Korean J Gastroenterol.  2011 Nov;58(5):235-244. 10.4166/kjg.2011.58.5.235.

Emerging Drugs in the Treatment of Inflammatory Bowel Disease: Beyond Anti-TNF-alpha

• Kim KO
• Jang BI

• KMID: 1026364
• DOI: http://doi.org/10.4166/kjg.2011.58.5.235

Abstract

Understanding of the pathophysiology of inflammatory bowel disease (IBD) is constantly evolving and, recently, a number of biologic agents have been developed. They selectively target specific molecule or pathways and correct the imbalance of the gut immune system. Among them, antibody to tumor necrosis factor (anti-TNF-alpha) is the first developed drugs, and it dramatically improved the IBD management. However, more than one-third of the patients do not respond to the drugs due to antibody formation. To increase treatment efficacy, enormous effort to develop novel anti-cytokines which can be an alternative to anti-TNF-alpha has been made. They are anti CD4+ T cell cytokine including interleukin (IL)-12/23 and IL-17 blockers, selective anti-adhesion molecule known as natalizumab, vedolizumab and alicaforsen, T-cell proliferation inhibitor, anti-inflammatory cytokine, immune stimulator, growth factor, and mitogen-activated protein kinase inhibitor. The efficacy and safety of each drugs are under investigation. Some drugs reported very promising data, however, others showed disappointing and different results. In addition, most of the trials were done in a very small number of patients, and there is no trial comparing to anti-TNF-alpha. The present paper reviews the action mechanism, short or long term efficacy and safety of variable drugs other than anti-TNF-alpha in IBD.

Keyword

Inflammatory bowel disease; Therapeutics; Infliximab; Biological products

MeSH Terms

Antibodies, Monoclonal/therapeutic use
Cell Migration Inhibition
Colony-Stimulating Factors/therapeutic use
Cytokines/antagonists & inhibitors
Gene Therapy
Humans
Immunosuppressive Agents/therapeutic use
Inflammatory Bowel Diseases/drug therapy/*therapy
Intercellular Signaling Peptides and Proteins/therapeutic use
Mitogen-Activated Protein Kinases/antagonists & inhibitors
Stem Cell Transplantation
Tumor Necrosis Factor-alpha/*antagonists & inhibitors/immunology

Reference

References

1. Sands BE. Biologic therapy for inflammatory bowel disease. Inflamm Bowel Dis. 1997; 3:95–113.

2. Sandborn WJ, Targan SR. Biologic therapy of inflammatory bowel disease. Gastroenterology. 2002; 122:1592–1608.

3. Danese S, Angelucci E. New and emerging biologics in the treatment of inflammatory bowel disease: Quo vadis? Gastroenterol Clin Biol. 2009; 33(Suppl 3):S217–S227.

4. Baumgart DC, Sandborn WJ. Inflammatory bowel disease: Clinical aspects and established and evolving therapies.

5. Ainsworth MA, Bendtzen K, Brynskov J. Tumor necrosis factoralpha binding capacity and anti-infliximab antibodies measured by fluid-phase radioimmunoassays as predictors of clinical efficacy of infliximab in Crohn's disease. Am J Gastroenterol. 2008; 103:944–948.

6. Ma HL, Napierata L, Stedman N, et al. Tumor necrosis factor alpha blockade exacerbates murine psoriasis-like disease by enhancing Th17 function and decreasing expansion of Treg cells. Arthritis Rheum. 2010; 62:430–440.

7. Podolsky DK. Inflammatory bowel disease. N Engl J Med. 2002; 347:417–429.

8. Fuss IJ, Neurath M, Boirivant M, et al. Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol. 1996; 157:1261–1270.

9. Yamazaki K, Onouchi Y, Takazoe M, Kubo M, Nakamura Y, Hata A. Association analysis of genetic variants in IL23R, ATG16L1 and 5p13.1 loci with Crohn's disease in Japanese patients. J Hum Genet. 2007; 52:575–583.

