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. 1997 Nov;110(2):158–166. doi: 10.1111/j.1365-2249.1997.tb08312.x

Humanized anti-CD4 monoclonal antibody therapy of autoimmune and inflammatory disease

J D ISAACS *, N BURROWS *, M WING †, M T KEOGAN ‡, P R U B REBELLO §, R A WATTS , R J PYE *, P NORRIS *, B L HAZELMAN , G HALE *, H WALDMANN *
PMCID: PMC2265492  PMID: 9367397

Abstract

We have investigated the biological and therapeutic properties of a humanized anti-CD4 MoAb, hlgGl-CD4, in patients with refractory psoriasis and rheumatoid arthritis (RA). hIgGl-CD4 is a modulating, non-depleting MoAb, which induced a first-dose reaction in most patients treated. It provided brief symptomatic relief in both conditions, and psoriasis appeared easier to control with conventional agents after MoAb therapy. At the doses used, hIgGl-CD4 did not synergize therapeutically with the pan-lymphocyte MoAb CAMPATH-1H (C1H) in patients with RA treated sequentially with both agents. There were no serious adverse effects definitely attributable to therapy. Our results are compared with those of other CD4 MoAb studies, and factors influencing the outcome of therapy are discussed.

Keywords: anti-CD4, immunotherapy, CAMPATH, psoriasis, rheumatoid arthritis

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References

  • 1.Benjamin RJ, Waldmann H. Induction of tolerance by monoclonal antibody therapy. Nature. 1986;320:449–51. doi: 10.1038/320449a0. [DOI] [PubMed] [Google Scholar]
  • 2.Gutstein NL, Seaman WE, Scott JH, Wofsy D. Induction of immune tolerance by administration of monoclonal antibody therapy to L3T4. J Immunol. 1986;137:1127–32. [PubMed] [Google Scholar]
  • 3.Qin S, Cobbold S, Benjamin R, Waldmann H. Induction of classical transplantation tolerance in the adult. J Exp Med. 1989;169:779–94. doi: 10.1084/jem.169.3.779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Cobbold SP, Qin S, Leong LYW, Martin G, Waldmann H. Reprogramming the immune system for peripheral tolerance with CD4 and CD8 monoclonal antibodies. Immunol Rev. 1992;129:165–201. doi: 10.1111/j.1600-065x.1992.tb01423.x. [DOI] [PubMed] [Google Scholar]
  • 5.Qin S, Cobbold SP, Pope H, Elliott J, Kioussis D, Davies J, Waldmann H. Infectious’ transplantation tolerance. Science. 1993;259:974–7. doi: 10.1126/science.8094901. [DOI] [PubMed] [Google Scholar]
  • 6.Herzog C, Walker C, Muller W, et al. Anti-CD4 antibody treatment of patients with rheumatoid arthritis; I. Effect on clinical course and circulating T cells. J Autoimmun. 1989;2:627–42. doi: 10.1016/s0896-8411(89)80002-2. [DOI] [PubMed] [Google Scholar]
  • 7.Reiter C, Kakarand B, Rieber EP, Schattenkirchner M, Riethmuller G, Kruger K. Treatment of rheumatoid arthritis with monoclonal anti-CD4 antibody M-T151. Clinical results and immunopharmacologic effects in an open study, including repeated administration. Arthritis Rheum. 1991;34:525–36. doi: 10.1002/art.1780340504. [DOI] [PubMed] [Google Scholar]
  • 8.Goldberg D, Morel P, Chatenoud L, Boitard C, Menkes C-J, Bertoye PH, Revillard J-P, Bach J-F. Immunological effects of high dose administration of anti-CD4 antibody in rheumatoid arthritis patients. J Autoimmun. 1991;4:617–30. doi: 10.1016/0896-8411(91)90181-b. [DOI] [PubMed] [Google Scholar]
  • 9.Homeff G, Burmester GR, Emmrich F, Kalden JR. Treatment of rheumatoid arthritis with an anti-CD4 monoclonal antibody. Arthritis Rheum. 1991;34:129–40. doi: 10.1002/art.1780340202. [DOI] [PubMed] [Google Scholar]
