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Integrin-based therapeutics: biological basis, clinical use and new drugs

Key Points

  • Integrin antagonists are highly successful drugs for targeting the ligand binding site of αIIbβ3, α4-containing or α4β7 integrins.

  • Antagonists to αIIbβ3 integrin are still being used in patients receiving percutaneous angioplasty but are being replaced in many instances by new classes of anticoagulants and platelet inhibitors.

  • Natalizumab, a monoclonal antibody against α4-containing integrins, is highly successful at treating multiple sclerosis, but can reactivate John Cunningham virus and cause lethal progressive multifocal leukoencephalopathy (PML).

  • Vedolizumab, a monoclonal antibody against α4β7 integrin, and new antibodies against the β7 integrin subunit have not shown any signs of inducing PML.

  • Vedolizumab is safe and effective in the treatment of inflammatory bowel disease and has effectively replaced natalizumab for the treatment of Crohn disease.

Abstract

Integrins are activatable molecules that are involved in adhesion and signalling. Of the 24 known human integrins, 3 are currently targeted therapeutically by monoclonal antibodies, peptides or small molecules: drugs targeting the platelet αIIbβ3 integrin are used to prevent thrombotic complications after percutaneous coronary interventions, and compounds targeting the lymphocyte α4β1 and α4β7 integrins have indications in multiple sclerosis and inflammatory bowel disease. New antibodies and small molecules targeting β7 integrins (α4β7 and αEβ7 integrins) and their ligands are in clinical development for the treatment of inflammatory bowel diseases. Integrin-based therapeutics have shown clinically significant benefits in many patients, leading to continued medical interest in the further development of novel integrin inhibitors. Of note, almost all integrin antagonists in use or in late-stage clinical trials target either the ligand-binding site or the ligand itself.

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Figure 1: Integrin families.
Figure 2: Inside-out activation of αIIbβ3 integrin in platelets.
Figure 3: The three integrins, α4β1, α4β7 and αEβ7, that are targeted by therapeutic α4 and β7 antibodies.

References

  1. 1

    Tadokoro, S. et al. Talin binding to integrin β tails: a final common step in integrin activation. Science 302, 103–106 (2003).

    CAS  Google Scholar 

  2. 2

    Moser, M., Legate, K. R., Zent, R. & Fassler, R. The tail of integrins, talin, and kindlins. Science 324, 895–899 (2009).

    CAS  Google Scholar 

  3. 3

    Mocsai, A. et al. Integrin signaling in neutrophils andmacrophages uses adaptors containing immunoreceptor tyrosine-based activation motifs. Nat. Immunol. 7, 1326–1333 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Mocsai, A., Zhou, M., Meng, F., Tybulewicz, V. L. & Lowell, C. A. Syk is required for integrin signaling in neutrophils. Immunity 16, 547–558 (2002).

    CAS  Google Scholar 

  5. 5

    Arias-Salgado, E. G. et al. Src kinase activation by direct interaction with the integrin β cytoplasmic domain. Proc. Natl Acad. Sci. USA 100, 13298–13302 (2003).

    CAS  PubMed  Google Scholar 

  6. 6

    Scharffetter-Kochanek, K. et al. Spontaneous skin ulceration and defective T cell function in CD18 null mice. J. Exp. Med. 188, 119–131 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Shimaoka, M. & Springer, T. A. Therapeutic antagonists and conformational regulation of integrin function. Nat. Rev. Drug Discov. 2, 703–716 (2003).

    CAS  PubMed  Google Scholar 

  8. 8

    Mitroulis, I. et al. Leukocyte integrins: role in leukocyte recruitment and as therapeutic targets in inflammatory disease. Pharmacol. Ther. 147, 123–135 (2015).

    CAS  PubMed  Google Scholar 

  9. 9

    Wright, D. B., Meurs, H. & Dekkers, B. G. Integrins: therapeutic targets in airway hyperresponsiveness and remodelling? Trends Pharmacol. Sci. 35, 567–574 (2014).

