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  • Review Article
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Biologic therapies in rheumatology: lessons learned, future directions

Nature Reviews Drug Discovery volume 6, pages 75–92 (2007)Cite this article

Key Points

  • During the past decade biologic therapies such as monoclonal antibodies and fusion proteins have revolutionized the management of rheumatic disease. By targeting key cytokines and immune cells they have provided more specific therapeutic interventions with less immunosuppression.

  • Clinical use of biologic therapies has revealed that their theoretical simplicity hides a more complex reality. Efficacy, toxicity and even pharmacodynamic effects can deviate from those predicted, as poignantly illustrated by the catastrophic effects witnessed during the first-into-human administration of TGN1412.

  • This review summarizes lessons gleaned from practical experience with biologic therapies and discusses how these can inform future discovery and development of new biologic therapies for rheumatology.

  • The exquisite specificity of monoclonal antiboides (mAbs) and soluble receptors can limit the information provided by preclinical models, making prediction of beneficial and adverse effects in humans challenging.

  • The Fc regions of mAbs and fusion proteins can modulate their clinical effects, influencing their potency (for example, for target cell lysis), immunogenicity and adverse effects (for example, the cytokine storm associated with first administration of some mAbs).

  • Immunogenicity is common with all biologic therapies, including 'fully human' products. The consequences vary but antiglobulins shorten circulating half-life, can reduce efficacy and result in adverse effects ranging from infusion reactions to anaphylaxis.

  • Subtle changes in manufacturing processes can significantly alter efficacy and tolerability profiles, and can result in previously unrecognized immunogenicity.

  • With most biologic agents clinical trials have been designed to maximize efficacy so that it is not known whether pharmacokinetic or pharmacodynamic effects might best predict efficacy or safety (for example, Cmax, Cmin or AUC or whole-blood assay results). This information can significantly inform treatment regimens and advisability of induction regimens.

  • Efficacy is not always explicable by expected mechanisms of action. For example, etanercept, adalimumab, infliximab and certolizumab pegol each neutralize TNFα.Certolizumab pegol, an Fab' construct lacking an Fc, cannot mediate ADCC, CDC or apoptosis in ex vivo assays, in contrast to the other three. Adalimumab, infliximab and certolizumab are effective in Crohn's disease whereas etanercept is not.

Abstract

During the past decade biologic therapies such as monoclonal antibodies and fusion proteins have revolutionized the management of rheumatic disease. By targeting key cytokines and immune cells biologics have provided more specific therapeutic interventions with less immunosuppression. Clinical use, however, has revealed that their theoretical simplicity hides a more complex reality. Efficacy, toxicity and even pharmacodynamic effects can deviate from those predicted, as poignantly illustrated by the catastrophic effects witnessed during the first-into-human administration of TGN1412. This review summarizes lessons gleaned from practical experience and discusses how these can inform future discovery and development of new biologic therapies for rheumatology.

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Figure 1: Cartoon of a normal joint and rheumatoid arthritis joint.
Figure 2: Current ideas on the pathogenesis of rheumatoid arthritis.
Figure 3: Potential mechanisms of action for TNFα inhibitors.

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References

  1. Choy, E. H. & Panayi, G. S. Cytokine pathways and joint inflammation in rheumatoid arthritis. N. Engl. J. Med. 344, 907–916 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Begovich, A. B. et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am. J. Hum. Genet. 75, 330–337 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Padyukov, L., Silva, C., Stolt, P., Alfredsson, L. & Klareskog, L. A gene–environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis. Arthritis Rheum. 50, 3085–3092 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Klareskog, L. et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 54, 38–46 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Marshall, E. Drug trials. Violent reaction to monoclonal antibody therapy remains a mystery. Science 311, 1688–1689 (2006).

    Article  PubMed  Google Scholar 

  6. Cobbold, S., Qin, S., Leong, L., Martin, G. & Waldmann, H. Reprogramming the immune system for peripheral tolerance with CD4 and CD8 monoclonal antibodies. Immunol. Rev. 129, 165–201 (1992). An excellent overview of how anti-T-cell monoclonal antibodies can be used to induce tolerance to foreign antigens.

    Article  CAS  PubMed  Google Scholar 

  7. Kremer, J. M. et al. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase iib, double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 52, 2263–2271 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Genovese, M. C. et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor α inhibition. N. Engl. J. Med. 353, 1114–1123 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Fishwild, D., Hudson, D., Deshpande, U. & Kung, A. Differential effects of administration of a human anti-CD4 monoclonal antibody, HM6G, in nonhuman primates. Clin. Immunol. 92, 138–152 (1999). An excellent example that findings in old world and cynomolgus monkeys do not predict biologic effects in humans.

    Article  CAS  PubMed  Google Scholar 

  10. Mason, U. et al. CD4 coating, but not CD4 depletion, is a predictor of efficacy with primatized monoclonal anti-CD4 treatment of active rheumatoid arthritis. J. Rheumatol. 29, 220–229 (2002).

    CAS  PubMed  Google Scholar 

  11. Black, L., Bendele, A., Bendele, R., Zack, P. & Hamilton, M. Regulatory decision strategy for entry of a novel biologic therapeutic with a clinically unmonitorible toxicity into clinical trials: pre-IND meetings and a case example. Toxicol. Pathol. 27, 22–26 (1999). A useful discusion of the limitations in preclinical testing.

    Article  CAS  PubMed  Google Scholar 

  12. Olsen, N. et al. A double blind, placebo controlled study of anti-CD5 immunoconjugate in patients with rheumatoid arthritis. Arthritis Rheum. 39, 1002–1008 (1996).

    Article  Google Scholar 

  13. Isaacs, J. D. & Waldmann, H. Regaining self-control — regulation and immunotherapy. Br J. Rheumatol. 37, 926–929 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Piccirillo, C. A. & Shevach, E. M. Naturally-occurring CD4+CD25+ immunoregulatory T cells: central players in the arena of peripheral tolerance. Semin. Immunol. 16, 81–88 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Choy, E. et al. Repeat-cycle study of high-dose intravenous 4162W94 anti-CD4 humanized monoclonal antibody in rheumatoid arthritis. A randomized placebo-controlled trial. Rheumatology 41, 1142–1148 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Gutstein, N., Seaman, W., Scott, J. & Wofsy, D. Induction of immune tolerance by administration of monoclonal antibodies to L3T4. J. Immunol. 137, 1127–1132 (1986).

    CAS  PubMed  Google Scholar 

  17. Hale, G., Xia, M. Q., Tighe, H. P., Dyer, M. J. & Waldmann, H. The CAMPATH-1 antigen (CDw52). Tissue Antigens 35, 118–127 (1990).

    Article  CAS  PubMed  Google Scholar 

  18. Isaacs, J. et al. Humanised monoclonal antibody therapy for rheumatoid arthritis. Lancet 340, 748–752 (1992). The first description of humanized monoclonal antibody therapy of rheumatic disease.

    Article  CAS  PubMed  Google Scholar 

  19. Isaacs, J. D. et al. CAMPATH-1H in rheumatoid arthritis — an intravenous dose-ranging study. Br J. Rheumatol. 35, 231–240 (1996).

    Article  CAS  PubMed  Google Scholar 

  20. Matteson, E. L. et al. Treatment of active refractory rheumatoid arthritis with humanized monoclonal antibody CAMPATH-1H administered by daily subcutaneous injection. Arthritis Rheum. 38, 1187–1193 (1995).

    Article  CAS  PubMed  Google Scholar 

  21. Weinblatt, M. et al. CAMPATH-1H, a humanized monoclonal antibody, in refractory rheumatoid arthritis: An intravenous dose-escalation study. Arthritis Rheum. 38, 1589–1594 (1995).

    Article  CAS  PubMed  Google Scholar 

  22. Schnitzer, T. et al. Subcutaneous administration of CAMPATH™-1H: Clinical and biological outcomes. J. Rheumatol. 24, 1031–1036 (1997).

    CAS  PubMed  Google Scholar 

  23. Moreau, T. et al. Transient increase in symptoms associated with cytokine release in patients with multiple sclerosis. Brain 119, 225–237 (1996).