  • 10.Wendling D, Wijdenes J, Racadot E, Morel-Fourrier B. Therapeutic use of monoclonal anti-CD4 antibody in rheumatoid arthritis. J Rheumatol. 1991;18:325–7. [PubMed] [Google Scholar]
  • 11.Moreland LW, Bucy RP, Tilden A, et al. Use of a chimeric monoclonal anti-CD4 antibody in patients with refractory rheumatoid arthritis. Arthritis Rheum. 1993;36:307–18. doi: 10.1002/art.1780360304. [DOI] [PubMed] [Google Scholar]
  • 12.Morel P, Revillard J-P, Nicolas J-F, Wijdenes J, Rizova H, Thivolet J. Anti-CD4 monoclonal antibody therapy in severe psoriasis. J Autoimmun. 1992;5:465–77. doi: 10.1016/0896-8411(92)90006-c. [DOI] [PubMed] [Google Scholar]
  • 13.Hiepe F, Volk H-D, Apostoloff E, Baehr RV, Emrnrich F. Treatment of severe systemic lupus erythematosus with anti-CD4 monoclonal antibody. Lancet. 1991;338:1529–30. doi: 10.1016/0140-6736(91)92353-4. [DOI] [PubMed] [Google Scholar]
  • 14.Racadot E, Rumbach L, Bataillard M, et al. Treatment of multiple sclerosis with anti-CD4 monoclonal antibody. A preliminary report on BF-5 in 21 patients. J Autoimmun. 1993;6:771–86. doi: 10.1006/jaut.1993.1063. [DOI] [PubMed] [Google Scholar]
  • 15.Lindsey JW, Hodgkinson S, Mehta R, et al. Phase 1 clinical trial of chimeric monoclonal anti-CD4 antibody in multiple sclerosis. Neurology. 1994;44:413–19. doi: 10.1212/wnl.44.3_part_1.413. [DOI] [PubMed] [Google Scholar]
  • 16.Moreland LW, Pratt PW, Mayes MD, et al. Double-blind, placebo-controlled multicenter trial using chimeric monoclonal anti-CD4 antibody, CM-T412 in rheumatoid arthritis patients receiving methotrexate. Arthritis Rheum. 1995;38:1581–8. doi: 10.1002/art.1780381109. [DOI] [PubMed] [Google Scholar]
  • 17.Van der Lubbe PA, Dijkmans BAC, Markusse HM, Nassander U, Breedveld FC. A randomized, double-blind, placebo-controlled study of CD4 monoclonal antibody therapy in early rheumatoid arthritis. Arthritis Rheum. 1995;38:1097–106. doi: 10.1002/art.1780380812. [DOI] [PubMed] [Google Scholar]
  • 18.Levy R, Weisman M, Weizenhutter C, et al. Results of a placebo-controlled, multicenter trial using a primatized, non-depleting, anti-CD4 monoclonal antibody in the treatment of rheumatoid arthritis. Arthritis Rheum. 1996;39:S122. [Google Scholar]
  • 19.Lockwood CM, Thiru S, Isaacs JD, Hale G, Waldmann H. Long-term remission of intractable systemic vasculitis with monoclonal antibody therapy. Lancet. 1993;341:1620–2. doi: 10.1016/0140-6736(93)90759-a. [DOI] [PubMed] [Google Scholar]
  • 20.Lockwood CM, Thiru S, Stewart S, Hale G, Isaacs J, Wraight P, Elliott J, Waldmann H. Treatment of refractory Wegener's granulomatosis with humanized monoclonal antibodies. Q J Med. 1996;89:903–12. doi: 10.1093/qjmed/89.12.903. [DOI] [PubMed] [Google Scholar]
  • 21.Gorman SD, Clark MR, Routledge EG, Cobbold SP, Waldmann H. Reshaping a therapeutic CD4 antibody. Proc Natl Acad Sci USA. 1991;88:4181–5. doi: 10.1073/pnas.88.10.4181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Riechmann L, Clark M, Waldmann H, Winter G. Reshaping human antibodies for therapy. Nature. 1988;332:323–7. doi: 10.1038/332323a0. [DOI] [PubMed] [Google Scholar]
  • 23.Baker BS, Swain AF, Valdimarsson H, Fry L T. cell subpopulations in the blood and skin of patients with psoriasis. Br J Dermatol. 1984;110:37. doi: 10.1111/j.1365-2133.1984.tb07309.x. [DOI] [PubMed] [Google Scholar]
  • 24.Janossy G, Panayi G, Duke O, Bofill M, Poulter LW, Goldstein G. Rheumatoid arthritis; a disease of T-lymphocyte/macrophage immunoregulation. Lancet. 1981;ii:839–42. doi: 10.1016/s0140-6736(81)91107-7. [DOI] [PubMed] [Google Scholar]
