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Adhesion Molecules: Function and Inhibition pp 289–303Cite as

Promises and limitations of targeting adhesion molecules for therapy

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Part of the book series: Progress in Inflammation Research ((PIR))

Abstract

Dramatic progress in elucidating the molecular basis of inflammation over the past two decades has led to the development new anti-inflammatory and immunomodulatory therapies. In particular, the adhesion molecules involved in leukocyte trafficking from the blood stream to tissue have emerged as important therapeutic targets. Extensive preclinical studies have shown that blockade of leukocyte or endothelial adhesion molecules is efficacious in diverse disease models, prompting many pharmaceutical and biotechnology companies to develop adhesion antagonists. However, because of the close relationship between inflammation and host defense and tissue repair, anti-adhesion therapy may also be a double-edged sword. This chapter reviews the promises and limitations of anti-adhesion therapy, focusing on those drugs that have completed clinical trials.

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References

  1. Romano SJ (2005) Selectin antagonists: therapeutic potential in asthma and COPD. Treat Resptr Med 4: 85–94

    Article  CAS  Google Scholar 

  2. Bochner B (2004) Adhesion molecules as therapeutic targets. Immunol Allergy Clin North Am 24: 615–630

    Article  PubMed  Google Scholar 

  3. Wallstreet Online. United States Securities and Exchange Commission Annual Report. Available at: http://www.wallstreet-online.de/community/thread/108514-l.html (accessed 26 November 2006)

  4. APM Health Europe. Healthcare Business News for European Pharmaceutical Markets. Available at: http://www.apmhealtheurope.com/story.php?Numero=4243&profil=34 (accessed 26 November 2006)

  5. Gauvreau GM, Becker AB, Boulet LP, Chakir J, Fick RB, Greene WL, Killian KJ, O’Byrne PM, Reid JK, Cockcroft DW (2003) The effects of an anti-CD11a mAb, efalizumab, on allergen-induced airway responses and airway inflammation in subjects with atopic asthma. J Allergy Clin Immunol 112: 331–338

    Article  PubMed  CAS  Google Scholar 

  6. Revotar Biopharmaceuticals AG. Product Pipeline. Available at: http://www.revotar.com (accessed 2 January 2007)

  7. Cybulsky MI, Iiyama K, Li H, Zhu S, Chen M, Iiyama M, Davis V, Gutierrez-Ramos JC, Connelly PW, Milstone DS (2001) A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J Clin Invest 107: 1255–1262

    PubMed  CAS  Google Scholar 

  8. Kunsch C, Luchoomun J, Grey JY, Olliff LK, Saint LB, Arrendale RF, Wasserman MA, Saxena U, Medford RM (2004) Selective inhibition of endothelial and monocyte redoxsensitive genes by AGI-1067: a novel antioxidant and anti-inflammatory agent. J Pharmacol Exp Ther 308: 820–829

    Article  PubMed  CAS  Google Scholar 

  9. Tardif JC, Gregoire J, Schwartz L, Title L, Laramee L, Reeves F, Lesperance J, Bourassa MG, L’Allier PL, Glass M et al (2003) Effects of AGI-1067 and probucol after percutaneous coronary interventions. Circulation 107: 552–558

    Article  PubMed  CAS  Google Scholar 

  10. AtheroGenics Inc. Science & Technology Product Pipeline. Available at: http://www. atherogenics.com/science/product.html (accessed 26 November 2006)

  11. Mileski WJ, Rothlien R, Lipsky P (1994) Interference with the function of leukocyte adhesion molecules by monoclonal antibodies: a new approach to burn injury. Eur J Pedtatr Surg 4: 225–230

    CAS  Google Scholar 

  12. Mileski WJ, Burkhart D, Hunt JL, Kagan RJ, Saffle JR, Herndon DN, Heimbach DM, Luterman A, Yurt RW, Goodwin CW et al (2003) Clinical effects of inhibiting leukocyte adhesion with monoclonal antibody to intercellular adhesion molecule-1 (enlimomab) in the treatment of partial-thickness burn injury. J Trauma 54: 950–958

    PubMed  Google Scholar 

  13. Thiagarajan RR, Winn RK, Harlan JM (1997) The role of leukocyte and endothelial adhesion molecules in ischemia-reperfusion injury. Thromb Haemost 78: 310–314