    CAS  PubMed  Google Scholar 

  10. 10

    Goodman, S. L. & Picard, M. Integrins as therapeutic targets. Trends Pharmacol. Sci. 33, 405–412 (2012).

    CAS  PubMed  Google Scholar 

  11. 11

    Shimaoka, M. et al. Structures of the αL I domain and its complex with ICAM-1 reveal a shape-shifting pathway for integrin regulation. Cell 112, 99–111 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Hynes, R. O. Integrins: bidirectional, allosteric signaling machines. Cell 110, 673–687 (2002).

    CAS  PubMed  Google Scholar 

  13. 13

    Kim, M., Carman, C. V. & Springer, T. A. Bidirectional transmembrane signaling by cytoplasmic domain separation in integrins. Science 301, 1720–1725 (2003).

    CAS  PubMed  Google Scholar 

  14. 14

    Shattil, S. J., Kim, C. & Ginsberg, M. H. The final steps of integrin activation: the end game. Nat. Rev. Mol. Cell. Biol. 11, 288–300 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Luo, B. H., Carman, C. V. & Springer, T. A. Structural basis of integrin regulation and signaling. Annu. Rev. Immunol. 25, 619–647 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Ye, F., Kim, C. & Ginsberg, M. H. Reconstruction of integrin activation. Blood 119, 26–33 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Pierschbacher, M. D. & Ruoslahti, E. Cell attachment activity of fibronectin can be duplicated by small synthetic fragments of the molecule. Nature 309, 30–33 (1984).

    CAS  PubMed  Google Scholar 

  18. 18

    Wayner, E. A., Garcia-Pardo, A., Humphries, M. J., McDonald, J. A. & Carter, W. G. Identification and characterization of the T lymphocyte adhesion receptor for an alternative cell attachment domain (CS-1) in plasma fibronectin. J. Cell Biol. 109, 1321–1330 (1989).

    CAS  PubMed  Google Scholar 

  19. 19

    Shimaoka, M., Salas, A., Yang, W., Weitz-Schmidt, G. & Springer, T. A. Small molecule integrin antagonists that bind to the β2 subunit I-like domain and activate signals in one direction and block them in the other. Immunity 19, 391–402 (2003).

    CAS  PubMed  Google Scholar 

  20. 20

    Xiao, T., Takagi, J., Coller, B. S., Wang, J. H. & Springer, T. A. Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics. Nature 432, 59–67 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Salas, A. et al. Rolling adhesion through an extended conformation of integrin αLβ2 and relation to α I and β I-like domain interaction. Immunity 20, 393–406 (2004).

    CAS  PubMed  Google Scholar 

  22. 22

    Kuwano, Y., Spelten, O., Zhang, H., Ley, K. & Zarbock, A. Rolling on E- or P-selectin induces the extended but not high-affinity conformation of LFA-1 in neutrophils. Blood 116, 617–624 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Zarbock, A., Lowell, C. A. & Ley, K. Spleen tyrosine kinase Syk is necessary for E-selectin-induced αLβ2 integrin mediated rolling on Intercellular Adhesion Molecule-1. Immunity 26, 773–783 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Lefort, C. T. et al. Distinct roles for talin-1 and kindlin-3 in LFA-1 extension and affinity regulation. Blood 119, 4275–4283 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Weitz-Schmidt, G. et al. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat. Med. 7, 687–692 (2001).

    CAS  PubMed  Google Scholar 

  26. 26

    Chigaev, A. et al. Real-time analysis of the inside-out regulation of lymphocyte function-associated antigen-1 revealed similarities and differences with very late antigen-4. J. Biol. Chem. 286, 20375–20386 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Chigaev, A., Wu, Y., Williams, D. B., Smagley, Y. & Sklar, L. A. Discovery of very late antigen-4 (VLA-4, α4β1 integrin) allosteric antagonists. J. Biol. Chem. 286, 5455–5463 (2011).

