whole mAb. Transplantation 1990;49:1117–1123.PubMedCrossRefGoogle Scholar
  51. 51.
    Parlevliet KJ, Ten Berge IJ, Yong SL, Surachno J, Wilmink JM, Schellekens PT. In vivo effects of IgA and IgG2a anti-CD3 isotype switch variants. J Clin Invest 1994;93:2519–2525.PubMedCrossRefGoogle Scholar
  52. 52.
    Chatenoud L, Thervet E, Primo J, Bach JF. Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc Natl Acad Sci USA 1994;91:123–127.PubMedCrossRefGoogle Scholar
  53. 53.
    Chatenoud L, Primo J, Bach JF. CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice. J Immunol 1997;158:2947–2954.PubMedGoogle Scholar
  54. 54.
    Woodle ES, Xu D, Zivin RA, et al. Phase I trial of a humanized, Fe receptor nonbinding OKT3 antibody, huOKT3gammal(Ala-Ala) in the treatment of acute renal allograft rejection. Tansplantation 1999;68:608–616.CrossRefGoogle Scholar
  55. 55.
    Friend PJ, Hale G, Chatenoud L, et al. Phase I study of an engineered aglycosylated humanized CD3 antibody in renal transplant rejection. Transplantation 1999;68:1632–1637.PubMedCrossRefGoogle Scholar
  56. 56.
    Hirsch R, Archibald J, Gress RE. Differential T cell hyporesponsiveness induced by in vivo administration of intact or F(ab’)2 fragments of anti-CD3 monoclonal antibody. F(ab’)2 fragments induce a selective T helper dysfunction. J Immunol 1991;147:2088–2093.PubMedGoogle Scholar
  57. 57.
    Hughes C, Wolos JA, Giannini EH, Hirsch R. Induction of T helper cell hyporesponsiveness in an experimental model of autoimmunity by using nonmitogenic anti-CD3 monoclonal antibody. J Immunol 1994;153:3319–3325.PubMedGoogle Scholar
  58. 58.
    Herold KC, Bluestone JA, Montag AG, et al. Prevention of autoimmune diabetes with nonactivating anti-CD3 monoclonal antibody. Diabetes 1992;41:385–391.PubMedCrossRefGoogle Scholar
  59. 59.
    Johnson BD, McCabe C, Hanke CA, Truitt RL. Use of anti-CD3 epsilon F(ab’)2 fragments in vivo to modulate graft-versus-host disease without loss of graft-versus-leukemia reactivity after MHC-matched bone marrow transplantation. J Immunol 1995;154:5542–5554.PubMedGoogle Scholar
  60. 60.
    Swinnen U, Costanzo-Nordin MR, Fisher SG, et al. Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac-transplant recipients. N Engl J Med 1990;323:1723–1728.PubMedCrossRefGoogle Scholar
  61. 61.
    Nicolls MR, Aversa GG, Pearce NW, et al. Induction of long-term specific tolerance to allografts in rats by therapy with an anti-CD3-like monoclonal antibody. Transplantation 1993;55:459–468.PubMedCrossRefGoogle Scholar
  62. 62.
    Nooij FJ, Jonker M, Balner H. Differentiation antigens on rhesus monkey lymphocytes. II. Characterization of RhT3, a CD3-like antigen on T cells. Eur J Immunol 1986;16:981–984.PubMedCrossRefGoogle Scholar
  63. 63.
    Neville Dm JR, Scharff J, Hu HZ, et al. A new reagent for the induction of T-cell depletion, anti-CD3-CRM9. Journal of Immunotherapy With Emphasis on Tumor Immunology 1996;19:85–92.PubMedCrossRefGoogle Scholar
  64. 64.
    Hamawy MM, Knechtle SJ, trategies for tolerance induction in nonhuman primates. [Review] [26 refs. Curr Opin Immunol 1998;10:513–517.PubMedCrossRefGoogle Scholar
  65. 65.
    Kirk AD, Burkly LC, Batty DS, et al. reatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates [see comments. Nat Med 1999;5:686–693.PubMedCrossRefGoogle Scholar
  66. 66.
    Contreras JL, Wang PX, Eckhoff DE, et al. Peritransplant tolerance induction with anti-CD3-immunotoxin: a matter of proinflammatory cytokine control. Tansplantation 1998; 65:1159–1169.CrossRefGoogle Scholar
  67. 67.
    Thomas FT, Ricordi C, Contreras JL, et al. Reversal of naturally occuring diabetes in primates by unmodified islet xenografts without chronic immunosuppression. Tansplantation 1999;67:846–854.CrossRefGoogle Scholar
  68. 68.
    Castano L, Eisenbarth GS. Type-I diabetes: a chronic autoimmune disease of human, mouse, and rat. Annu Rev Immunol 1990;8:647–679.PubMedCrossRefGoogle Scholar
  69. 69.
    Bach JF. Insulin-dependent diabetes mellitus as an autoimmune disease. Endocrine Rev 1994;15:516–542.Google Scholar
  70. 70.
    Leo 0, Foo M, Sachs DH, Samelson LE, Bluestone JA. Identification of a monoclonal antibody specific for a murine T3 polypeptide. Proc Natl Acad Sci USA 1987;84:1374–1378.PubMedCrossRefGoogle Scholar
  71. 71.
    Hirsch R, Eckhaus M, Auchincloss H JR, Sachs DH, Bluestone JA. Effects of in vivo administration of anti-T3 monoclonal antibody on T cell function in mice. I. Immunosuppression of transplantation responses. J Immunol 1988;140:3766–3772.PubMedGoogle Scholar