    PubMed  CAS  Google Scholar 

  14. Paparella D, Yau TM, Young E (2002) Cardiopulmonary bypass induced inflammation: pathophysiology and treatment. An update. Eur J Cardiothorac Surg 21: 232–244

    Article  PubMed  CAS  Google Scholar 

  15. Clinicaltrials.gov. Cylexin for reduction of reperfusion injury in infant heart surgery. Available at: http://clinicaltrials.gov/ct/gui/show/NCT00226369 (accessed 26 November 2006)

  16. Kerr KM, Auger WR, Marsh JJ, Comito RM, Fedullo RL, Smits GJ, Kapelanski DP, Fedullo PF, Channick RN, Jamieson SW et al (2000) The use of Cylexin (CY-1503) in prevention of reperfusion lung injury in patients undergoing pulmonary thromboendarterectomy. Am J Respir Crit Care Med 162: 14–20

    PubMed  CAS  Google Scholar 

  17. Podolsky DK (2002) Inflammatory bowel disease. N Engl J Med 347: 417–429

    Article  PubMed  CAS  Google Scholar 

  18. Schreiber S, Nikolaus S, Malchow H, Kruis W, Lochs H, Raedler A, Hahn EG, Krummenerl T, Steinmann G, German ICAM Study Group (2001) Absence of efficacy of subcutaneous antisense ICAM-1 treatment of chronic active Crohn’s disease. Gastroenterology 120: 1339–1346

    Article  PubMed  CAS  Google Scholar 

  19. Yacyshyn BR, Chey WY, Goff J, Salzberg B, Baerg R, Buchman AL, Tami J, Yu R, Gibiansky E, Shanahan WR (2002) 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 51: 30–36

    Article  PubMed  CAS  Google Scholar 

  20. Millennium. Millennium announces Phase II data for MLN02 in Crohn’s disease. Available at: http://investor.millennium.com/phoenix.zhtml?c=80159&p=irol-newsmediaArti cle&ID=333736&highlight= (accessed 26 November 2006)

  21. Van Deventer SJH, Wedel MK, Baker B, Xia S, Chuang E, Miner PB (2006) 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 23: 1415–1425

    Article  PubMed  CAS  Google Scholar 

  22. Millennium. In Phase II study, Millennium investigational drug MLN02 produced significant improvement in ulcerative colitis remission rates as compared to placebo. Available at: http://investor.millennium.com/phoenix.zhtml?c=80159&p=irol-newsmed iaArticle&ID=415406&highlight= (accessed 26 November 2006)

  23. Sandborn WJ, Colombel JF, Enns R, Feagan BG, Hanauer SB, Lawrance IC, Panaccione R, Sanders M, Schreiber S, Targan S et al (2005) Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med 353: 1912–1925

    Article  PubMed  CAS  Google Scholar 

  24. Macdonald JK, McDonald JW (2006) Natalizumab for induction of remission in Crohn’s disease. Cochrane Database Syst Rev 3: CD006097

    PubMed  CAS  Google Scholar 

  25. Ghosh S, Goldin E, Gordon FH, Malchow HA, Rask-Madsen J, Rutgeerts P, Vyhnalek P, Zadorova Z, Palmer T, Donoghue S et al (2003) Natalizumab for active Crohn’s disease. N Engl J Med 348: 24–32

    Article  PubMed  CAS  Google Scholar 

  26. Biogen Idec. Tysabri® maintained remission in patients with moderate-to-severe Crohn’s disease treated for longer than two years according to data presented this week. Available at: http://www.biogenidec.com/site/019_0.html (accessed 26 November 2006)

  27. Yousry TA, Major EO, Ryschkewitsch C, Fahle G, Fischer S, Hou J, Curfman B, Miszkiel K, Mueller-Lenke N, Sanchez E et al (2006) Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 354: 924–933

    Article  PubMed  CAS  Google Scholar 

  28. Hafler DA (2004) Multiple sclerosis. J Clin Invest 113: 788–794

    Article  PubMed  CAS  Google Scholar 

  29. Yednock TA, Cannon C, Fritz LC, Sanchez-Madrid F, Steinman L, Karin N (1992) Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature 356: 63–66

    Article  PubMed  CAS  Google Scholar 

  30. Gordon EJ, Myers KJ, Dougherty JP, Rosen H, Ron Y (1995) Both anti-CD11a (LFA-1) and anti-CD11b (MAC-1) therapy delay the onset and diminish the severity of experimental autoimmune encephalomyelitis. J Neuroimmunol 62: 153–160