10. Monteleone G, Biancone L, Marasco R, et al. Interleukin 12 is expressed and actively released by Crohn's disease intestinal lamina propria mononuclear cells. Gastroenterology. 1997; 112:1169–1178.

11. Parronchi P, Romagnani P, Annunziato F, et al. Type 1 T-helper cell predominance and interleukin-12 expression in the gut of patients with Crohn's disease. Am J Pathol. 1997; 150:823–832.

12. Uhlig HH, McKenzie BS, Hue S, et al. Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity. 2006; 25:309–318.

13. Mannon PJ, Fuss IJ, Mayer L, et al. Anti-interleukin-12 antibody for active Crohn's disease. N Engl J Med. 2004; 351:2069–2079.

14. Sandborn WJ, Feagan BG, Fedorak RN, et al. Ustekinumab Crohn's Disease Study Group. A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn's disease. Gastroenterology. 2008; 135:1130–1141.

15. Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem. 2003; 278:1910–1914.

16. Park H, Li Z, Yang XO, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005; 6:1133–1141.

17. Seiderer J, Elben I, Diegelmann J, et al. Role of the novel Th17 cytokine IL-17F in inflammatory bowel disease (IBD): upregulated colonic IL-17F expression in active Crohn's disease and analysis of the IL17F p.His161Arg polymorphism in IBD. Inflamm Bowel Dis. 2008; 14:437–445.

18. Dambacher J, Beigel F, Zitzmann K, et al. The role of the novel Th17 cytokine IL-26 in intestinal inflammation. Gut. 2009; 58:1207–1217.

19. Brand S, Beigel F, Olszak T, et al. IL-22 is increased in active Crohn's disease and promotes proinflammatory gene expression and intestinal epithelial cell migration. Am J Physiol Gastrointest Liver Physiol. 2006; 290:G827–G838.

20. Ouyang W, Kolls JK, Zheng Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity. 2008; 28:454–467.

21. Zhang Z, Zheng M, Bindas J, Schwarzenberger P, Kolls JK. Critical role of IL-17 receptor signaling in acute TNBS-induced colitis. Inflamm Bowel Dis. 2006; 12:382–388.

22. Schmidt C, Giese T, Ludwig B, et al. Expression of inter-leukin-12-related cytokine transcripts in inflammatory bowel disease: elevated interleukin-23p19 and interleukin-27p28 in Crohn's disease but not in ulcerative colitis. Inflamm Bowel Dis. 2005; 11:16–23.

23. Fujino S, Andoh A, Bamba S, et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut. 2003; 52:65–70.

24. Nakamura S, Ohtani H, Watanabe Y, et al. In situ expression of the cell adhesion molecules in inflammatory bowel disease. Evidence of immunologic activation of vascular endothelial cells. Lab Invest. 1993; 69:77–85.

25. Gordon FH, Lai CW, Hamilton MI, et al. A randomized placebo-controlled trial of a humanized monoclonal antibody to alpha4 integrin in active Crohn's disease. Gastroenterology. 2001; 121:268–274.

26. Ghosh S, Goldin E, Gordon FH, et al. Natalizumab Pan-Euro-pean Study Group. Natalizumab for active Crohn's disease. N Engl J Med. 2003; 348:24–32.

27. Targan SR, Feagan BG, Fedorak RN, et al. International Efficacy of Natalizumab in Crohn's Disease Response and Remission (ENCORE) Trial Group. Natalizumab for the treatment of active Crohn's disease: results of the ENCORE Trial. Gastroenterology. 2007; 132:1672–1683.

28. MacDonald JK, McDonald JW. Natalizumab for induction of remission in Crohn's disease. Cochrane Database Syst Rev. 2007; (1):CD006097.

29. Gordon FH, Hamilton MI, Donoghue S, et al. A pilot study of treatment of active ulcerative colitis with natalizumab, a humanized monoclonal antibody to alpha-4 integrin. Aliment Pharmacol Ther. 2002; 16:699–705.