    CAS  PubMed  Google Scholar 

  28. 28

    Coller, B. S. & Shattil, S. J. The GPIIb/IIIa (integrin αIIbβ3) odyssey: a technology driven saga of a receptor with twists, turns and even a bend. Blood 112, 3011–3025 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Nieswandt, B. & Watson, S. P. Platelet-collagen interaction: is GPVI the central receptor? Blood 102, 449–461 (2003).

    CAS  PubMed  Google Scholar 

  30. 30

    Bledzka, K., Smyth, S. S. & Plow, E. F. Integrin αIIbβ3: from discovery to efficacious therapeutic target. Circ. Res. 112, 1189–1200 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Hawiger, J., Timmons, S., Kloczewiak, M., Strong, D. D. & Doolittle, R. F. γ and α chains of human fibrinogen possess sites reactive with human platelet receptors. Proc. Natl Acad. Sci. USA 79, 2068–2071 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Plow, E. F., Pierschbacher, M. D., Ruoslahti, E., Marguerie, G. A. & Ginsberg, M. H. The effect of Arg-Gly-Asp-containing peptides on fibrinogen and von Willebrand factor binding to platelets. Proc. Natl Acad. Sci. USA 82, 8057–8061 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Moser, M., Nieswandt, B., Ussar, S., Pozgajova, M. & Fassler, R. Kindlin-3 is essential for integrin activation and platelet aggregation. Nat. Med. 14, 325–330 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Kuijpers, T. W. et al. LAD-1/variant syndrome is caused by mutations in FERMT3. Blood 113, 4740–4746 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Ye, F. et al. The mechanism of kindlin-mediated activation of integrin αIIbβ3. Curr. Biol. 23, 2288–2295 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Coller, B. S. Platelet GPIIb/IIIa antagonists: The first anti-integrin receptor therapeutics. J. Clin. Invest. 99, 1467–1471 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Phillips, D. R. & Scarborough, R. M. Clinical pharmacology of eptifibatide. Am J. Cardiol. 80, 11B–20B (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Cook, J. J. et al. Tirofiban (Aggrastat(R)). Cardiovasc. Drug Rev. 17, 199–224 (1999).

    CAS  Google Scholar 

  39. 39

    Estevez, B., Shen, B. & Du, X. Targeting integrin and integrin signaling in treating thrombosis. Arterioscler. Thromb. Vasc. Biol. 35, 24–29 (2014).

    PubMed  PubMed Central  Google Scholar 

  40. 40

    Felding-Habermann, B. & Cheresh, D. A. Vitronectin and its receptors. Curr. Opin. Cell Biol. 5, 864–868 (1993).

    CAS  Google Scholar 

  41. 41

    Chinot, O. L. Cilengitide in glioblastoma: when did it fail? Lancet Oncol. 15, 1044–1045 (2014).

    Google Scholar 

  42. 42

    Reynolds, A. R. et al. Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors. Nat. Med. 15, 392–400 (2009).

    CAS  Google Scholar 

  43. 43

    Wong, P. P. et al. Dual-action combination therapy enhances angiogenesis while reducing tumor growth and spread. Cancer Cell 27, 123–137 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Coller, B. S. Anti-GPIIb/IIIa drugs: current strategies and future directions. Thromb. Haemost. 86, 427–443 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Artoni, A. et al. Integrin β3 regions controlling binding of murine mAb 7E3: implications for the mechanism of integrin αIIbβ3 activation. Proc. Natl Acad. Sci. USA 101, 13114–13120 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Tam, S. H., Sassoli, P. M., Jordan, R. E. & Nakada, M. T. Abciximab (ReoPro, chimeric 7E3 Fab) demonstrates equivalent affinity and functional blockade of glycoprotein IIb/IIIa and avb3 integrins. Circulation 98, 1085–1091 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Kintscher, U. et al. Effects of abciximab and tirofiban on vitronectin receptors in human endothelial and smooth muscle cells. Eur. J. Pharmacol. 390, 75–87 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Scarborough, R. M. Structure-activity relationships of b-amino acid-containing integrin antagonists. Curr. Med. Chem. 6, 971–981 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Aster, R. H. Immune thrombocytopenia caused by glycoprotein IIb/IIIa inhibitors. Chest 127, 53S–59S (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Bougie, D. W. et al. Acute thrombocytopenia after treatment with tirofiban or eptifibatide is associated with antibodies specific for ligand-occupied GPIIb/IIIa. Blood 100, 2071–2076 (2002).