  • 25.Mathieson PW, Cobbold SP, Hale G, Clark MR, Oliveira DBG, Lockwood CM, Waldmann H. Monoclonal antibody therapy in systemic vasculitis. New Engl J Med. 1990;323:250–4. doi: 10.1056/NEJM199007263230407. [DOI] [PubMed] [Google Scholar]
  • 26.Isaacs JD, Watts RA, Hazleman BL, Hale G, Keogan MT, Cobbold SP, Waldmann H. Humanized monoclonal antibody therapy for rheumatoid arthritis. Lancet. 1992;340:748–52. doi: 10.1016/0140-6736(92)92294-p. [DOI] [PubMed] [Google Scholar]
  • 27.Frederickson T, Pettersson U. Severe psoriasis-Oral therapy with a new retinoid. Dermatologica. 1978;157:238–44. doi: 10.1159/000250839. [DOI] [PubMed] [Google Scholar]
  • 28.Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association revized criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315–24. doi: 10.1002/art.1780310302. [DOI] [PubMed] [Google Scholar]
  • 29.Ritchie DM, Boyle JA, Mclnnes JM, Jasani MK, Dalakos TG, Grieveson P, Buchanan WW. Clinical studies with an articular index for the assessment of joint tenderness in patients with rheumatoid arthritis. Q J Med. 1968;147:393–406. [PubMed] [Google Scholar]
  • 30.Isaacs JD, Wing M, Greenwood JD, Hazleman BL, Hale G, Waldmann H. A therapeutic human IgG4 monoclonal antibody that depletes target cells in humans. Clin Exp Immunol. 1996;106:427–33. doi: 10.1046/j.1365-2249.1996.d01-876.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Cobbold SP, Rebello PRUB, Davies HFFS, Friend PJ, Clark MR. A simple method for measuring patient antiglobulin responses against isotypic or idiotypic determinants. J Immunol Methods. 1990;127:19–24. doi: 10.1016/0022-1759(90)90335-s. [DOI] [PubMed] [Google Scholar]
  • 32.Bruggemann M, Williams GT, Bmdon CI, Clark MR, Walker MR, Jefferis R, Waldmann H, Neuberger MS. Comparison of the effector functions of human immunoglobulins using a matched set of chimeric antibodies. J Exp Med. 1987;166:1351–61. doi: 10.1084/jem.166.5.1351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Bruggemann MC, Teale C, Clark MR, Bindon C, Waldmann H. A matched set of rat/mouse chimeric antibodies; identification and biological properties of rat H chain constant regions ü., γI, γ2a, γ2b, γ2c, ε and ε. J Immunol. 1989;142:3145–50. [PubMed] [Google Scholar]
  • 34.Bindon CI, Hale G, Waldmann H. Importance of antigen specificity for complement-mediated lysis by monoclonal antibodies. Eur J Immunol. 1988;18:1507–14. doi: 10.1002/eji.1830181006. [DOI] [PubMed] [Google Scholar]
  • 35.Bindon CI, Hale G, Waldmann H. Complement activation by immunoglobulin does not depend solely on Clq binding. Eur J Immunol. 1990;20:277–81. doi: 10.1002/eji.1830200208. [DOI] [PubMed] [Google Scholar]
  • 36.Bindon CI, Hale G, Bruggemann M, Waldmann H. Human monoclonal IgG isotypes differ in complement activating function at the level of C4 as well as Clq. J Exp Med. 1988;168:127–42. doi: 10.1084/jem.168.1.127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Moreland LW, Pratt PW, Bucy RP, Jackson BS, Feldman JW, Koopman WJ. Treatment of refractory rheumatoid arthritis with a chimeric anti-CD4 monoclonal antibody. Long-term follow-up of CD4+ T cell counts. Arthritis Rheum. 1994;37:834–8. doi: 10.1002/art.1780370610. [DOI] [PubMed] [Google Scholar]
  • 38.Isaacs JD, Clark MR, Greenwood J, Waldmann H. Therapy with monoclonal antibodies. An in vivo model for the assessment of therapeutic potential. J Immunol. 1992;148:3062–71. [PubMed] [Google Scholar]