30. Feagan BG, Greenberg GR, Wild G, et al. Treatment of active Crohn's disease with MLN0002, a humanized antibody to the alpha4beta7 integrin. Clin Gastroenterol Hepatol. 2008; 6:1370–1377.

31. Feagan BG, Greenberg GR, Wild G, et al. Treatment of ulcerative colitis with a humanized antibody to the alpha4beta7 integrin. N Engl J Med. 2005; 352:2499–2507.

32. Yacyshyn BR, Bowen-Yacyshyn MB, Jewell L, et al. A placebo-controlled trial of ICAM-1 antisense oligonucleotide in the treatment of Crohn's disease. Gastroenterology. 1998; 114:1133–1142.

33. Schreiber S, Nikolaus S, Malchow H, et al. German ICAM-1 Study Group. Absence of efficacy of subcutaneous antisense ICAM-1 treatment of chronic active Crohn's disease. Gastroenterology. 2001; 120:1339–1346.

34. Yacyshyn BR, Chey WY, Goff J, et al. ISIS 2302-CS9 Investigators. 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 dependent Crohn's disease. Gut. 2002; 51:30–36.

35. Yacyshyn BR, Barish C, Goff J, et al. Dose ranging pharmacokinetic trial of high-dose alicaforsen (intercellular adhesion molecule-1 antisense oligodeoxynucleotide) (ISIS 2302) in active Crohn's disease. Aliment Pharmacol Ther. 2002; 16:1761–1770.

36. Yacyshyn B, Chey WY, Wedel MK, Yu RZ, Paul D, Chuang E. 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; 5:215–220.

37. van Deventer SJ, Tami JA, Wedel MK. A randomised, controlled, double blind, escalating dose study of alicaforsen enema in active ulcerative colitis. Gut. 2004; 53:1646–1651.

38. van Deventer SJ, Wedel MK, Baker BF, Xia S, Chuang E, Miner PB Jr. A phase II dose ranging, double-blind, placebo-controlled study of alicaforsen enema in subjects with acute exacerbation of mild to moderate left-sided ulcerative colitis. Aliment Pharmacol Ther. 2006; 23:1415–1425.

39. Miner PB Jr, Wedel MK, Xia S, Baker BF. Safety and efficacy of two dose formulations of alicaforsen enema compared with mesalazine enema for treatment of mild to moderate left-sid-ed ulcerative colitis: a randomized, double-blind, active-controlled trial. Aliment Pharmacol Ther. 2006; 23:1403–1413.

40. Creed TJ, Probert CS, Norman MN, et al. BASBUC INVESTIGATORS. Basiliximab for the treatment of steroid-resistant ulcerative colitis: further experience in moderate and severe disease. Aliment Pharmacol Ther. 2006; 23:1435–1442.

41. Van Assche G, Dalle I, Noman M, Aerden I, et al. A pilot study on the use of the humanized anti-interleukin-2 receptor anti-body daclizumab in active ulcerative colitis. Am J Gastroenterol. 2003; 98:369–376.

42. Van Assche G, Sandborn WJ, Feagan BG, et al. Daclizumab, a humanised monoclonal antibody to the interleukin 2 receptor (CD25), for the treatment of moderately to severely active ulcerative colitis: a randomised, double blind, placebo controlled, dose ranging trial. Gut. 2006; 55:1568–1574.

43. Plevy SE, Salzberg BA, Requeiro M. A humanized anti-CD3 monoclonal antibody, in severe steroid-refractory ulcerative colitis: Preliminary results of a phase 1 study. Gastroenterology. 2003; 126:A75.

44. Plevy S, Salzberg B, Van Assche G, et al. A phase I study of visilizumab, a humanized anti-CD3 monoclonal antibody, in severe steroid-refractory ulcerative colitis. Gastroenterology. 2007; 133:1414–1422.

45. Steidler L, Hans W, Schotte L, et al. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science. 2000; 289:1352–1355.

46. Braat H, Rottiers P, Hommes DW, et al. A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn's disease. Clin Gastroenterol Hepatol. 2006; 4:754–759.