    CAS  Google Scholar 

  51. 51

    Kastrati, A. et al. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. JAMA 295, 1531–1538 (2006).

    CAS  Google Scholar 

  52. 52

    Franchi, F. & Angiolillo, D. J. Novel antiplatelet agents in acute coronary syndrome. Nat. Rev. Cardiol. 12, 30–47 (2015).

    CAS  Google Scholar 

  53. 53

    Kristensen, S. D. et al. Contemporary use of glycoprotein IIb/IIIa inhibitors. Thromb. Haemost. 107, 215–224 (2012).

    CAS  Google Scholar 

  54. 54

    Cox, D. Oral GPIIb/IIIa antagonists: what went wrong? Curr. Pharm. Des. 10, 1587–1596 (2004).

    CAS  Google Scholar 

  55. 55

    Bassler, N. et al. A mechanistic model for paradoxical platelet activation by ligand-mimetic αIIbβ3 (GPIIb/IIIa) antagonists. Arterioscler. Thromb. Vasc. Biol. 27, e9–e15 (2007).

    CAS  Google Scholar 

  56. 56

    Li, J. et al. RUC-4: a novel αIIbβ3 antagonist for prehospital therapy of myocardial infarction. Arterioscler. Thromb. Vasc. Biol. 34, 2321–2329 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Takagi, J., Petre, B., Walz, T. & Springer, T. Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell 110, 599–611 (2002).

    CAS  Google Scholar 

  58. 58

    Xie, C. et al. Structure of an integrin with an alphaI domain, complement receptor type 4. EMBO J. 29, 666–679 (2010).

    CAS  Google Scholar 

  59. 59

    Springer, T. A., Thompson, W. S., Miller, L. J., Schmalstieg, F. C. & Anderson, D. C. Inherited deficiency of the Mac-1, LFA-1, 150,95 glycoprotein family and its molecular basis. J. Exp. Med. 160, 1901–1918 (1984).

    CAS  Google Scholar 

  60. 60

    Grakoui, A. et al. The immunological synapse: a molecular machine controlling T cell activation. Science 285, 221–227 (1999).

    CAS  Google Scholar 

  61. 61

    Henderson, R. B. et al. The use of lymphocyte function-associated antigen (LFA)-1-deficient mice to determine the role of LFA-1, Mac-1, and α4 integrin in the inflammatory response of neutrophils. J. Exp. Med. 194, 219–226 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Coxon, A. et al. A novel role for the β-2 integrin CD11b/CD18 in neutrophil apoptosis — a homeostatic mechanism in inflammation. Immunity 5, 653–666 (1996).

    Google Scholar 

  63. 63

    Tang, T. et al. A role for Mac-1 (CD11b/CD18) in immune complex-stimulated neutrophil function in vivo — Mac-1 deficiency abrogates sustained Fc-γ receptor-dependent neutrophil adhesion and complement-dependent proteinuria in acute glomerulonephritis. J. Exp. Med. 186, 1853–1863 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Hom, G. et al. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N. Engl. J. Med. 358, 900–909 (2008).

    CAS  Google Scholar 

  65. 65

    Nath, S. K. et al. A nonsynonymous functional variant in integrin-αM (encoded by ITGAM) is associated with systemic lupus erythematosus. Nat. Genet. 40, 152–154 (2008).

    CAS  Google Scholar 

  66. 66

    Wu, H. et al. Functional role of CD11c+ monocytes in atherogenesis associated with hypercholesterolemia. Circulation 119, 2708–2717 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Berlin, C. et al. α4β7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell 74, 185–195 (1993).

    CAS  Google Scholar 

  68. 68

    Iwata, M. et al. Retinoic acid imprints gut-homing specificity on T cells. Immunity 21, 527–538 (2004).