    Article  PubMed  Google Scholar 

  24. Wing, M., Waldmann, H., Isaacs, J., Compston, D. & Hale, G. Ex vivo whole blood cultures for predicting cytokine release syndrome: dependence on target antigen and antibody isotype. Ther. Immunol. 2, 183–190 (1995).

    CAS  PubMed  Google Scholar 

  25. Wing, M. et al. Mechanism of first-dose cytokine-release syndrome by CAMPATH 1-H: involvement of CD16 (FcγRIII) and CD11a/CD18 (LFA-1) on NK cells. J. Clin. Invest. 98, 2819–2826 (1996). An in vitro dissection of the mechanism underlying the first-dose, cytokine release reaction to CamPath.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Brett, S. et al. Repopulation of blood lymphocyte subpopulations in rheumatoid arthritis patients treated with the depleting humanized monoclonal antibody CAMPATH 1H. Immunol 88, 13–19 (1996).

    Article  CAS  Google Scholar 

  27. Ponchel, F. et al. Dysregulated lymphocyte proliferation and differentiation in patients with rheumatoid arthritis. Blood 100, 4550–4556 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Ponchel, F. et al. Interleukin-7 deficiency in rheumatoid arthritis: consequences for therapy-induced lymphopenia. Arthritis Res. Ther. 7, R80–R92 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Moreland, L. W. et al. Treatment of refractory rheumatoid arthritis with a chimeric anti-CD4 monoclonal antibody. Long-term followup of CD4+ T cell counts. Arthritis Rheum. 37, 834–838 (1994).

    Article  CAS  PubMed  Google Scholar 

  30. Isaacs, J. et al. Morbidity and mortality in rheumatoid arthritis patients with profound and prolonged therapy-induced lymphopenia. Arthritis Rheum. 44, 1998–2008 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Isaacs, J. et al. Survival of patients after lymphocytotoxic monoclonal antibody therapy for rheumatoid arthritis. Arthritis Rheum. 50, S700 (2004).

    Google Scholar 

  32. Ruderman, E. M., Weinblatt, M. E., Thurmond, L. M., Pinkus, G. S. & Gravallese, E. M. Synovial tissue response to treatment with Campath-1H. Arthritis Rheum. 38, 254–258 (1995).

    Article  CAS  PubMed  Google Scholar 

  33. Jendro, M., Ganten, T., Matteson, E., Weyand, C. & Goronzy, J. Emergence of oligoclonal T cell populations following therapeutic T cell depletion in rheumatoid arthritis. Arthritis Rheum. 38, 1242–1250 (1995).

    Article  CAS  PubMed  Google Scholar 

  34. Ernst, B., Lee, D. S., Chang, J. M., Sprent, J. & Surh, C. D. The peptide ligands mediating positive selection in the thymus control T cell survival and homeostatic proliferation in the periphery. Immunity 11, 173–181 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Coles, A. J. et al. Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet 354, 1691–1695 (1999). The first in-depth description of secondary autoimmunity following lymphodepleting therapy in humans.

    Article  CAS  PubMed  Google Scholar 

  36. Cox, A. L. et al. Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur. J. Immunol. 35, 3332–3342 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Isaacs, J. et al. A therapeutic human IgG4 monoclonal antibody that depletes target cells in humans. Clin. Exp. Immunol. 106, 427–433 (1996). A demonstration that in vitro parameters do not always predict the in vivo effects of monoclonal antibody therapy in humans.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Schulze-Koops, H., Davis, L., Haverty, P., Wacholtz, M. & Lipsky, P. Reduction of Th1 cell activity in peripheral circulation of patients with rheumatoid arthritis after treatment with a non-depleting humanized monoclonal antibody to CD4. J. Rheumatol. 25, 2065–2076 (1998).

    CAS  PubMed  Google Scholar 

  39. Moreland, L. et al. Nondepleting humanized anti-CD4 monoclonal antibody in patients with refractory rheumatoid arthritis. J. Rheumatol. 25, 221–228 (1998).

    CAS  PubMed  Google Scholar 

  40. Greenwood, J., Clark, M. & Waldmann, H. Structural motifs involved in human IgG antibody effector functions. Eur. J. Immunol. 23, 1098–1104 (1993).

    Article  CAS  PubMed  Google Scholar 

  41. Wu, J. et al. A novel polymorphism of FcγRIIIa (CD16) alters receptor function and predisposes to autoimmune disease. J. Clin. Invest. 100, 1059–1070 (1997). This study identified a genomically encoded polymorphism affecting the ligand binding site in human CD16A which altered receptor function and which has subsequently been shown to influence the efficacy of therapeutic monoclonal antibodies.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lockwood, C., Thiru, S., Isaacs, J., Hale, G. & Waldmann, H. Long term remission of intractable systemic vasculitis with monoclonal antibody therapy. Lancet 341, 1620–1622 (1993).

    Article  CAS  PubMed  Google Scholar 

  43. Stephens, S. et al. Comprehensive pharmacokinetics of a humanized antibody and analysis of residual anti-idiotypic responses. Immunology 85, 668–674 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Brett, S. et al. Emergence of CD52-, glycosylphosphatidylinositol-anchor-deficient lymphocytes in rheumatoid arthritis patients following Campath-1H treatment. Int. Immunol. 8, 325–334 (1996).

    Article  CAS  PubMed  Google Scholar 

  45. Beyersdorf, N. et al. Selective targeting of regulatory T cells with CD28 superagonists allows effective therapy of experimental autoimmune encephalomyelitis. J. Exp. Med. 202, 445–455 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hunig, T. & Dennehy, K. CD28 superagonists: mode of action and therapeutic potential. Immunol. Lett. 100, 21–28 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Wilde, M. I. & Goa, K. L. Muromonab CD3: a reappraisal of its pharmacology and use as prophylaxis of solid organ transplant rejection. Drugs 51, 865–894 (1996).

    Article  CAS  PubMed  Google Scholar 

  48. Ferran, C., Bach, J. F. & Chatenoud, L. In vivo T cell activation properties of anti-T cell monoclonal antibodies. Exp. Nephrol. 1, 83–89 (1993).

    CAS  PubMed  Google Scholar 

  49. Suntharalingam, G. et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N. Engl. J. Med. 355, 1018–1028 (2006). A description of the serious consequences that followed the administration of TGN 1412 to human volunteers.

    Article  CAS  PubMed  Google Scholar 

  50. Elflein, K., Rodriguez-Palmero, M., Kerkau, T. & Hunig, T. Rapid recovery from T lymphopenia by CD28 superagonist therapy. Blood 102, 1764–1770 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Marshall, E. Clinical medicine. Accident prompts a closer look at antibody trials. Science 312, 172 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. Leandro, M. J., Cambridge, G., Ehrenstein, M. R. & Edwards, J. C. Reconstitution of peripheral blood B cells after depletion with rituximab in patients with rheumatoid arthritis. Arthritis Rheum. 54, 613–620 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Looney, R. et al. B cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab. Arthritis Rheum. 50, 2580–2589 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Sfikakis, P. P., Boletis, J. N. & Tsokos, G. C. Rituximab anti-B-cell therapy in systemic lupus erythematosus: pointing to the future. Curr. Opin. Rheumatol. 17, 550–557 (2005). Summary of data from open-label series in SLE.

    CAS  PubMed  Google Scholar 

  55. Cohen, S. et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary safety and efficacy at twenty-four weeks. Arthritis Rheum. 54, 2793–2806 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Emery, P. et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: Results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum. 54, 1390–1400 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Edwards, J. C., Cambridge, G. & Abrahams, V. M. Do self-perpetuating B lymphocytes drive human autoimmune disease? Immunology 97, 188–196 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Panayi, G. S. B cells: a fundamental role in the pathogenesis of rheumatoid arthritis? Rheumatology (Oxford) 44 (Suppl. 2), ii3–ii7 (2005).

    Article  CAS  Google Scholar 

  59. Edwards, J. et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N. Engl. J. Med. 350, 2572–2581 (2004). The pivotal Phase IIa study of B-cell-depleting therapy for rheumatoid arthritis.