47. Pena-Rossi C, Schreiber S, Golubovic G, et al. Clinical trial: a multicentre, randomized, double-blind, placebo-controlled, dose-finding, phase II study of subcutaneous interferon-beta-la in moderately active ulcerative colitis. Aliment Pharmacol Ther. 2008; 28:758–767.

48. Korzenik JR, Dieckgraefe BK. An open-labelled study of granulocyte colony-stimulating factor in the treatment of active Crohn's disease. Aliment Pharmacol Ther. 2005; 21:391–400.

49. Dieckgraefe BK, Korzenik JR. Treatment of active Crohn's disease with recombinant human granulocyte-macrophage col-ony-stimulating factor. Lancet. 2002; 360:1478–1480.

50. Korzenik JR, Dieckgraefe BK, Valentine JF, Hausman DF, Gilbert MJ. Sargramostim in Crohn's Disease Study Group. Sargramostim for active Crohn's disease. N Engl J Med. 2005; 352:2193–2201.

51. Feagan BG, Anderson F, Radford-Smith GL. Efficacy and safety of sargramostim in moderate to severe Crohn's disease: Results of N.O.V.E.L 4, a phase III multicenter study. Gastroenterology. 2007; 132(Supple 2):A103.

52. Slonim AE, Bulone L, Damore MB, Goldberg T, Wingertzahn MA, McKinley MJ. A preliminary study of growth hormone therapy for Crohn's disease. N Engl J Med. 2000; 342:1633–1637.

53. Sandborn WJ, Sands BE, Wolf DC, et al. Repifermin (keratinocyte growth factor-2) for the treatment of active ulcerative colitis: a randomized, double-blind, placebo-controlled, dose-es-calation trial. Aliment Pharmacol Ther. 2003; 17:1355–1364.

54. Sinha A, Nightingale J, West KP, Berlanga-Acosta J, Playford RJ. Epidermal growth factor enemas with oral mesalamine for mild-to-moderate left-sided ulcerative colitis or proctitis. N Engl J Med. 2003; 349:350–357.

55. Travis S, Yap LM, Hawkey C, et al. RDP Investigators Study Group. RDP58 is a novel and potentially effective oral therapy for ulcerative colitis. Inflamm Bowel Dis. 2005; 11:713–719.

56. Holtmann MM. RDP-58 (SangStat Medical). IDrugs. 2003; 6:1188–1194.

57. Schreiber S, Feagan B, D'Haens G, et al. BIRB 796 Study Group. Oral p38 mitogen-activated protein kinase inhibition with BIRB 796 for active Crohn's disease: a randomized, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol. 2006; 4:325–334.

58. Hommes D, van den Blink B, Plasse T, et al. Inhibition of stress-activated MAP kinases induces clinical improvement in moderate to severe Crohn's disease. Gastroenterology. 2002; 122:7–14.

59. Westbrook CA, Chmura SJ, Arenas RB, Kim SY, Otto G. Human APC gene expression in rodent colonic epithelium in vivo using liposomal gene delivery. Hum Mol Genet. 1994; 3:2005–2010.

60. Schmid RM, Weidenbach H, Draenert GF, et al. Liposome mediated in vivo gene transfer into different tissues of the gastrointestinal tract. Z Gastroenterol. 1994; 32:665–670.

61. Lozier JN, Yankaskas JR, Ramsey WJ, Chen L, Berschneider H, Morgan RA. Gut epithelial cells as targets for gene therapy of hemophilia. Hum Gene Ther. 1997; 8:1481–1490.

62. Li M, Lonial H, Citarella R, Lindh D, Colina L, Kramer R. Tumor inhibitory activity of anti-ras ribozymes delivered by retroviral gene transfer. Cancer Gene Ther. 1996; 3:221–229.

63. Seppen J, Barry SC, Klinkspoor JH, et al. Apical gene transfer into quiescent human and canine polarized intestinal epithelial cells by lentivirus vectors. J Virol. 2000; 74:7642–7645.

