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Biologic Therapy of Crohn’s Disease: Natalizumab, Vedolizumab, CCX282-B

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Crohn's Disease and Ulcerative Colitis

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Abstract

There is still an unmet need for new, safer, and more effective therapies in patients with Crohn’s disease. Adhesion molecules, which are involved in leukocyte recruitment, are a relatively new target for therapy in Crohn’s disease. Inhibition of leukocyte adhesion and migration would decrease the density of leukocytes within the gastrointestinal tract, reduce the secretion of proinflammatory soluble mediators, and diminish cellular immune events, which ultimately attenuates tissue inflammation.

Natalizumab is a monoclonal antibody against α4 integrin and inhibits the binding of α4β1 and α4β7 to their corresponding endothelial receptors, VCAM-1 and MAdCAM-1. As an induction agent, natalizumab is superior to placebo, but the magnitude of the effect is small. What is more impressive is its ability to maintain remission in patients in who responded initially to natalizumab. The major issue regarding the use of natalizumab in Crohn’s disease is the 1 in 1,000 risk of developing progressive multifocal leukoencephalopathy, a disabling neurological disease with a high mortality.

Vedolizumab is a highly selective adhesion molecule antagonist to α4β7 integrin. The results from a phase 2 induction study show significant benefit in the secondary endpoint of clinical remission but not the primary endpoint of clinical response. A phase 3 study is currently in progress.

CCX-282 (Traficet-En™) is an orally bioavailable antagonist to the chemokine receptor CCR9. The results of clinical studies, which have only been published in abstract form currently, suggest that CCX-282 is effective for induction and maintenance therapy in Crohn’s disease.

Lastly, alicaforsen is a first-generation phosphorothioate antisense oligodeoxynucleotide, which hybridizes selectively with messenger RNA encoding human intercellular adhesion molecule-2 (ICAM-1). Results of clinical studies show a lack of clinical efficacy of this class of medication in the management of Crohn’s disease.

There is currently insufficient data to recommend antiadhesion molecules as first- or second-line therapy in Crohn’s disease patients who have failed immunomodulatory treatment. Publication of further large randomized controlled trials is eagerly awaited.

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References

  1. Ley K, Laudanna C, Cybulsky MI, et al. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol. 2007;7:678–89.

    Article  PubMed  CAS  Google Scholar 

  2. Binion DG, West GA, Volk EE, et al. Acquired increase in leukocyte binding by intestinal microvascular endothelium in inflammatory bowel disease. Lancet. 1998;352:1742–6.

    Article  PubMed  CAS  Google Scholar 

  3. Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell. 2002;110:673–87.

    Article  PubMed  CAS  Google Scholar 

  4. Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep system. Cell. 1994;76:301–14.

    Article  PubMed  CAS  Google Scholar 

  5. Berlin C, Bargatze RF, Campbell JJ, et al. α(alpha)4 integrins mediate lymphocyte attachment under physiological flow. Cell. 1995;80:413–22.

    Article  PubMed  CAS  Google Scholar 

  6. Rivera-Nieves J, Gorfu G, Ley K. Leukocyte adhesion molecules in animal models of inflammatory bowel disease. Inflamm Bowel Dis. 2008;14:1715–35.

    Article  PubMed  Google Scholar 

  7. Gorfu G, Rivera-Nieves J, Ley K. Role of β(beta)7 integrins in intestinal lymphocyte homing and retention. Curr Mol Med. 2009;9:836–50.

    Article  PubMed  CAS  Google Scholar 

  8. Hesterberg PE, Insor-Hines D, Briskin MJ, et al. Rapid resolution of chronic colitis in the cotton-top tamarin with an antibody to a gut-homing integrin alpha 4 beta 7. Gastroenterology. 1996;111:1373–80.

    Article  PubMed  CAS  Google Scholar 

  9. Podolsky DK. Attenuation of colitis in the cotton-top tamarin by anti-alpha 4 integrin monoclonal antibody. J Clin Invest. 1993;92:372–80.

    Article  PubMed  CAS  Google Scholar 

  10. Gorfu G, Rivera-Nieves J, Ley K. Role of beta7 integrins in intestinal lymphocyte homing and retention. Curr Mol Med. 2009;9:836–50.

    Article  PubMed  CAS  Google Scholar 

  11. Middleton J, Patterson AM, Ashton BA, et al. Leukocyte extravasation: chemokine transport and presentation by the endothelium. Blood. 2002;100:3853–60.