    Article  PubMed  CAS  Google Scholar 

  31. All about multiple sclerosis. Icos Corp Won’t Study LeukArrest as chronic MS treatment. Available at: http://www.mult-sclerosis.org/news/Octl999/LeukArrestStudyStopped.html (accessed 26 November 2006)

  32. Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A et al (2006) A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engt J Med 354: 899–910

    Article  CAS  Google Scholar 

  33. U.S. Food and Drug Administration. FDA approves resumed marketing of Tysabri under a special distribution program. Available at: http://www.fda.gov/bbs/topics/ NEWS/2006/NEW01380.html (accessed 26 November 2006)

  34. Kakkar AK, Lefer DJ (2004) Leukocyte and endothelial adhesion molecule studies in knockout mice. Curr Opin Pharmacol 4: 154–158

    Article  PubMed  CAS  Google Scholar 

  35. Faxon DP, Gibbons RJ, Chronos NAF, Gurbel PA, Sheehan F (2002) The effect of blockade of the CD11/CD18 integrin receptor on infarct size in patients with acute myocardial infarction treated with direct angioplasty: the results of the HALT-MI study. J Am Coll Cardiol 40: 1199–1204

    Article  PubMed  CAS  Google Scholar 

  36. Baran KW, Nguyen M, McKendall GR, Lambrew CT, Dykstra G, Palmen ST, Gibbons RJ, Borzak S, Sobel BE, Gourlay SG et al (2001) Double-blind, randomized trial of an anti-CD18 antibody in conjunction with recombinant tissue plasminogen activator for acute myocardial infarction: limitation of myocardial infarction following thrombolysis in acute myocardial infarction (LIMIT AMI) study. Circulation 104: 2778–2783

    Article  PubMed  CAS  Google Scholar 

  37. Mertens P, Maes A, Nuyts J, Belmans A, Desmet W, Esplugas E, Charlier F, Figueras J, Sambuceti G, Schwaiger M (2006) Recombinant P-selectin glycoprotein ligand-immunoglobulin, a P-selectin antagonist, as an adjunct to thrombolysis in acute myocardial infarction. The P-Selectin Antagonist Limiting Myonecrosis (PSALM) trial. Am Heart J 152: 125.e1–125.e8

    Article  CAS  Google Scholar 

  38. Nickoloff BJ, Nestle FO (2004) Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities. J Clin Invest 113: 1664–1675

    Article  PubMed  CAS  Google Scholar 

  39. Gordon KB, Papp KA, Hamilton TK, Walicke PA, Dummer W, Li N, Bresnahan BW, Menter A (2003) Efalizumab for patients with moderate to severe plaque psoriasis: a randomized controlled trial. JAMA 290: 3073–3080

    Article  PubMed  CAS  Google Scholar 

  40. Lebwohl M, Tyring SK, Hamilton TK, Toth D, Glazer S, Tawfik NH, Walicke P, Dummer W, Wang X, Garovoy MR et al (2003) A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N Engl J Med 349: 2004–2013

    Article  PubMed  CAS  Google Scholar 

  41. Genetech. Genentech and XOMA announce results of Phase II study of Raptiva in psoriatic arthritis patients. Available at: http://www.gene.com/gene/news/press-releases/ display.do?method=detail&id=7287 (accessed 26 November 2006)

  42. Friedrich M, Vollhardt K, Zahlten R, Sterry W, Wolff G. Demonstration of antipsoriatic efficacy of a new topical formulation of the small molecule selectin antagonist bimosiamose. Available at: http://mcic3.textor.com/cgi-bin/mc/printabs. pl?APP=PSORIASIS2004-abstract&TEMPLATE=&keyf=0099&showHide=show&clie nt= (accessed 5 January 2007)

  43. Kavanaugh AF, Davis LS, Nichols LA, Norris SH, Rothlein R, Scharschmidt LA, Lipsky PE (1994) Treatment of refractory rheumatoid arthritis with a monoclonal antibody to intercellular adhesion molecule 1. Arthritis Rheum 37: 992–999