    Article  CAS  PubMed  Google Scholar 

  60. Emery P, F. D., Ferraccioli G, Udell J, Van Vollenhoven RF, Rowe K, Agarwal S, Shaw T. Long-term efficacy and safety of a repeat treatment course of rituximab in RA patients with an inadequate response to disease-modifying anti-rheumatic drugs. Ann. Rheumatic Dis. 65, 58 (2006).

    Google Scholar 

  61. Cambridge, G L. M., Isenberg DA, Teodorescu M, Ehrenstein MR, Edwards JC. B cell depletion therapy in systemic lupus erythematosus: effect on autoantibody and anti-microbial antibody profile. Arthritis and Rheumatism 50, S227–S228 (2004).

    Article  CAS  Google Scholar 

  62. Roll, P., Palanichamy, A., Kneitz, C., Dorner, T. & Tony, H. P. Regeneration of B cell subsets after transient B cell depletion using anti-CD20 antibodies in rheumatoid arthritis. Arthritis Rheum. 54, 2377–2386 (2006).

    Article  CAS  PubMed  Google Scholar 

  63. Silverman, G. J. Therapeutic B cell depletion and regeneration in rheumatoid arthritis: emerging patterns and paradigms. Arthritis Rheum. 54, 2356–2367 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Sfikakis, P. P. et al. Remission of proliferative lupus nephritis following B cell depletion therapy is preceded by down-regulation of the T cell costimulatory molecule CD40 ligand: an open-label trial. Arthritis Rheum. 52, 501–513 (2005).

    Article  CAS  PubMed  Google Scholar 

  65. Gunnarsson, I. et al. Histopathological and clinical changes in patients with severe lupus nephritis treated with rituximab plus cyclophosphamide: a rebiopsy study in 7 patients. Ann. Rheum. Dis. 65, 64 (2006).

    Article  Google Scholar 

  66. Dass, S. et al. Response to rituximab therapy in RA correlates with variable B cell expression in peripheral blood and synovium. Ann. Rheum. Dis. 65, 186 (2006).

    Google Scholar 

  67. Leandro, M. J., Cambridge, G., Edwards, J. C., Ehrenstein, M. R. & Isenberg, D. A. B-cell depletion in the treatment of patients with systemic lupus erythematosus: a longitudinal analysis of 24 patients. Rheumatology (Oxford) 44, 1542–1545 (2005).

    Article  CAS  Google Scholar 

  68. Isenberg, D. A. B cell targeted therapies in autoimmune diseases. J. Rheumatol. Suppl 77, 24–28 (2006).

    CAS  PubMed  Google Scholar 

  69. Wallace, D. & al., e. Belimumab (BMAB), a fully human monoclonal antibody to B-lymphocyte stimulator (BLyS) shows bioactivity and reduces systemic lupus erythematosus disease activity. Ann. Rheum. Dis. 65, 62 (2006).

    Google Scholar 

  70. Furie, R. & al., e. Multiple SLE disease activity measures in a multi-centre phase 2 SLE trial demonstrate belimumab (fully human monoclonal antibody to B-lymphocyte stimulator [BLyS]) improves ot stabilizes SLE activity. Ann. Rheum. Dis. 65, 63 (2006).

    Google Scholar 

  71. Dorner, T. et al. Initial clinical trial of epratuzumab (humanized anti-CD22 antibody) for immunotherapy of systemic lupus erythematosus. Arthritis Res. Ther. 8, R74 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Steinfeld, S., Tant, L., Burmester, G. & al., e. Epratuzumab [humanized anti CD22 antibody] in primary Sjögren's syndrome: an open label phase I/II study:. Arthritis Res. Ther. 8, R129 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Pijpe, J. et al. Rituximab treatment in patients with primary Sjögren's syndrome: an open-label phase II study. Arthritis Rheum. 52, 2740–2750 (2005).

    Article  CAS  PubMed  Google Scholar 

  74. Gong, Q. et al. Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy. J. Immunol. 174, 817–826 (2005). A description of how the in vivo micro-environment can influence the consequences of monoclonal antibody targeting of cellular populations.

    Article  CAS  PubMed  Google Scholar 

  75. Uchida, J. et al. The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor-dependent mechanisms during anti-CD20 antibody immunotherapy. J. Exp. Med. 199, 1659–1669 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Hamaguchi, Y. et al. The peritoneal cavity provides a protective niche for B1 and conventional B lymphocytes during anti-CD20 immunotherapy in mice. J. Immunol. 174, 4389–4399 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Seyler, T. et al. BLyS and APRIL in rheumatoid arthritis. J. Clin. Invest. 115, 3083–3092 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Fisher, C. J., Jr. et al. Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. N. Engl. J. Med. 334, 1697–1702 (1996).

    Article  CAS  PubMed  Google Scholar 

  79. Suitters, A. J. et al. Differential effect of isotype on efficacy of anti-tumor necrosis factor α chimeric antibodies in experimental septic shock. J. Exp. Med. 179, 849–856 (1994).

    Article  CAS  PubMed  Google Scholar 

  80. Aderka, D., Engelmann, H., Maor, Y., Brakebusch, C. & Wallach, D. Stabilization of the bioactivity of tumor necrosis factor by its soluble receptors. J. Exp. Med. 175, 323–329 (1992).

    Article  CAS  PubMed  Google Scholar 

  81. Bendtzen, K., Hansen, M., Ross, C., Poulsen, L. & Svenson, M. Cytokines and autoantibodies to cytokines. Stem Cells 13, 206–222 (1995).

    Article  CAS  PubMed  Google Scholar 

  82. Ulfgren, A. et al. Systemic anti-tumor necrosis factor α therapy in rheumatoid arthritis down-regulates synovial tumor necrosis factor α synthesis. Arthritis Rheum. 43, 2391–2396 (2000).

    Article  CAS  PubMed  Google Scholar 

  83. De Silva, A. et al. Pharmacogenetics of infliximab in Crohn's disease: the 5q31/IBD5 risk haplotype predicts response. Gastroenterology 122, M1423 (2002).

  84. Louis, E. et al. A positive response to infliximab in Crohn disease: association with a higher systemic inflammation before treatment but not with –308 TNF gene polymorphism. Scand. J. Gastroenterol. 37, 818–824 (2002).

    Article  CAS  PubMed  Google Scholar 

  85. Mascheretti, S. et al. Pharmacogenetic investigation of the TNF/TNF-receptor system in patients with chronic active Crohn's disease treated with infliximab. Pharmacogenomics 2, 127–136 (2002).

    Article  CAS  Google Scholar 

  86. Mugnier, B. et al. Polymorphism at position –308 of the tumor necrosis factor α gene influences outcome of infliximab therapy in rheumatoid arthritis. Arthritis Rheum. 48, 1849–1852 (2003).

    Article  CAS  PubMed  Google Scholar 

  87. Criswell, L. A. et al. The influence of genetic variation in the HLA-DRB1 and LTA-TNF regions on the response to treatment of early rheumatoid arthritis with methotrexate or etanercept. Arthritis Rheum. 50, 2750–2756 (2004).

    Article  CAS  PubMed  Google Scholar 

  88. Tutuncu, Z. et al. Fc-γ receptor type IIIA polymorphisms influence treatment outcomes in patients with inflammatory arthritis treated with tumor necrosis factor α-blocking agents. Arthritis Rheum. 52, 2693–2696 (2005).

    Article  CAS  PubMed  Google Scholar 

  89. Anolik, J. et al. The relationship of FcγRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus. Arthritis Rheum. 48, 455–459 (2003). Demonstration of a relationship between FcγR genotype and B-cell depletion following rituximab therapy.

    Article  CAS  PubMed  Google Scholar 

  90. Catrina, A. et al. Evidence that anti-tumor necrosis factor therapy with both etanercept and infliximab induces apoptosis in macrophages, but not lymphocytes, in rheumatoid arthritis joints: extended report. Arthritis Rheum. 52, 61–72 (2005).