    CAS  Google Scholar 

  69. 69

    Hemler, M. E., Huang, C. & Schwarz, L. The VLA protein family: characterization of five distinct cell surface heterodimers each with a common 130,000 Mr subunit. J. Biol. Chem. 262, 3300–3309 (1987).

    CAS  Google Scholar 

  70. 70

    Cybulsky, M. I. & Gimbrone, M. A. Jr. Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science 251, 788–791 (1991).

    CAS  Google Scholar 

  71. 71

    Vedder, N. B. et al. 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 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Yonekawa, K. & Harlan, J. M. Targeting leukocyte integrins in human diseases. J. Leukoc. Biol. 77, 129–140 (2005).

    CAS  Google Scholar 

  73. 73

    Briskin, M. J., McEvoy, L. M. & Butcher, E. C. MAdCAM-1 has homology to immunoglobulin and mucin-like adhesion receptors and to IgA1. Nature 363, 461–464 (1993).

    CAS  Google Scholar 

  74. 74

    Yednock, T. A. et al. Prevention of experimental autoimmune encephalomyelitis by antibodies against α4β1 integrin. Nature 356, 63–66 (1992).

    CAS  Google Scholar 

  75. 75

    Calabresi, P. A. et al. The incidence and significance of anti-natalizumab antibodies: results from AFFIRM and SENTINEL. Neurology 69, 1391–1403 (2007).

    CAS  Google Scholar 

  76. 76

    Hesterberg, P. E. et al. Rapid resolution of chronic colitis in the cotton-top tamarin with an antibody to a gut-homing integrin α4β7 . Gastroenterology 111, 1373–1380 (1996).

    CAS  Google Scholar 

  77. 77

    Picarella, D. et al. Monoclonal antibodies specific for β7 integrin and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) reduce inflammation in the colon of scid mice reconstituted with CD45RBhigh CD4+ T cells. J. Immunol. 158, 2099–2106 (1997).

    CAS  Google Scholar 

  78. 78

    Grant, A. J., Lalor, P. F., Hubscher, S. G., Briskin, M. & Adams, D. H. MAdCAM-1 expressed in chronic inflammatory liver disease supports mucosal lymphocyte adhesion to hepatic endothelium (MAdCAM-1 in chronic inflammatory liver disease). Hepatology 33, 1065–1072 (2001).

    CAS  Google Scholar 

  79. 79

    Pan, W. J. et al. Pharmacology of AMG 181, a human anti-α4β7 antibody that specifically alters trafficking of gut-homing T cells. Br. J. Pharmacol. 169, 51–68 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Pan, W. J. et al. Clinical pharmacology of AMG 181, a gut-specific human anti-α4β7 monoclonal antibody, for treating inflammatory bowel diseases. Br. J. Clin. Pharmacol. 78, 1315–1333 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Mucida, D. et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317, 256–260 (2007).

    CAS  PubMed  Google Scholar 

  82. 82

    Stefanich, E. G. et al. A humanized monoclonal antibody targeting the β7 integrin selectively blocks intestinal homing of T lymphocytes. Br. J. Pharmacol. 162, 1855–1870 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Rutgeerts, P. J. et al. A randomised phase I study of etrolizumab (rhuMAb β7) in moderate to severe ulcerative colitis. Gut 62, 1122–1130 (2012).

    PubMed  PubMed Central  Google Scholar 

  84. 84

    Vermeire, S. et al. Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, Phase 2 trial. Lancet 384, 309–318 (2014).

    CAS  PubMed  Google Scholar 

  85. 85

    Masopust, D. et al. Dynamic T cell migration program provides resident memory within intestinal epithelium. J. Exp. Med. 207, 553–564 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Sugiura, T. et al. A novel, orally active α4 integrin antagonist, AJM300 prevents the development of experimental colitis induced by adoptive transfer of IL-10 deficient CD4+ T cells in mice. J. Pharmacol. Exp. Ther. (2012).