    Article  PubMed  CAS  Google Scholar 

  44. Kavanaugh AF, Davis LS, Jain RI, Nichols LA, Norns SH, Lipsky PE (1996) A Phase I/II open label study of the safety and efficacy of an anti-ICAM-1 (intercellular adhesion molecule-1; CD54) monoclonal antibody in early rheumatoid arthritis. J Rheumatol 23: 1338–1344

    PubMed  CAS  Google Scholar 

  45. Genetech. Genentech and XOMA discontinue rheumatoid arthritis trial. Available at: http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=6107 (accessed 26 November 2006)

  46. Maksymowych WP, Blackburn WD Jr, Tami JA, Shanahan WR Jr (2002) A randomized, placebo controlled trial of an antisense oligodeoxynucleotide to intercellular adhesion molecule-1 in the treatment of severe rheumatoid arthritis. J Rheumatol 29: 447–453

    PubMed  CAS  Google Scholar 

  47. Sughrue ME, Mehra A, Connolly ES Jr, D’Ambrosio AL (2004) Anti-adhesion molecule strategies as potential neuroprotective agents in cerebral ischemia: a critical review of the literature. Inflamm Res 53: 497–508

    Article  PubMed  CAS  Google Scholar 

  48. Stroke Center at Barnes-Jewish Hospital and Washington University School of Medicine. Stroke Trials Registry. Available at: http://www.strokecenter.org/trials/trialDetail. aspx?tid=50 (accessed 26 November 2006)

  49. Krams M, Lees KR, Hacke W, Grieve AP, Orgogozo JM, Ford GA (2003) Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN): an adaptive dose-response study of UK-279,276 in acute ischemic stroke. Stroke 34: 2543–2548

    Article  PubMed  CAS  Google Scholar 

  50. Enlimomab Acute Stroke Trial Investigators (2001) Use of anti-ICAM-1 therapy in ischemie stroke: results of the enlimomab acute stroke trial. Neurology 57: 1428–1434

    Google Scholar 

  51. Fuggle SV, Koo DD (1998) Cell adhesion molecules in clinical renal transplantation. Transplantation 65: 763–769

    Article  PubMed  CAS  Google Scholar 

  52. Tamo JW, Basu CB, Albelda SM, Eisen HJ (1994) Differential expression of the cell adhesion molecules ICAM-1, VCAM-1, and E-selectin in normal and posttransplantation myocardium. Cell adhesion molecule expression in human cardiac allografts. Circulation 89: 1760–1768

    Google Scholar 

  53. Dedrick RL, Bodary S, Garovoy MR (2003) Adhesion molecules as therapeutic targets for autoimmune diseases and transplant rejection. Expert Opin Biol Ther 3: 85–95

    Article  PubMed  CAS  Google Scholar 

  54. Fischer A, Friedrich W, Fasth A, Blanche S, Le Deist F, Girault D, Veber F, Vossen J, Lopez M, Griscelli C et al (1991) Reduction of graft failure by a monoclonal antibody (anti-LFA-1 CDU a) after HLA nonidentical bone marrow transplantation in children with immunodeficiencies, osteopetrosis, and Fanconi’s anemia: a European Group for Immunodeficiency/European Group for Bone Marrow Transplantation report. Blood 77: 249–256

    PubMed  CAS  Google Scholar 

  55. Cavazzana-Calvo M, Bordigoni P, Michel G, Esperou H, Souillet G, Leblanc T, Stephan JL, Vannier JP, Mechinaud F, Reiffers J et al (1996) A Phase II trial of partially incompatible bone marrow transplantation for high-risk acute lymphoblastic leukaemia in children: prevention of graft rejection with anti-LFA-1 and anti-CD2 antibodies. Societe Francaise de Greffe de Moelle Osseuse. Br J Haematol 93: 131–138

    Article  PubMed  CAS  Google Scholar 

  56. Hourmant M, Bedrossian J, Durand D, Lebranchu Y, Renoult E, Caudrelier P, Buffet R, Oulillou JP (1996) A randomized multicenter trial comparing leukocyte function-associated antigen-1 monoclonal antibody with rabbit antithymocyte globulin as induction treatment in first kidney transplantations. Transplantation 62: 1565–1570

    Article  PubMed  CAS  Google Scholar 

  57. Matthews JB, Ramos E, Bluestone JA (2003) Clinical trials of transplant tolerance: slow but steady progress. Am J Transplant 3: 794–803