    Article  CAS  PubMed  Google Scholar 

  91. Scallon, B. J., Moore, M. A., Trinh, H., Knight, D. M. & Ghrayeb, J. Chimeric anti-TNF-α monoclonal antibody cA2 binds recombinant transmembrane TNF-α and activates immune effector functions. Cytokine 7, 251–259 (1995).

    Article  CAS  PubMed  Google Scholar 

  92. Ehrenstein, M. et al. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNF α therapy. J. Exp. Med. 200, 277–285 (2004). This study demonstrates that TNFα blockade has immunoregulatory effects, by enhancing the function of regulatory T cells in rheumatoid arthritis patients.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Valencia, X. et al. TNF downmodulates the function of human CD4+CD25hi T-regulatory cells. Blood 108, 253–61 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Shen, C. et al. Adalimumab induces apoptosis of human monocytes: a comparative study with infliximab and etanercept. Aliment. Pharmacol. Ther. 21, 251–258 (2005).

    Article  CAS  PubMed  Google Scholar 

  95. Mitoma, H. et al. Infliximab induces potent anti-inflammatory responses by outside-to-inside signals through transmembrane TNF-α. Gastroenterology 128, 376–392 (2005).

    Article  CAS  PubMed  Google Scholar 

  96. Mitoma, H., Horiuchi, T. & Tsukamoto, H. Binding activities of infliximab and etanercept to transmembrane tumor necrosis factor-α. Gastroenterology 126, 934–935; author reply 935–936 (2004).

    Article  PubMed  Google Scholar 

  97. Goedkoop, A. et al. Early effects of tumour necrosis factor α blockade on skin and synovial tissue in patients with active psoriasis and psoriatic arthritis. Ann. Rheum. Dis. 63, 769–773 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Choy, E. H. et al. Efficacy of a novel PEGylated humanized anti-TNF fragment (CDP870) in patients with rheumatoid arthritis: a phase II double-blinded, randomized, dose-escalating trial. Rheumatology (Oxford) 41, 1133–1137 (2002).

    Article  CAS  Google Scholar 

  99. Schreiber, S. et al. A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn's disease. Gastroenterology 129, 807–818 (2005).

    Article  CAS  PubMed  Google Scholar 

  100. Rankin, E. et al. The therapeutic effects of an engineered human anti-tumor necrosis factor α antibody (CDP571) in rheumatoid arthritis. Brit J. Rheumatol. 53, 1485–1493 (1995).

    Google Scholar 

  101. Sandborn, W. et al. CDP571, a humanised monoclonal antibody to tumour necrosis factor α, for moderate to severe Crohn's disease: a randomised, double blind, placebo controlled trial. Gut 53, 1485–1493 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Zou, J. et al. Downregulation of the nonspecific and antigen-specific T cell cytokine response in ankylosing spondylitis during treatment with infliximab. Arthritis Rheum. 48, 780–790 (2003).

    Article  CAS  PubMed  Google Scholar 

  103. Zou, J. et al. Up regulation of the production of tumour necrosis factor α and interferon γ by T cells in ankylosing spondylitis during treatment with etanercept. Ann. Rheum. Dis. 62, 561–564 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Saliu, O. Y., Sofer, C., Stein, D. S., Schwander, S. K. & Wallis, R. S. Tumor-necrosis-factor blockers: differential effects on mycobacterial immunity. J. Infect. Dis. 194, 486–492 (2006). This study demonstrates that monoclonal antibody and soluble receptor TNF antagonists have differing effects on some T-cell responses to Mycobacterium tuberculosis (proliferation, IFNγ production) but not others (IL-10 production).

    Article  CAS  PubMed  Google Scholar 

  105. De Rycke, L. et al. Infliximab, but not etanercept, induces IgM anti-double-stranded DNA autoantiodies as main antinuclear reactivity: biologic and clinical implications in autoimmune arthritis. Arthritis Rheum. 52, 2192–2201 (2005).

    Article  CAS  PubMed  Google Scholar 

  106. Jonsdottir, T. et al. Treatment with tumour necrosis factor α antagonists in patients with rheumatoid arthritis induces anticardiolipin antibodies. Ann. Rheum. Dis. 63, 1075–1078 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. van Vollenhoven, R., Harju, A., Brannemark, S. & Klareskog, L. Treatment with infliximab (Remicade) when etancercept (Enbrel) has failed or vice versa: data from the STURE registry showing that switching tumour necrosis factor α blockers can make sense. Ann. Rheum. Dis. 62, 1195–1198 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Hansen, K. E. et al. The efficacy of switching from etanercept to infliximab in patients with rheumatoid arthritis. J. Rheumatol. 31, 1098–1102 (2004).

    CAS  PubMed  Google Scholar 

  109. Nikas, S. N. et al. Efficacy and safety of switching from infliximab to adalimumab: a comparative controlled study. Ann. Rheum. Dis. 65, 257–260 (2006).

    Article  CAS  PubMed  Google Scholar 

  110. Buch, M. H. et al. C-reactive protein as a predictor of infliximab treatment outcome in patients with rheumatoid arthritis: defining subtypes of nonresponse and subsequent response to etanercept. Arthritis Rheum. 52, 42–8 (2005).

    Article  CAS  PubMed  Google Scholar 

  111. Buch, M. H., B. S., Bryer, D. & Emery, P. Type of previous infliximab non-response in rheumatoid arthritis determines subsequent response to adalimumab. Arthritis and Rheumatism 52, S348 (2005).

    Google Scholar 

  112. Wendling, D., Racadot, E. & Wijdenes, J. Treatment of severe rheumatoid arthritis by anti-interleukin 6 monoclonal antibody. J. Rheumatol. 20, 259–262 (1993).

    CAS  PubMed  Google Scholar 

  113. Haringman, J. J. et al. A randomized controlled trial with an anti-CCL2 (anti-monocyte chemotactic protein 1) monoclonal antibody in patients with rheumatoid arthritis. Arthritis Rheum. 54, 2387–2392 (2006).

    Article  CAS  PubMed  Google Scholar 

  114. Boyman, O., Kovar, M., Rubinstein, M. P., Surh, C. D. & Sprent, J. Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science 311, 1924–1927 (2006). This study demonstrates how theoretically neutralizing anticytokine antibodies can, in fact, enhance cytokine potency.

    Article  CAS  PubMed  Google Scholar 

  115. Cohen, S. et al. Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: Results of a twenty-four-week, multicenter, randomised, double-blind, placebo-controlled trial. Arthritis Rheum. 46, 614–624 (2002).

    Article  CAS  PubMed  Google Scholar 

  116. Hawkins, P., Bybee, A., Aganna, E. & McDermott, M. Response to anakinra in a de novo case of neonatal-onset multisystem inflammatory disease. Arthritis Rheum. 50, 2708–2709 (2004).

    Article  PubMed  Google Scholar 

  117. Fitzgerald, A., LeClercq, S., Yan, A., Homik, J. & Dinarello, C. Rapid responses to anakinra in patients with refractory adult-onset Still's disease. Arthritis Rheum. 52, 1794–1803 (2005).

    Article  CAS  PubMed  Google Scholar 

  118. Genovese, M. et al. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum. 50, 1412–1419 (2004).

    Article  CAS  PubMed  Google Scholar 

  119. Marvin, J. S. & Zhu, Z. Bispecific antibodies for dual-modality cancer therapy: killing two signaling cascades with one stone. Curr. Opin. Drug Discov. Devel. 9, 184–193 (2006).

    CAS  PubMed  Google Scholar 

  120. Presta, L. Antibody engineering for therapeutics. Curr. Opin. Struct. Biol. 13, 519–525 (2003).

    Article  CAS  PubMed  Google Scholar 

  121. Junghans, R. P. & Anderson, C. L. The protection receptor for IgG catabolism is the beta2-microglobulin-containing neonatal intestinal transport receptor. Proc. Natl Acad. Sci. USA 93, 5512–5516 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Duncan, A. & Winter, G. The binding site for C1q on IgG. Nature 332, 738–740 (1988).

    Article  CAS  PubMed  Google Scholar 

  123. Duncan, A., Woof, J., Partridge, L., Burton, D. & Winter, G. Localization of the binding site for the human high-affinity Fc receptor on IgG. Nature 332, 563–564 (1988).