  87. 87

    Takazoe, M. Oral α-4 integrin inhibitor (AJM300) in patients with active Crohn's disease — a randomized, double-blind, placebo-controlled trial. Gastroenterology 136 (Suppl. 1), A-181 (2009).

    Google Scholar 

  88. 88

    Connor, E. M., Eppihimer, M. J., Morise, Z., Granger, D. N. & Grisham, M. B. Expression of mucosal addressin cell adhesion molecule-1 (MAdCAM- 1) in acute and chronic inflammation. J. Leukocyte Biol. 65, 349–355 (1999).

    CAS  PubMed  Google Scholar 

  89. 89

    Briskin, M. et al. Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. Am. J. Pathol. 151, 97–110 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Sikorski, E. E., Hallmann, R., Berg, E. L. & Butcher, E. C. The Peyer's patch high endothelial receptor for lymphocytes, the mucosal vascular addressin, is induced on a murine endothelial cell line by tumor necrosis factor-α and IL- 1. J. Immunol. 151, 5239–5250 (1993).

    CAS  PubMed  Google Scholar 

  91. 91

    Adams, D. H. & Eksteen, B. Aberrant homing of mucosal T cells and extra-intestinal manifestations of inflammatory bowel disease. Nat. Rev. Immunol. 6, 244–251 (2006).

    CAS  PubMed  Google Scholar 

  92. 92

    Salmi, M., Andrew, D. P., Butcher, E. C. & Jalkanen, S. Dual binding capacity of mucosal immunoblasts to mucosal and synovial endothelium in humans: dissection of the molecular mechanisms. J. Exp. Med. 181, 137–149 (1995).

    CAS  PubMed  Google Scholar 

  93. 93

    Pullen, N. et al. Pharmacological characterization of PF-00547659, an anti-human MAdCAM monoclonal antibody. Br. J. Pharmacol. 157, 281–293 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Reinisch, W. A. Randomized, multicenter double-blind, placebo-controlled study of the safety and efficacy of anti-MAdCAM antibody PF-00547659 (PF) in patients with moderate to severe ulcerative colitis: results of the TURANDOT study. Gastroenterology 148 (Suppl. 1), S-1193 (2015).

    Google Scholar 

  95. 95

    Sandborn, W. J. Anti-MAdCAM-1 antibody (PF-00547659) for active refractory crohn's disease: results of the OPERA study. J. Crohns Colitis 9 (Suppl.), S14 (2015).

    Google Scholar 

  96. 96

    Lazaar, A. L. et al. T lymphocytes adhere to airway smooth muscle cells via integrins and CD44 and induce smooth muscle cell DNA synthesis. J. Exp. Med. 180, 807–816 (1994).

    CAS  PubMed  Google Scholar 

  97. 97

    Enlimomab Acute Stroke Trial Investigators Use of anti-ICAM-1 therapy in ischemic stroke: results of the Enlimomab Acute Stroke Trial. Neurology 57, 1428–1434 (2001).

  98. 98

    Monkley, S. J. et al. Disruption of the talin gene arrests mouse development at the gastrulation stage. Dev. Dyn. 219, 560–574 (2000).

    CAS  PubMed  Google Scholar 

  99. 99

    Moser, M. et al. Kindlin-3 is required for β2 integrin–mediated leukocyte adhesion to endothelial cells. Nat. Med. 15, 300–305 (2009).

    CAS  PubMed  Google Scholar 

  100. 100

    Shattil, S. J. Integrins and Src: dynamic duo of adhesion signaling. Trends Cell Biol. 15, 399–403 (2005).

    CAS  PubMed  Google Scholar 

  101. 101

    Mocsai, A., Ruland, J. & Tybulewicz, V. L. The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat. Rev. Immunol. 10, 387–402 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Polman, C. H. et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 354, 899–910 (2006).

    CAS  PubMed  Google Scholar 

  103. 103

    Natalizumab: new drug. Multiple sclerosis: risky market approval. Prescrire Int. 17, 7–10 (2008).

  104. 104

    Balcer, L. J. et al. Natalizumab reduces visual loss in patients with relapsing multiple sclerosis. Neurology 68, 1299–1304 (2007).