    Article  PubMed  CAS  Google Scholar 

  12. Papdakis K, Prehn J, Targan S, et al. The role of thymus-expressed chemokine and its receptor CCR9 on lymphocytes in the regional specialization of the mucosal immune system. J Immunol. 2000;163:5069–76.

    Google Scholar 

  13. Rivera-Nieves J, Ho J, Cominelli F, et al. Antibody blockade of CCL25/CCR9 ameliorates early but not late chronic murine ileitis. Gastroenterology. 2006;131:1518–29.

    Article  PubMed  CAS  Google Scholar 

  14. Gordon FH, Lai CWY, Pounder RE, et al. A randomized placebo-controlled trial of a humanized monoclonal antibody to α(alpha)4 integrin in active Crohn’s disease. Gastroenterology. 2001;121:268–74.

    Article  PubMed  CAS  Google Scholar 

  15. Ghosh S, Goldin E, Donoghue S, et al. Natalizumab for active Crohn’s disease. N Engl J Med. 2003;348:24–32.

    Article  PubMed  CAS  Google Scholar 

  16. Kubes P, Niu XF, Smith CW, et al. A novel β(beta)1-dependant adhesion pathway on neutrophils: A mechanism invoked by dihydrocytochalasin B or endothelial transmigration. FASEB J. 1995;9:1103–11.

    PubMed  CAS  Google Scholar 

  17. Sandborn WJ, Colombel JF, Rutgeerts P, et al. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2005;353:1912–25.

    Article  PubMed  CAS  Google Scholar 

  18. Targan SR, Feagan BG, Sandborn WJ, et al. Natalizumab for the treatment of active Crohn’s disease: results of the ENCORE trial. Gastroenterology. 2007;132:1672–83.

    Article  PubMed  CAS  Google Scholar 

  19. MacDonald JK, McDonald JWD. Natalizumab for induction of remission in Crohn’s disease. Cochrane Database of Systematic Reviews 2007;(1).

    Google Scholar 

  20. Schreiber S, Targan S. Efficacy of natalizumab in Crohn’s patients with disease duration less than three years. Gastroenterology. 2010;138 Suppl 1:A509.

    Google Scholar 

  21. Lashner B, Feagan B, Targan S, et al. Natalizumab does not require the concomitant use of immunosuppressants for the induction of sustained response and remission in Crohn’s disease patients. Gastroenterology. 2010;138 Suppl 1:A507.

    Google Scholar 

  22. Panaccione R, Feagan B, Targan S, et al. Natalizumab induces sustained response and remission in patients with Crohn’s disease activity index scores ≥330: results from the Encore trial. Gastroenterology. 2010;138 Suppl 1:A508.

    Google Scholar 

  23. Present D, Feagan B, Targan S, et al. Natalizumab induces sustained response and remission in Crohn’s disease patients after previous Infliximab failure: results from the Encore trial. Gastroenterology. 2010;138 Suppl 1:A507.

    Google Scholar 

  24. Sands BE, Kozarek R, Hanauer SB, et al. Safety and tolerability of concurrent Natalizumab treatment for patients with Crohn’s disease not in remission while receiving Infliximab. Inflamm Bowel Dis. 2007;13:2–11.

    Article  PubMed  Google Scholar 

  25. Bezabeh S, Flowers C, Avigan M, et al. Clinically significant liver injury in patients treated with natalizumab. Aliment Pharmacol Ther. 2010;31:1028–35.

    PubMed  CAS  Google Scholar 

  26. Berger JR. Progressive multifocal leukoencephalopathy. Curr Neurol Neurosci Rep. 2007;7:461–9.

    Article  PubMed  CAS  Google Scholar 

  27. Yousry TA, Major EO, Clifford DB, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med. 2006;354:924–33.

    Article  PubMed  CAS  Google Scholar 

  28. Tysabri® (natalizumab) safety update: 17 December 2010, Biogen Idec Elan, December 2010.

    Google Scholar 

  29. Verbeeck J, Van Assche G, Ryding J, et al. JC viral loads in patients with Crohn’s disease treated with immunosuppression: can we screen for elevated risk of progressive multifocal leukoencephalopathy? Gut. 2008;57:1393–7.

    Article  PubMed  CAS  Google Scholar 

  30. Adelman B, Sandrock A, Panzara M. Natalizumab and progressive multifocal leukoencephalopathy. N Engl J Med. 2005;353:432–3.