    Article  CAS  PubMed  Google Scholar 

  124. Ghetie, V. et al. Increasing the serum persistence of an IgG fragment by random mutagenesis. Nature Biotechnol. 15, 637–640 (1997).

    Article  CAS  Google Scholar 

  125. Keymeulen, B. et al. Insulin Needs after CD3-Antibody Therapy in New-Onset Type 1 Diabetes. N. Engl. J. Med. 352, 2598–2608 (2005).

    Article  CAS  PubMed  Google Scholar 

  126. Friend, P. J. et al. Phase I study of an engineered aglycos-ylated humanized CD3 antibody in renal transplant rejection. Transplantation 68, 1632–1637 (1999).

    Article  CAS  PubMed  Google Scholar 

  127. Herold, K. C. et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N. Engl. J. Med. 346, 1692–1698 (2002). First demonstration of immunomodulatory effects of 'non-activating' anti-CD3 monoclonal antibody in type 1 diabetes mellitus.

    Article  CAS  PubMed  Google Scholar 

  128. Utset, T. O. et al. Modified anti-CD3 therapy in psoriatic arthritis: a phase I/II clinical trial. J. Rheumatol. 29, 1907–1913 (2002).

    CAS  PubMed  Google Scholar 

  129. Bindon, C., Hale, G. & Waldmann, H. Complement activation by immunoglobulin does not depend solely on C1q binding. Eur. J. Immunol. 20, 277–282 (1990).

    Article  CAS  PubMed  Google Scholar 

  130. Alters, S., Sakai, K., Steinman, L. & Oi, V. Mechanisms of anti-CD4-mediated depletion and immunotherapy. A study using a set of chimeric andti-CD4 antibodies. J. Immunol. 144, 4587–4592 (1990).

    CAS  PubMed  Google Scholar 

  131. Isaacs, J., Clark, M., Greenwood, J. & Waldmann, H. Therapy with monoclonal antibodies. An in vivo model for the assessment of therapeutic potential. J. Immunol. 148, 3062–71 (1992).

    CAS  PubMed  Google Scholar 

  132. Isaacs, J., Greenwood, J. & Waldmann, H. Therapy with monoclonal antibodies II. The contribution of Fcg receptor binding and the influence of Ch1 and Ch3 domains on in vivo effector function. J. Immunol. 161, 3863–3869 (1998).

    Google Scholar 

  133. Bindon, C., Hale, G. & Waldmann, H. Importance of antigen specificity for complement mediated lysis by monoclonal antibodies. Eur. J. Immunol. 18, 1507–1514 (1988).

    Article  CAS  PubMed  Google Scholar 

  134. Xia, M., Hale, G. & Waldmann, H. Efficient complement-mediated lysis of cells containing the CAMPATH-1 (CDw52) antigen. Mol. Immunol. 30, 1089–1096 (1993).

    Article  CAS  PubMed  Google Scholar 

  135. Bruggemann, M. et al. Comparison of the effector functions of human immunoglobulins using a matched set of chimeric antibodies. J. Exp. Med. 166, 1351–1361 (1987).

    Article  CAS  PubMed  Google Scholar 

  136. Riechmann, L., Clark, M., Waldmann, H. & Winter, G. Reshaping human antibodies for therapy. Nature 332, 323–327 (1988). First report of humanization by 'CDR grafting' of a therapeutic monoclonal antibody.

    Article  CAS  PubMed  Google Scholar 

  137. Louis, E. et al. Association between polymorphism in IgG Fc receptor IIIa coding gene and biological response to infliximab in Crohn's disease. Inflamm. Bowel Dis. 11, 75–76 (2005).

    Article  Google Scholar 

  138. Morgan, A. W. et al. Fcγ receptor type IIIA is associated with rheumatoid arthritis in two distinct ethnic groups. Arthritis Rheum. 43, 2328–2334 (2000).

    Article  CAS  PubMed  Google Scholar 

  139. Morgan, A. et al. Fc RIIIA-158V and rheumatoid arthritis. A confirmation study. Rheumatology 42, 528–533 (2003).

    Article  CAS  PubMed  Google Scholar 

  140. Blom, A. B. et al. Increased expression of Fcγ receptors II and III on macrophages of rheumatoid arthritis patients results in higher production of tumor necrosis factor α and matrix metalloproteinase. Arthritis Rheum. 48, 1002–1014 (2003).

    Article  CAS  PubMed  Google Scholar 

  141. Chatenoud, L. et al. Clinical use of OKT3: the role of cytokine release and xenosensitization. J. Autoimmun. 1, 631–640 (1988).

    Article  Google Scholar 

  142. Tax, W. J., Tamboer, W. P., Jacobs, C. W., Frenken, L. A. & Koene, R. A. Role of polymorphic Fc receptor FcγRIIa in cytokine release and adverse effects of murine IgG1 anti-CD3/T cell receptor antibody (WT31). Transplantation 63, 106–112 (1997).

    Article  CAS  PubMed  Google Scholar 

  143. van der Pol, W. & van de Winkel, J. IgG receptor polymorphisms: risk factors for disease. Immunogenetics 48, 222–232 (1998).

    Article  CAS  PubMed  Google Scholar 

  144. Isaacs, J. The antiglobulin response to therapeutic antibodies. Sem. Immunol. 2, 449–456 (1990).

    CAS  Google Scholar 

  145. Koren, E., Zuckerman, A. & Mire-Sluis, A. Immune responses to therapeutic proteins in humans-clinical significance, assessment and prediction. Curr. Pharm. Biotechnol. 3, 349–360 (2002).

    Article  CAS  PubMed  Google Scholar 

  146. Pendley, C., Schantz, A. & Wagner, C. Immunogenicity of therapeutic monoclonal antibodies. Curr. Opin. Mol. Ther. 5, 172–179 (2003).

    CAS  PubMed  Google Scholar 

  147. FDA labelling information [online], <http://www.fda.gov/cder/foi/label/2006/125057s071,%20s095LBL.pdf> (2004).

  148. Gilliland, L. et al. Elimination of the immunogenicity of therapeutic antibodies. J. Immunol. 162, 3663–3671 (1999). A novel approach for tolerance induction to anti-globulin responses, using non-cell-binding variants of therapeutic monoclonal antibodies.

    CAS  PubMed  Google Scholar 

  149. Schroeder, T. et al. Antimurine antibody formation following OKT3 therapy. Transplantation 49, 48–51 (1990).

    Article  CAS  PubMed  Google Scholar 

  150. Patten, P. & Schellekens, H. The immunogenicity of biopharmaceuticals: lessons learned and consequences for protein drug development. Dev. Biol. 112, 81–97 (2003). A review of how production processes can influence the immunogenicity of biologics.

    CAS  Google Scholar 

  151. Hanauer, S. et al. Delayed hypersensitivity to infliximab (Remicade) re-infusion after a 2-4 year interval without treatment. Gastroenterology 116, A731 (1999).

    Google Scholar 

  152. Reiter, C. et al. 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. 34, 525–536 (1991).

    Article  CAS  PubMed  Google Scholar 

  153. Baslund, B., Skjoedt, H., Klausen, T. & al., e. A phase I double blind, randomized, placebo controlled study of a non-depleting fully human anti-CD4 monoclonal antibody (HuMax CD4/HM6G) in patients with active rheumatoid arthritis. Arthritis Rheum. 43, S89 (2000).

    Google Scholar 

  154. DeNardo, G. L., Bradt, B. M., Mirick, G. R. & DeNardo, S. J. Human antiglobulin response to foreign antibodies: therapeutic benefit? Cancer Immunol. Immunother. 52, 309–316 (2003).

    CAS  PubMed  Google Scholar 

  155. Cobbold, S., Rebello, P., Davies, H., Friend, P. & Clark, M. A simple method for measuring patient anti globulin responses against isotypic or idiotypic determinants. J. Immunol. Methods 127, 19 (1990).

    Article  CAS  PubMed  Google Scholar 

  156. Christen, U., Thuerkauf, R., Stevens, R. & Lesslauer, W. Immune response to a recombinant human TNFR55-IgGI fusion protein: autoantibodies in rheumatoid arthritis and multiple sclerosis patients have neither neutralizing nor agonist activities. Hum. Immunol. 60, 774–790 (1999).

