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Drug Insight: abatacept for the treatment of rheumatoid arthritis

Abstract

Although the development of tumor necrosis factor antagonists has improved the clinical outcome of many patients with rheumatoid arthritis (RA), some patients fail to respond to these drugs or have contraindications preventing their use. Other approaches for treating this disease are, therefore, keenly sought. As T cells promote numerous disease pathways in RA, these cells are a logical target for anti-inflammatory therapy. One of the approaches being investigated involves targeting the co-stimulatory signals that accompany antigen-derived signals involved in the activation of T cells. Abatacept is a recombinant fusion protein that interrupts the T-cell co-stimulatory signal mediated through the CD28−CD80/CD86 pathway. Several clinical trials have now confirmed the efficacy of this compound in the treatment of RA. This article discusses the proposed mechanism of action of abatacept and reviews the data from phase II and phase III clinical trials on the safety and efficacy of this drug in RA.

Key Points

  • T-cell activation requires an antigen-specific interaction between the T-cell receptor and the major histocompatability complex, and a second, co-stimulatory signal

  • The interaction between CD28 on the T cell and CD80 or CD86 on the antigen-presenting cell provides one of the most important co-stimulatory signals

  • Abatacept, a fusion protein containing components of IgG and cytotoxic T-lymphocyte-associated protein 4, can interrupt the CD28–CD80/CD86 interaction

  • Clinical trials have shown that abatacept is an effective agent in patients with rheumatoid arthritis who have failed to respond to treatment with methotrexate or tumor necrosis factor antagonists

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Figure 1: The two-signal hypothesis of T-cell activation and the potential mechanism of action of abatacept in the blockade of T-cell co-stimulation

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References

  1. Pope RM and Perlman H (1999) Rheumatoid arthritis: molecular pathogenesis. In Molecular Rheumatology, 325–361 (Ed. Dolgert P) New Jersey: Humana Press

    Google Scholar 

  2. Firestein GS (2003) Evolving concepts of rheumatoid arthritis. Nature 423: 356–361

    Article  CAS  Google Scholar 

  3. Keystone EC (2003) Abandoned therapies and unpublished trials in rheumatoid arthritis. Curr Opin Rheumatol 15: 253–258

    Article  CAS  Google Scholar 

  4. Moreland LW et al. (2002) Costimulatory blockade in patients with rheumatoid arthritis: a pilot, dose-finding, double-blind, placebo-controlled clinical trial evaluating CTLA-4Ig and LEA29Y eighty-five days after the first infusion. Arthritis Rheum 46: 1470–1479

    Article  CAS  Google Scholar 

  5. Kremer JM et al. (2003) Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med 349: 1907–1915

    Article  CAS  Google Scholar 

  6. Kremer JM et al. (2005) 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

    Article  CAS  Google Scholar 

  7. Genovese MC et al. (2005) Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med 353: 1114–1123

    Article  CAS  Google Scholar 

  8. Kremer JM et al. (2006) Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis. Ann Intern Med 144: 865–876

    Article  CAS  Google Scholar 

  9. Bluestone JA et al. (2006) CTLA4Ig: bridging the basic immunology with clinical application. Immunity 24: 233–238

    Article  CAS  Google Scholar 

  10. Salomon B et al. (2000) B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12: 431–440

    Article  CAS  Google Scholar 

  11. Linsley PS et al. (1991) CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med 174: 561–569

    Article  CAS  Google Scholar 

  12. Walunas TL et al. (1996) CTLA-4 ligation blocks CD28-dependent T cell activation. J Exp Med 183: 2541–2550

    Article  CAS  Google Scholar 

  13. Karandikar NJ et al. (1996) CTLA-4: a negative regulator of autoimmune disease. J Exp Med 184: 783–788

    Article  CAS  Google Scholar 

  14. Walunas TL and Bluestone JA. (1998) CTLA-4 regulates tolerance induction and T cell differentiation in vivo. J Immunol 160: 3855–3860

    CAS  PubMed  Google Scholar 

  15. Verwilghen J et al. (1994) Expression of functional B7 and CTLA4 on rheumatoid synovial T cells. J Immunol 153: 1378–1385

    CAS  PubMed  Google Scholar 

  16. Bluestone JA (2005) Regulatory T-cell therapy: is it ready for the clinic? Nat Rev Immunol 5: 343–349

    Article  CAS  Google Scholar 

  17. Bluestone JA and Tang Q (2005) How do CD4+CD25+ regulatory T cells control autoimmunity? Curr Opin Immunol 17: 638–642

    Article  CAS  Google Scholar 

  18. Tang Q et al. (2003) Cutting edge: CD28 controls peripheral homeostasis of CD4+CD25+ regulatory T cells. J Immunol 171: 3348–3352

    Article  CAS  Google Scholar 

  19. Grohmann U et al. (2002) CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat Immunol 3: 1097–1101

    Article  CAS  Google Scholar 

  20. Weinblatt M et al. (2006) Selective co-stimulation modulation using abatacept in patients with active rheumatoid arthritis while receiving etanercept: a randomized clinical trial. Ann Rheum Dis [doi:10.1136/ard.2006.055111]

  21. Kremer J et al. (2004) Sustained clinical efficacy demonstrated by the selective co-stimulation modulator abatacept (CTLA4Ig) in combination with methotrexate at 2 years in rheumatoid arthritis patients with an inadequate response to methotrexate. Arthritis Rheum 50 (Suppl): S183

    Google Scholar 

  22. Dougados M et al. (2004) Sustained remission and major clinical response at 2 years shown with abatacept (CTLA4Ig) in combination with methotrexate in rheumatoid arthritis patients with an inadequate response to methotrexate. Arthritis Rheum 50 (Suppl): S185

    Google Scholar 

  23. Moreland L et al. (2004) Abatacept (CTLA4Ig) in combination with methotrexate for the treatment of rheumatoid arthritis: favorable safety and tolerability profile sustained over 2 years. Arthritis Rheum 50 (Suppl): S563

    Google Scholar 

  24. Weinblatt M et al. (2006) Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease-modifying antirheumatic drugs: A one-year randomized, placebo-controlled study. Arthritis Rheum 54: 2807–2816

    Article  CAS  Google Scholar 

  25. Genovese MC et al. (2004) 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

    Article  CAS  Google Scholar 

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Correspondence to Eric M Ruderman.

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Competing interests

Dr Ruderman has received research grants and consulting fees (totalling less than $5,000) from Bristol-Meyers Squibb. Dr Pope has declared no competing interests.

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Ruderman, E., Pope, R. Drug Insight: abatacept for the treatment of rheumatoid arthritis. Nat Rev Rheumatol 2, 654–660 (2006). https://doi.org/10.1038/ncprheum0345

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