    Article  PubMed  CAS  Google Scholar 

  31. Johnson FR, Ozdemir S, Sands BE, et al. Crohn’s disease patients’ risk-benefit preferences: serious adverse event risks versus treatment efficacy. Gastroenterology. 2007;133:769–79.

    Article  PubMed  Google Scholar 

  32. Berlin C, Berg EL, Butcher EC, et al. Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell. 1993;74:185–95.

    Article  PubMed  CAS  Google Scholar 

  33. Erle DJ, Briskin MJ, Tidswell M, et al. Expression and function of the MAdCAM-1 receptor, integrin alpha 4 beta 7, on human leukocytes. J Immunol. 1994;153:517–28.

    PubMed  CAS  Google Scholar 

  34. Briskin M, Winsor-Hines D, Ringler D, et al. Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. Am J Pathol. 1997;151:97–110.

    PubMed  CAS  Google Scholar 

  35. Feagan B, Greenberg G, Parikh A, et al. Treatment of active Crohn’s disease with MLN0002, a humanized antibody to the α4β7 integrin. Clin Gastroenterol Hepatol. 2008;6:1370–7.

    Article  PubMed  CAS  Google Scholar 

  36. Feagan B, Greenberg G, Vandervoort K, et al. Treatment of ulcerative colitis with a humanized antibody to the α4β7 integrin. N Engl J Med. 2005;352:2499–507.

    Article  PubMed  CAS  Google Scholar 

  37. Keshav S, Johnson D, Schall T, et al. PROTECT-1 study demonstrated efficacy of the intestine-specific chemokine receptor antagonist CCX282-B (Traficet-EN) in treatment of patients with moderate to severe Crohn’s disease. Gastroenterology. 2009;136 Suppl 1:A65.

    Google Scholar 

  38. Keshav S, Johnson D, Bekker P, et al. Chemokine receptor antagonist CCX282-B (Traficet-EN™) maintained remission of Crohn’s disease in PROTECT-1 study. Gastroenterology. 2010;138 Suppl 1:S86.

    Google Scholar 

  39. Bennett C, Condon T, Chiang M, et al. Inhibition of endothelial cell adhesion molecule expression with antisense oligonucleotides. J Immunol. 1994;152:3530–40.

    PubMed  CAS  Google Scholar 

  40. Yacyshyn B, Bowen-Yacyshyn M, Shanahan W, et al. A placebo-controlled trial of ICAM-1 antisense oligonucleotide in the treatment of Crohn’s disease. Gastroenterology. 1998;114:1133–42.

    Article  PubMed  CAS  Google Scholar 

  41. Schreiber S, Nikolaus S, Steinmann G, et al. Absence of efficacy of subcutaneous antisense ICAM-1 treatment of chronic active Crohn’s disease. Gastroenterology. 2001;120:1339–46.

    Article  PubMed  CAS  Google Scholar 

  42. Yacyshyn B, Chey W, Shanahan W, et al. Double blind, placebo controlled trial of the remission inducing and steroid sparing properties of an ICAM-1 antisense oligodeoxynucleotide, alicaforsen (ISIS 2302), in active steroid dependant Crohn’s disease. Gut. 2002;51:30–6.

    Article  PubMed  CAS  Google Scholar 

  43. Yacyshyn B, Chey W, Chuang E, et al. A randomized, double-masked, placebo-controlled study of alicaforsen, an antisense inhibitor of intercellular adhesion molecule 1, for the treatment of subjects with active Crohn’s disease. Clin Gastroenterol Hepatol. 2007;5:215–20.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Eastern Health Clinical School, Eastern Health and Monash University, Box Hill Hospital, 5 Arnold Street, Box Hill, VIC, 3128, Australia

    Alvin Chung MBBS, FRACP & Peter R. Gibson MD, FRACP

Authors
  1. Alvin Chung MBBS, FRACP
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  2. Peter R. Gibson MD, FRACP
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Correspondence to Peter R. Gibson MD, FRACP .

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Editors and Affiliations

  1. Medical School of the Humboldt Universit, Department of Medicine, Charité Medical Center, Virchow Hospita, Berlin, 13344, Germany

    Daniel C. Baumgart

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Chung, A., Gibson, P.R. (2012). Biologic Therapy of Crohn’s Disease: Natalizumab, Vedolizumab, CCX282-B. In: Baumgart, D. (eds) Crohn's Disease and Ulcerative Colitis. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-0998-4_35

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  • DOI: https://doi.org/10.1007/978-1-4614-0998-4_35

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