    Article  CAS  PubMed  Google Scholar 

  157. Wadhwa, M., Bird, C., Dilger, P., Gaines-Das, R. & Thorpe, R. Strategies for detection, measurement and characterization of unwanted antibodies induced by therapeutic biologicals. J. Immunol. Methods 278, 1–17 (2003).

    Article  CAS  PubMed  Google Scholar 

  158. Indelicato, S. Bioassays for the measurement of neutralizing antibodies in serum (SNFs). Dev. Biol. 112, 113–125 (2003).

    CAS  Google Scholar 

  159. Swanson, S. New technologies for the detection of antibodies to therapeutic proteins. Dev. Biol. 112, 127–133 (2003).

    CAS  Google Scholar 

  160. Rosenberg, A. Immunogenicity of biological therapeutics: a hierarchy of concerns. Dev. Biol. 112, 15–21 (2003).

    CAS  Google Scholar 

  161. Cheifetz, A. et al. The incidence and management of infusion reactions to infliximab: a large center experience. Am. J. Gastroenterol. 98, 1315–1324 (2003).

    Article  CAS  PubMed  Google Scholar 

  162. Maini, R. N. et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor α monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum. 41, 1552–1563 (1998). One of the first demonstrations that methotrexate co-therapy can reduce the immunogenicity of biologics.

    Article  CAS  PubMed  Google Scholar 

  163. Klareskog, L. et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 363, 675–681 (2004). Demonstration that methotrexate can enhance the efficacy of even relatively non-immunogenic biologics.

    Article  CAS  PubMed  Google Scholar 

  164. Weinblatt, M. E. et al. Adalimumab, a fully human anti-tumor necrosis factor α monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 48, 35–45 (2003).

    Article  CAS  PubMed  Google Scholar 

  165. FDA labelling information [online], <http://www.fda.gov/cder/foi/label/2006/103772s5145LBL.pdf (2005).

  166. Ng, C., Bruno, R., Combs, D. & Davies, B. Population pharmacokinetics of rituximab (anti-CD20 monoclonal antibody) in rheumatoid arthritis patients during a phase II clinical trial. J. Clin. Pharmacol. 45, 792–7801 (2005).

    Article  CAS  PubMed  Google Scholar 

  167. Keane, J. et al. Tuberculosis associated with infliximab, a tumor necrosis factor α-neutralizing agent. N. Engl. J. Med. 345, 1098–1104 (2001). Seminal paper demonstrating reactivation of Mycobacterium tuberculosis in recipients of TNFα antagonists.

    Article  CAS  PubMed  Google Scholar 

  168. Gardam, M. A. et al. Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis 3, 148–155 (2003).

    Article  CAS  PubMed  Google Scholar 

  169. Wolfe, F., Michaud, K., Anderson, J. & Urbansky, K. Tuberculosis infection in patients with rheumatoid arthritis and the effect of infliximab therapy. Arthritis Rheum. 50, 372–379 (2004).

    Article  CAS  PubMed  Google Scholar 

  170. Kollias, B. & Kontoyiannis, D. Role of TNF/TNFR in autoimmunity: specific TNF receptor blockade may be advantageous to anti-TNF treatments. Cytokine growth Factor Rev 13, 315–321 (2002).

    Article  CAS  PubMed  Google Scholar 

  171. Olleros, M. L. et al. Contribution of transmembrane tumor necrosis factor to host defense against Mycobacterium bovis bacillus Calmette-guerin and Mycobacterium tuberculosis infections. Am J Pathol 166, 1109–1120 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Zalevsky, J. et al. Selective inhibitor of soluble TNF blocks inflammation without suppressing innate immunity. J. Clin. Invest. (in the press).

  173. Saunders, B. M. et al. Transmembrane TNF is sufficient to initiate cell migration and granuloma formation and provide acute, but not long-term, control of Mycobacterium tuberculosis infection. J. Immunol. 174, 4852–4859 (2005).

    Article  CAS  PubMed  Google Scholar 

  174. Dinarello, C. Differences between anti tumor necrosis factor a monoclonal antibodies and soluble TNF receptors in host defense impairment. J. Rheumatol. 32, 40–47 (2005).

    Google Scholar 

  175. Dixon, W. G. et al. Rates of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum. 54, 2368–2376 (2006). A good example of the utility of a 'biologics registry' for post-marketing surveillance of novel therapeutics.

    Article  CAS  PubMed  Google Scholar 

  176. Cope, A. P. et al. Chronic exposure to tumor necrosis factor (TNF) in vitro impairs the activation of T cells through the T cell receptor/CD3 complex; reversal in vivo by anti-TNF antibodies in patients with rheumatoid arthritis. J. Clin. Invest. 94, 749–760 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Cope, A. P. et al. Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling. J. Exp. Med. 185, 1573–1584 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Mohan, N. et al. Demyelination occurring during anti-tumor necrosis factor α therapy for inflammatory arthritides. Arthritis Rheum. 44, 2862–2869 (2001).

    Article  CAS  PubMed  Google Scholar 

  179. Robinson, W., Genovese, M. & Moreland, L. Demyelinating and neurologic events reported in association with tumor necrosis factor α antagonism: by what mechanisms could tumor necrosis factor α antagonists improve rheumatoid arthritis but exacerbate multiple sclerosis? Arthritis Rheum. 44, 1977–1983 (2001).

    Article  CAS  PubMed  Google Scholar 

  180. Arnett, H. A., Wang, Y., Matsushima, G. K., Suzuki, K. & Ting, J. P. Functional genomic analysis of remyelination reveals importance of inflammation in oligodendrocyte regeneration. J. Neurosci. 23, 9824–9832 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Chung, E., Packer, M., Lo, K., Fasanmade, A. & Willerson, J. Anti-TNF Therapy Against Congestive Heart Failure Investigators. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-α, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 107, 3133–3140 (2003).

    Article  CAS  PubMed  Google Scholar 

  182. Mann, D. et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 109, 1594–1602 (2004).

    Article  CAS  PubMed  Google Scholar 

  183. Kwon, H., Coté, T., Cuffe, M., Kramer, J. & Braun, M. Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann. Intern. Med. 138, 807–111 (2003).

    Article  PubMed  Google Scholar 

  184. Hurlimann, D. et al. Anti-tumor necrosis factor-α treatment improves endothelial function in patients with rheumatoid arthritis. Circulation 106, 2184–2187 (2002).

    Article  PubMed  Google Scholar 

  185. Wolfe, F. & Michaud, K. Heart failure in rheumatoid arthritis: rates, predictors, and the effect of anti-tumor necrosis factor therapy. Am. J. Med. 116, 305–311 (2004).

    Article  PubMed  Google Scholar 

  186. Baecklund, E., Ekbom, A., Sparen, P., Feltelius, N. & Klareskog, L. Disease activity and risk of lymphoma in patients with rheumatoid arthritis: nested case-control study. BMJ 317, 180–181 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Askling, J. et al. Hematopoietic malignancies in rheumatoid arthritis: lymphoma risk and characteristics after exposure to tumour necrosis factor antagonists. Ann. Rheum. Dis. 64, 1414–1420 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Kalunian, K. C., Davis, J. C., Jr., Merrill, J. T., Totoritis, M. C. & Wofsy, D. Treatment of systemic lupus erythematosus by inhibition of T cell costimulation with anti-CD154: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 46, 3251–3258 (2002).

    Article  CAS  PubMed  Google Scholar 

  189. Boumpas, D. T. et al. A short course of BG9588 (anti-CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis Rheum. 48, 719–727 (2003).

    Article  CAS  PubMed  Google Scholar 

  190. Combe, B. et al. Safety and Patient-Reported Outcomes Associated with Abatacept in the Treatment of Rheumatoid Arthritis Patients Receiving Background Disease Modifying Anti-Rheumatic Drugs (DMARDs): The ASSURE Trial. Arthritis Rheum. 52, S709 (2005).