64. During MJ, Xu R, Young D, Kaplitt MG, Sherwin RS, Leone P. Peroral gene therapy of lactose intolerance using an ad-eno-associated virus vector. Nat Med. 1998; 4:1131–1135.

65. During MJ, Symes CW, Lawlor PA, et al. An oral vaccine against NMDAR1 with efficacy in experimental stroke and epilepsy. Science. 2000; 287:1453–1460.

66. Wirtz S, Galle PR, Neurath MF. Efficient gene delivery to the inflamed colon by local administration of recombinant ad-enoviruses with normal or modified fibre structure. Gut. 1999; 44:800–807.

67. Brittan M, Wright NA. Gastrointestinal stem cells. J Pathol. 2002; 197:492–509.

68. Ishikawa T, Iwanami K, Okuda T, et al. Intestinal function and morphology after ex vivo irradiated small bowel transplantation. Transplant Proc. 2002; 34:988–989.

69. Kitani A, Fuss IJ, Nakamura K, Schwartz OM, Usui T, Strober W. Treatment of experimental (trinitrobenzene sulfonic acid) colitis by intranasal administration of transforming growth factor (TGF)-beta1 plasmid: TGFbeta1-mediated suppression of T helper cell type 1 response occurs by interleukin (IL)-10 induction and IL-12 receptor beta2 chain downregulation. J Exp Med. 2000; 192:41–52.

70. Barbara G, Xing Z, Hogaboam CM, Gauldie J, Collins SM. Interleukin 10 gene transfer prevents experimental colitis in rats. Gut. 2000; 46:344–349.

71. Lindsay J, Van Montfrans C, Brennan F, et al. IL-10 gene therapy prevents TNBS-induced colitis. Gene Ther. 2002; 9:1715–1721.

72. Lindsay JO, Ciesielski CJ, Scheinin T, Hodgson HJ, Brennan FM. The prevention and treatment of murine colitis using gene therapy with adenoviral vectors encoding IL-10. J Immunol. 2001; 166:7625–7633.

73. Van Montfrans C, Rodriguez Pena MS, Pronk I, Ten Kate FJ, Te Velde AA, Van Deventer SJ. Prevention of colitis by interleukin 10-transduced T lymphocytes in the SCID mice transfer model. Gastroenterology. 2002; 123:1865–1876.

74. van Bekkum DW. Experimental basis of hematopoietic stem cell transplantation for treatment of autoimmune diseases. J Leukoc Biol. 2002; 72:609–620.

75. Drakos PE, Nagler A, Or R. Case of Crohn's disease in bone marrow transplantation. Am J Hematol. 1993; 43:157–158.

76. Craig RM, Traynor A, Oyama Y, Burt RK. Hematopoietic stem cell transplantation for severe Crohn's disease. Bone Marrow Transplant. 2003; 32(Suppl 1):S57–S59.

77. Oyama Y, Craig RM, Traynor AE, et al. Autologous hematopoietic stem cell transplantation in patients with refractory crohn's disease. Gastroenterology. 2005; 128:552–563.

78. Gratwohl A, Passweg J, Bocelli-Tyndall C, et al. Autoimmune Diseases Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Autologous hematopoietic stem cell transplantation for autoimmune diseases. Bone Marrow Transplant. 2005; 35:869–879.

79. Gonzalez MA, Gonzalez-Rey E, Rico L, Buscher D, Delgado M. Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses. Gastroenterology. 2009; 136:978–989.

80. Garciá-Olmo D, Garciá-Arranz M, Herreros D, Pascual I, Peiro C, Rodriguez-Montes JA. A phase I clinical trial of the treatment of Crohn's fistula by adipose mesenchymal stem cell transplantation. Dis Colon Rectum. 2005; 48:1416–1423.

81. Garcia-Olmo D, Herreros D, Pascual I, et al. Expanded adipose-derived stem cells for the treatment of complex perianal fistula: A phase II clinical trial. Dis Colon Rectum. 2009; 52:79–86.

82. Duijvestein M, Vos AC, Roelofs H, et al. Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn's disease: Results of a phase I study. Gut. 2010; 59:1662–1669.