  • 39.Van der Lubbe PA, Reiter C, Breedveld FC, Kruker K, Schattenkirchner M, Sanders ME, Reithmuller G. Chimeric CD4 monoclonal antibody cM-T412 as a therapeutic approach to rheumatoid arthritis. Arthritis Rheum. 1993;36:1375–9. doi: 10.1002/art.1780361008. [DOI] [PubMed] [Google Scholar]
  • 40.Isaacs JD, Waldmann H. Helplessness as a strategy for avoiding antiglobulin responses to therapeutic antibodies. Ther Immunol. 1994;1:303–12. [PubMed] [Google Scholar]
  • 41.Benjamin RJ, Cobbold SP, Clark MR, Waldmann H. Tolerance to rat monoclonal antibodies. Implications for serotherapy. J Exp Med. 1986;163:1539–52. doi: 10.1084/jem.163.6.1539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Gutstein NL, Wofsy D. Administration of F(ab)2 fragments of monoclonal antibody to L3T4 inhibits humoral imunity in mice without depleting L3T4+ cells. J Immunol. 1986;137:3414–19. [PubMed] [Google Scholar]
  • 43.Moreau T, Coles A, Wing M, Isaacs J, Hale G, Waldmann H, Compston A. Transient increase in symptoms associated with cytokine release in patients with multiple sclerosis. Brain. 1996;119:225–37. doi: 10.1093/brain/119.1.225. [DOI] [PubMed] [Google Scholar]
  • 44.Chatenoud L, Ferran C, Legendre C, et al. In vivo cell activation following OKT3 administration. Systemic cytokine release and modulation by corticosteroids. Transplantation. 1990;49:697–702. doi: 10.1097/00007890-199004000-00009. [DOI] [PubMed] [Google Scholar]
  • 45.Bolt S, Routledge E, Lloyd I, Chatenoud L, Pope H, Gorman SD, Clark M, Waldmann H. The generation of a humanized, non-mitogenic CD3 monoclonal antibody which retains in vitro immunosuppressive properties. Eur J Immunol. 1993;23:403–11. doi: 10.1002/eji.1830230216. [DOI] [PubMed] [Google Scholar]
  • 46.Wing MG, Isaacs JD, Waldmann H, Compston DAS, Hale G. Ex-vivo blood cultures for predicting cytokine-release syndrome: dependence on target antigen and antibody isotype. Ther Immunol. 1999;2:183–90. [PubMed] [Google Scholar]
  • 47.Isaacs JD, Manna VK, Rapson N, et al. CAMPATH-1H in rheumatoid arthritis - an iv dose-ranging study. Br J Rheumatol. 1996;35:231–40. doi: 10.1093/rheumatology/35.3.231. [DOI] [PubMed] [Google Scholar]
  • 48.Waldmann H, Cobbold SP. How may immunosuppression lead to tolerance? The war analogy. In: Plotkin S, Fantini B, editors. Immune tolerance: Jenner, Pasteur and their successors. Paris: Elsevier; 1997. [Google Scholar]
  • 49.Matzinger P. Tolerance, danger and the extended family. Annu Rev Immunol. 1994;12:991–1045. doi: 10.1146/annurev.iy.12.040194.005015. [DOI] [PubMed] [Google Scholar]
  • 50.Isomaki HA, Hakulinen T, Joutsenlahti U. Excess risk of lymphomas, leukaemia and myeloma in patients with rheumatoid arthritis. J Chronic Dis. 1978;31:691–6. doi: 10.1016/0021-9681(78)90071-1. [DOI] [PubMed] [Google Scholar]
  • 51.Jones M, Symmons D, Finn J, Wolfe F. Does exposure to immunosuppressive therapy increase the 10 year malignancy and mortality risks in rheumatoid arthritis? A matched cohort study. Br J Rheumatol. 1996;35:738–45. doi: 10.1093/rheumatology/35.8.738. [DOI] [PubMed] [Google Scholar]
  • 52.Choy EHS, Connolly DJA, Regan T, Manna VK, Rapson N, Kingsley GH, Panayi GS, Johnston JM. T cell hypothesis in rheumatoid arthritis (RA) tested by humanized non-depleting anti-CD4 monoclonal antibody (mAb) treatment II: Clinical activity is related to pharmacodynamic effects. Arthritis Rheum. 1996;39:S244. [Google Scholar]

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