    Google Scholar 

  191. Group, T. W. s. G. E. T. W. R. Etanercept plus standard therapy for Wegener's granulomatosis. N. Engl. J. Med. 352, 351–361 (2005).

  192. Carmona, L. et al. Effectiveness of recommendations to prevent reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor antagonists. Arthritis Rheum. 52, 1766–1772 (2005).

    Article  CAS  PubMed  Google Scholar 

  193. Kerstan, A. & Hunig, T. Cutting edge: distinct TCR- and CD28-derived signals regulate CD95L, Bcl-xL, and the survival of primary T cells. J. Immunol. 172, 1341–1345 (2004).

    Article  CAS  PubMed  Google Scholar 

  194. Clark, M. Antibody humanization: a case of the 'Emperor's new clothes'? Immunol. Today 21, 397–402 (2000). A review that explains why humanization will not always reduce the immunogenicity of monoclonal antibodies.

    Article  CAS  PubMed  Google Scholar 

  195. Gorman, S. D. & Clark, M. R. Humanisation of monoclonal antibodies for therapy. Semin. Immunol. 2, 457–466 (1990).

    CAS  PubMed  Google Scholar 

  196. Moreland, L. W. et al. Phase I/II trial of recombinant methionyl human tumor necrosis factor binding protein PEGylated dimer in patients with active refractory rheumatoid arthritis. J. Rheumatol. 27, 601–609 (2000).

    CAS  PubMed  Google Scholar 

  197. Benjamin, R., Cobbold, S., Clark, M. & Waldmann, H. Tolerance to rat monoclonal antibodies. Implications for serotherapy. J. Exp. Med. 163, 1539–1552 (1986).

    Article  CAS  PubMed  Google Scholar 

  198. Thurmond, L., Reese, M., Donaldson, R. & Orban, B. A kinetic enzyme immunoassay for the quantitation of antibodies to a humanized monoclonal antibody in human serum. J. Pharm. Biomed. Anal. 16, 1317–138 (1998).

    Article  CAS  PubMed  Google Scholar 

  199. Routledge, E., Falconer, M., Pope, H., Lloyd, I. & Waldmann, H. The effect of aglycosylation on the immunogenicity of a humanized therapeutic CD3 monoclonal antibody. Transplantation 60, 847–853 (1995). A demonstration that first-dose 'cytokine release' syndromes might enhance the immunogenicity of biologics via an 'adjuvant' effect.

    Article  CAS  PubMed  Google Scholar 

  200. Carey, G., Lisi, P. & Schroeder, T. The incidence of antibody formation to OKT3 consequent to its use in organ transplantation. Transplantation 60, 151 (1995).

    Article  CAS  PubMed  Google Scholar 

  201. Eckardt, K. & Casadevall, N. Pure red-cell aplasia due to anti-erythropoietin antibodies. Nephrol. Dial. Transplant. 18, 865–869 (2003).

    Article  PubMed  Google Scholar 

  202. Isaacs, J. D. & Waldmann, H. Helplessness as a strategy for avoiding antiglobulin responses to therapeutic monoclonal antibodies. Ther. Immunol. 1, 303–312 (1994).

    CAS  PubMed  Google Scholar 

  203. Strand, V. et al. Effects of administration of an anti-CD5 plus immunoconjugate in rheumatoid arthritis. Results of two phase II studies. The CD5 Plus Rheumatoid Arthritis Investigators Group. Arthritis Rheum. 36, 620–630 (1993).

    Article  CAS  PubMed  Google Scholar 

  204. Baert, F. et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N. Engl. J. Med. 348, 601–608 (2003).

    Article  CAS  PubMed  Google Scholar 

  205. Targan, S. et al. A Short-Term Study of Chimeric Monoclonal Antibody cA2 to Tumor Necrosis Factor for Crohn's Disease. N. Engl. J. Med. 337, 1029–1036 (1997).

    Article  CAS  PubMed  Google Scholar 

  206. Present, D. et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N. Engl. J. Med. 340, 1398–1405 (1999). Demonstrates the efficacy of infliximab for complications of Crohn's disease.

    Article  CAS  PubMed  Google Scholar 

  207. Rutgeerts, P. et al. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease. Gastroenterology 117, 761–769 (1999).

    Article  CAS  PubMed  Google Scholar 

  208. Hanauer, S. et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 359, 1541–1549 (2002).

    Article  CAS  PubMed  Google Scholar 

  209. Wolbink, G. J. et al. Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. Arthritis Rheum. 54, 711–715 (2006). Demonstrates the potential adverse sequelae of antiglobulin formation to biologic therapies.

    Article  CAS  PubMed  Google Scholar 

  210. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

    Article  CAS  PubMed  Google Scholar 

  211. McInnes, I. B., Leung, B. P., Sturrock, R. D., Field, M. & Liew, F. Y. Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factor-α production in rheumatoid arthritis. Nature Med. 3, 189–195 (1997).

    Article  CAS  PubMed  Google Scholar 

  212. Braun, A., Takemura, S., Vallejo, A. N., Goronzy, J. J. & Weyand, C. M. Lymphotoxin beta-mediated stimulation of synoviocytes in rheumatoid arthritis. Arthritis Rheum. 50, 2140–2150 (2004).

    Article  CAS  PubMed  Google Scholar 

  213. Firestein, G. S. Evolving concepts of rheumatoid arthritis. Nature 423, 356–361 (2003).

    Article  CAS  PubMed  Google Scholar 

  214. Herzog, C. et al. Monoclonal anti-CD4 in arthritis. Lancet 8573, 1461–1462 (1987).

    Article  Google Scholar 

  215. Herzog, C. et al. Anti-CD4 antibody treatment of patients with rheumatoid arthritis: I. Effect on clinical course and circulating T cells. J. Autoimmun. 2, 627–642 (1989).

    Article  CAS  PubMed  Google Scholar 

  216. Goldberg, D. et al. Immunological effects of high dose administration of anti-CD4 antibody in rheumatoid arthritis. J. Autoimmun. 4, 617 (1991).

    Article  CAS  PubMed  Google Scholar 

  217. Horneff, G., Burmester, G., Emmrich, F. & Kalden, J. Treatment of rheumatoid arthritis with an anti-CD4 monoclonal antibody. Arthritis Rheum. 34, 129–140 (1991).

    Article  CAS  PubMed  Google Scholar 

  218. Horneff, G., Winkler, T., Kalden, J. R., Emmrich, F. & Burmester, G. R. Human anti-mouse antibody response induced by anti-CD4 monoclonal antibody therapy in patients with rheumatoid arthritis. Clin. Immunol. Immunopathol. 59, 89–103 (1991).

    Article  CAS  PubMed  Google Scholar 

  219. Wendling, D. et al. A randomized, double blind, placebo controlled multicenter trial of murine anti-CD4 monoclonal antibody therapy in rheumatoid arthritis. J. Rheumatol. 25, 1457–1461 (1998).

    CAS  PubMed  Google Scholar 

  220. Moreland, L. W. et al. Double-blind, placebo-controlled multicenter trial using chimeric monoclonal anti-CD4 antibody, cM-T412, in rheumatoid arthritis patients receiving concomitant methotrexate. Arthritis Rheum. 38, 1581–1588 (1995).

    Article  CAS  PubMed  Google Scholar 

  221. van der Lubbe, P. A., Dijkmans, B. A., Markusse, H. M., Nassander, U. & Breedveld, F. C. A randomized, double-blind, placebo-controlled study of CD4 monoclonal antibody therapy in early rheumatoid arthritis. Arthritis Rheum. 38, 1097–1106 (1995).

    Article  CAS  PubMed  Google Scholar 

  222. Choy, E. H., Schantz, A., Pitzalis, C., Kingsley, G. H. & Panayi, G. S. The pharmacokinetics and human anti-mouse antibody response in rheumatoid arthritis patients treated with a chimeric anti-CD4 monoclonal antibody. Br J. Rheumatol. 37, 801–802 (1998).

    Article  CAS  PubMed  Google Scholar 

  223. Choy, E. et al. Percentage of anti CD4 monoclonal antibody coated lymphocytes in the rheumatoid joint is associated with clinical improvement. Arthritis Rheum. 39, 52–56 (1996).