    Article  PubMed  Google Scholar 

  58. Salmela K, Wramner L, Ekberg H, Häuser I, Bentdal O, Lins LE, Isoniemi H, Backman L, Persson N, Neumayer HH et al (1999) A randomized multicenter trial of the anti-ICAM-1 monoclonal antibody (enlimomab) for the prevention of acute rejection and delayed onset of graft function in cadaveric renal transplantation: a report of the European Anti-ICAM-1 Renal Transplant Study Group. Transplantation 67: 729–736

    Article  PubMed  CAS  Google Scholar 

  59. Kuypers DRJ, Vanrenterghem YFC (2004) Monoclonal antibodies in renal transplantation: old and new. Nephrol Dial Transplant 19: 297–300

    Article  PubMed  CAS  Google Scholar 

  60. Ferrara JL, Reddy P (2006) Pathophysiology of graft-versus-host disease. Semin Hematol 43: 3–10

    Article  PubMed  CAS  Google Scholar 

  61. Stoppa AM, Maraninchi D, Blaise D, Viens P, Hirn M, Olive D, Reiffers J, Milpied N, Gaspard MH, Mawas C (1991) Anti-LFA1 monoclonal antibody (25.3) for treatment of steroid-resistant grade III-IV acute grait-versus-host disease. Transpl Int 4: 3–7

    Article  PubMed  CAS  Google Scholar 

  62. Vedder NB, Fouty BW, Winn RK, Harlan JM, Rice CL (1989) Role of neutrophils in generalized reperfusion injury associated with resuscitation from shock. Surgery 106: 509–516

    PubMed  CAS  Google Scholar 

  63. Vedder N, Winn RK, Rice CL, Chi EY, Arfors KE, Harlan JM (1988) A monoclonal antibody to the adherence-promoting leukocyte glycoprotein, CD18, reduces organ injury and improves survival from hemorrhagic shock and resuscitation in rabbits. J Clin Invest 81: 939–944

    Article  PubMed  CAS  Google Scholar 

  64. Mileski WJ, Winn RK, Vedder N, Pohlman TH, Harlan JM, Rice CL (1990) Inhibition of CD18-dependent neutrophil adherence reduces organ injury after hemorrhagic shock in primates. Surgery 108: 206–212

    PubMed  CAS  Google Scholar 

  65. Rhee P, Morris J, Durham R, Häuser C, Cipolle M, Wilson R, Luchette F, McSwain N, Miller R (2000) Recombinant humanized monoclonal antibody against CD18 (rhuMAb CD18) in traumatic hemorrhagic shock: results of a phase II clinical trial. Traumatic Shock Group. J Trauma 49: 611–619

    Article  PubMed  CAS  Google Scholar 

  66. Vedder N, Harlan JM, Winn RK, Maier R, Hoyt D, Moore F, Fabian T, West M, Peitzman A, Moore E et al (2000) Immunomodulators: inhibitors of adhesion. Shock 13: 1

    Google Scholar 

  67. Seekamp A, van Griensven M, Dhondt E, Diefenbeck M, Demeyer I, Vundelinckx G, Haas N, Schaechinger U, Wolowicka L, Rammelt S et al (2004) The effect of anti-Lselectin (aselizumab) in multiple traumatized patients — Results of a Phase II clinical trial. Crit Care Med 32: 2021–2028

    Article  PubMed  CAS  Google Scholar 

  68. Iwata A, Harlan JM, Vedder NB, Winn RK (2002) The caspase inhibitor z-VAD is more effective than CD18 adhesion blockade in reducing muscle ischemia-reperfusion injury: implication for clinical trials. Blood 100: 2077–2080

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Division of Nephrology, Department of Pediatrics, University of Washington, Seattle, WA, 98195, USA

    Karyn Yonekawa

  2. Division of Hematology, Department of Medicine, University of Washington, Seattle, WA, 98195, USA

    John M. Harlan

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  1. Karyn Yonekawa
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  2. John M. Harlan
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Editors and Affiliations

  1. La Jolla Institute for Allergy & Immunology, 9420 Athena Circle, La Jolla, CA, 92037, USA

    Klaus Ley

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Yonekawa, K., Harlan, J.M. (2007). Promises and limitations of targeting adhesion molecules for therapy. In: Ley, K. (eds) Adhesion Molecules: Function and Inhibition. Progress in Inflammation Research. Birkhäuser Basel. https://doi.org/10.1007/978-3-7643-7975-9_13

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