  72. 72.
    Chatenoud L, Bach JF. Antigenic modulation: a major mechanism of antibody action. Immunol Today 1984;5:20–25.CrossRefGoogle Scholar
  73. 73.
    Chatenoud L, Baudrihaye MF, Kreis H, Goldstein G, Schindler J, Bach JF. Human in vivo antigenic modulation induced by the anti-T cell OKT3 monoclonal antibody. Eur J Immunol 1982;12:979–982.PubMedCrossRefGoogle Scholar
  74. 74.
    Wong JT, Colvin RB. Selective reduction and proliferation of the CD4+ and CD8+ T cell subsets with bispecific monoclonal antibodies: evidence for inter-T cell-mediated cytolysis. Clin Immunol Immunopathol 1991;58:236–250.PubMedCrossRefGoogle Scholar
  75. 75.
    Smith CA, Williams GT, Kingston R, Jenkinson EJ, Owen JJ. Antibodies to CD3/T cell receptor complex induce death by apoptosis in immature T cells in thymic cultures. Nature 1989;337:181–184.PubMedCrossRefGoogle Scholar
  76. 76.
    Wesselborg S, Janssen 0, Kabelitz D. Induction of activation-driven death (apoptosis) in activated but not resting peripheral blood T cells. J Immunol 1993;150:4338–4345.PubMedGoogle Scholar
  77. 77.
    Choy EH, Adjaye J, Forrest L, Kingsley GH, Panayi GS. Chimaeric anti-CD4 monoclonal antibody cross-linked by monocyte Fc gamma receptor mediates apoptosis of human CD4 lymphocytes. Eur J Immunol 1993;23:2676–2681.PubMedCrossRefGoogle Scholar
  78. 78.
    Thomas JM, Neville DM, Contreras JL, et al. Preclinical studies of allograft tolerance in rhesus monkeys: a novel anti-CD3-immunotoxin given peritransplant with donor bone marrow induces operational tolerance to kidney allografts. Tansplantation 1997;64:124–135.CrossRefGoogle Scholar
  79. 79.
    Smith JA, Tang Q, Bluestone JA. Partial TCR signals delivered by FcR-nonbinding anti-CD3 monoclonal antibodies differentially regulate individual Th subsets. J Immunol 1998;160:4841–4849.PubMedGoogle Scholar
  80. 80.
    Smith JA, Tso JY, Clark MR, Cole MS, Bluestone JA. Nonmitogenic anti-CD3 monoclonal antibodies deliver a partial T cell receptor signal and induce clonal anergy. J Exp Med 1997;185:1413–1422.PubMedCrossRefGoogle Scholar
  81. 81.
    Plain KM, Chen J, Merten S, He XY, Hall BM. Induction of specific tolerance to allografts in rats by therapy with non-mitogenic, non-depleting anti-CD3 monoclonal antibody: association with TH2 cytokines not anergy. Tansplantation 1999;67:605–613.CrossRefGoogle Scholar
  82. 82.
    Le Moine A, Flamand V, Demoor FX, et al. Critical roles for IL-4, IL-5, and eosinophils in chronic skin allograft rejection. J Clin Invest 1999;103:1659–1667.PubMedCrossRefGoogle Scholar
  83. 83.
    Wissing KM, Desalle F, Abramowicz D, et al. Down-regulation of interleukin-2 and interferon-gamma and maintenance of interleukin-4 and interleukin-10 production after administration of an anti-CD3 monoclonal antibody in mice. Tansplantation 1999;68:677–684.CrossRefGoogle Scholar
  84. 84.
    Boitard C, Yasunami R, Dardenne M, Bach JF. T cell-mediated inhibition of the transfer of autoimmune diabetes in NOD mice. J Exp Med 1989;169:1669–1680.PubMedCrossRefGoogle Scholar
  85. 85.
    Hutchings PR, Cooke A. The transfer of autoimmune diabetes in NOD mice can be inhibited or accelerated by distinct cell populations present in normal splenocytes taken from young males. J Autoimmun 1990;3:175–185.PubMedCrossRefGoogle Scholar
  86. 86.
    Yasunami R, Debray-Sachs M, Bach JF. Ontogeny of regulatory and effector T cells in autoimmune NOD mice. In: Shafrir E, editors. Frontiers in diabetes research. Lessons from animal diabetes III. London: Smith-Gordon, 1990:88–93.Google Scholar
  87. 87.
    Delovitch TL, Singh B. The nonobese diabetic mouse as a model of autoimmune diabetes: immune dysregulation gets the NOD. Immunity 1997;7:727–738.PubMedCrossRefGoogle Scholar
  88. 88.
    Cobbold SP, Qin SX, Waldmann H. Reprogramming the immune system for tolerance with monoclonal antibodies. Semin Immunol 1990;2:377–387.PubMedGoogle Scholar
  89. 89.
    Strober S. Natural suppressor (NS) cells, neonatal tolerance, and total lymphoid irradiation: exploring obscure relationships. Annu Rev Immunol 1984;2:219–237.PubMedCrossRefGoogle Scholar

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© Kluwer Academic Publishers 2001

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  • Lucienne Chatenoud

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