    Article  CAS  PubMed  Google Scholar 

  224. Yocum, D. et al. Clinical and immunologic effects of a primatized anti-CD4 monoclonal antibody in active rheumatoid arthritis: results of a phase I, single dose, dose escalating trial. J. Rheumatol. 25, 1257–1262 (1998).

    CAS  PubMed  Google Scholar 

  225. Hepburn, T. W., Totoritis, M. C. & Davis, C. B. Antibody-mediated stripping of CD4 from lymphocyte cell surface in patients with rheumatoid arthritis. Rheumatology (Oxford) 42, 54–61 (2003).

    Article  CAS  Google Scholar 

  226. Isaacs, J. et al. Humanized anti-CD4 monoclonal antibody therapy of autoimmune and inflammatory disease. Clin. Exp. Immunol. 110, 158–166 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Choy, E. H. et al. Pharmacokinetic, pharmacodynamic and clinical effects of a humanized IgG1 anti-CD4 monoclonal antibody in the peripheral blood and synovial fluid of rheumatoid arthritis patients. Rheumatology (Oxford) 39, 1139–1146 (2000).

    Article  CAS  Google Scholar 

  228. Nesbitt, A. & Henry, A. Assessment of the affinity for soluble TNF and the neutralising potency against soluble and membrane TNF of the anti-TNF agents certolizumab pegol, adalimumab, etanercept and infliximab. Ann. Rheum. Dis. 65, 456 (2006).

    Google Scholar 

  229. Fossati, G. & Nesbitt, A. The effect of anti-TNF agents on degranulation, necrosis and apoptosis of peripheral blood neutrophils. Gastroenterology 128, A653 (2005).

    Google Scholar 

  230. Nesbitt, A. & Fossati, G. In vitro complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity by the anti-TNF agents certolizumab pegol, adalimumab, etanercept and infliximab. Ann. Rheum. Dis. 65, 455 (2006).

    Google Scholar 

  231. Nesbitt, A. & Fossati, G. Effect of the anti-TNF agents adalimumab, etanercept, Infliximab and certolizumab PEGol (CDP870) on the induction of apoptosis in activated peripheral blood lymphocytes and monocytes. Am. J. Gastroenterol. 100, S299 (2005).

    Article  CAS  Google Scholar 

  232. Kohler, G. & Milstein, C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256, 495–497 (1975).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank J. Armstrong, B. Schwieterman and D. Szymkowski for their detailed reviews and helpful comments.

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Authors and Affiliations

  1. Division of Immunology/Rheumatology, Stanford University, 306 Ramona Road, Portola Valley, 94028, California, USA

    Vibeke Strand

  2. Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, 172 Shelby Interdisciplinary Biomedical Science Building, 1825 University Boulevard, Birmingham, 35294, Alabama, USA

    Robert Kimberly

  3. Wilson Horne Immunotherapy Centre, Institute of Cellular Medicine, The Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK

    John D. Isaacs

Authors
  1. Vibeke Strand
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Correspondence to John D. Isaacs.

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Competing interests

Since September 1991 V.S. has worked as an independent biopharmaceutical consultant in clinical development and regulatory affairs, and has consulted for the following companies: Abbott Immunology; Abgenix; Amgen Corp.; BiogenIdec; Celltech; Centocor; Enzon; Fibrogen; Genelabs; Genentech; Immunomedics; Incyte; Millennium; Novartis; Omeros; Pfizer; Procter & Gamble; Roche; Sanofi-Aventis; Scios; Serono; and SKK. V.S. has previously consulted for Alexion; Alza Corp.; AstraZeneca; Becton Dickinson; Boeringer Ingelheim; Cell Therapeutics; Connectics; Cypress Biosciences, Inc.; Entelos; Geron; GlaxoSmithKline; Icos Corp.; Immune Response Corp.; Janssen Pharmaceuticals; Eli Lilly and Co.; La Jolla Pharmaceuticals; Medarex; Organon; RWJ Pharmaceutical Res Inst; Schering Plough; Sumitomo; UCB; Vertex; Wyeth Ayerst; Xoma Corp. V.S. has served on Advisory Boards for Abbott; Abgenix; Amgen; Centocor; Eli Lilly; Roche; RWJ Pharmaceutical Res Inst; Novartis; Pfizer; and Sanofi-Aventis. V.S. has previously been employed by Syntex Research (1986–88), Applied Immune Sciences (1988–90) and Xoma Corp. (1990–91). V.S. serves on speaking bureaus for Abbott; Amgen; Centocor; Pfizer; and Sanofi-Aventis. V.S. does not hold stock in any company.

Since 1995, J.D.I. has been an advisory board member or acted as a consultant for Roche Pharmaceuticals; Bristol-Myers Squibb; GlaxoSmithKline PLC; AstraZeneca; UCB-Celltech; Amgen; Millennium Pharmaceuticals; and Cambridge Antibody Technology. J.D.I. has been in receipt of educational/research grants from Wyeth Pharmaceuticals; Abbott Pharmaceuticals; and Ilex Oncology. J.D.I. has received honoraria from Xencor; Tolerrx; Biogen Idec; Genzyme; and Ilex Oncology. J.D.I. has received sponsorship towards attendance at national/international meetings from Roche Pharmaceuticals; MSD; Wyeth Pharmaceuticals; Pfizer Pharmaceuticals; Pharmacia; Abbott Pharmaceuticals; Novartis Pharmaceuticals; Sanofi-Aventis; and Boehringer Ingelheim.

R.K. has potential intellectual property in a research relationship with Daiichi-Sankyo Co., Ltd.

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DATABASES

OMIM

Ankylosing spondylitis

Crohn's disease

Muckle–Wells syndrome

Multiple sclerosis

Psoriatic arthritis

Rheumatoid arthritis

Sjögren's syndrome

SLE

Ulcerative colitis

Wegner's granulomatosis

Glossary

Complement-dependent cytotoxicity

Cell death that results when a monoclonal antibody, bound to a target cell, initiates the complement cascade leading to formation of a membrane attack complex that disrupts the cell membrane.

Antibody-dependent cellular cytotoxicity

Cell death that results when the Fc fragment of a monoclonal antibody, bound to a target cell, interacts with Fcγ receptors on monocytes, macrophages or natural killer cells. These cells in turn ingest the target cell or secrete products that result in its death.

Lymphopaenia

A condition marked by lower than normal circulating lymphocytes.

Oligoclonal expansions

The proliferation and resultant increase in cell numbers of a limited number of T- and/or B-cell clones, typically of a restricted specificity for antigen.

Monocytopaenia

A condition marked by lower than normal circulating monocytes.

Systemic lupus erythematosus

(SLE). A systemic autoimmune disease involving multiple organ systems and characterized by circulating autoantibodies, immune complexes and activation of immune system cells. SLE is a complex genetic trait of unknown aetiology.

Kupffer cells

Fixed-tissue phagocytes of the myeloid lineage which line the liver sinusoids.

Phage-display technology

A molecular technique that permits the display of a large and diverse range of peptides and/or proteins on the surface of filamentous phage. These can then be screened for binding to a target, enabling their selection in an efficient, high-throughput fashion.

Ankylosing spondylitis

One type of inflammatory arthritis, also known as a sero-negative spondyloarthropathy. Ankylosing spondylitis has a characteristic distribution of joints affected, typically the spine, the sacroiliac joints and large peripheral joints.

Crohn's disease

A granulomatous, idiopathic inflammatory bowel disease that affects men and women equally. Symptoms include bloody diarrhoea and abdominal pain. Strictures, which can form in the affected bowel, and peri-anal sepsis and fistulae, are serious complications.

Cmax

Maximal plasma or serum concentration of an administered product.

Cmin

Minimal plasma or serum concentration levels of an administered product.

AUC

Area under the curve concentrations of an administered product, usually over 24 hours.

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Strand, V., Kimberly, R. & Isaacs, J. Biologic therapies in rheumatology: lessons learned, future directions. Nat Rev Drug Discov 6, 75–92 (2007). https://doi.org/10.1038/nrd2196

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