    CAS  PubMed  Google Scholar 

  105. 105

    Rudick, R. A. et al. Health-related quality of life in multiple sclerosis: effects of natalizumab. Ann. Neurol. 62, 335–346 (2007).

    CAS  PubMed  Google Scholar 

  106. 106

    Rudick, R. A. & Miller, D. M. Health-related quality of life in multiple sclerosis: current evidence, measurement and effects of disease severity and treatment. CNS Drugs 22, 827–839 (2008).

    CAS  PubMed  Google Scholar 

  107. 107

    Miller, D. H. et al. MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology 68, 1390–1401 (2007).

    CAS  PubMed  Google Scholar 

  108. 108

    Berger, J. R. & Houff, S. A. Neurological infections: the year of PML and influenza. Lancet Neurol. 9, 14–17 (2010).

    PubMed  Google Scholar 

  109. 109

    Sandborn, W. J. et al. Natalizumab induction and maintenance therapy for Crohn's disease. N. Engl. J. Med. 353, 1912–1925 (2005).

    CAS  PubMed  Google Scholar 

  110. 110

    Targan, S. R. et al. Natalizumab for the treatment of active Crohn's disease: results of the ENCORE Trial. Gastroenterology 132, 1672–1683 (2007).

    CAS  Google Scholar 

  111. 111

    Gordon, F. H. et al. A pilot study of treatment of active ulcerative colitis with natalizumab, a humanized monoclonal antibody to α-4 integrin. Aliment. Pharmacol. Ther. 16, 699–705 (2002).

    CAS  Google Scholar 

  112. 112

    Ghosh, S. et al. Natalizumab for active Crohn's disease. New Engl. J. Med. 348, 24–32 (2003).

    CAS  Google Scholar 

  113. 113

    Best, W. R., Becktel, J. M., Singleton, J. W. & Kern, F. Jr. Development of a Crohn's disease activity index. National Cooperative Crohn's Disease Study. Gastroenterology 70, 439–444 (1976).

    CAS  Google Scholar 

  114. 114

    Du Pasquier, R. A. et al. A prospective study demonstrates an association between JC virus-specific cytotoxic T lymphocytes and the early control of progressive multifocal leukoencephalopathy. Brain 127, 1970–1978 (2004).

    Google Scholar 

  115. 115

    Krumbholz, M., Meinl, I., Kumpfel, T., Hohlfeld, R. & Meinl, E. Natalizumab disproportionately increases circulating pre-B and B cells in multiple sclerosis. Neurology 71, 1350–1354 (2008).

    CAS  Google Scholar 

  116. 116

    Carson, K. R. et al. Monoclonal antibody-associated progressive multifocal leucoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab: a review from the Research on Adverse Drug Events and Reports (RADAR) Project. Lancet Oncol. 10, 816–824 (2009).

    CAS  Google Scholar 

  117. 117

    Feagan, B. G. et al. An ascending dose trial of a humanised a4b7 antibody in ulcerative colitis (UC). Gastroenterology 118 (Suppl. 2), A874 (2000).

    Google Scholar 

  118. 118

    Feagan, B. G. et al. Treatment of ulcerative colitis with a humanized antibody to the α4β7 integrin. N. Engl. J. Med. 352, 2499–2507 (2005).

    CAS  Google Scholar 

  119. 119

    Feagan, B. G. et al. Treatment of active Crohn's disease with MLN0002, a humanized antibody to the α4β7 integrin. Clin. Gastroenterol. Hepatol 6, 1370–1377 (2008).

    CAS  Google Scholar 

  120. 120

    Sands, B. E. et al. Effects of vedolizumab induction therapy for patients with Crohn's disease who failed tumor necrosis factor antagonist treatment. Gastroenterology 147, 618–627.e3 (2013).

    Google Scholar 

  121. 121

    Parikh, A. et al. Vedolizumab for the treatment of active ulcerative colitis: a randomized controlled phase 2 dose-ranging study. Inflamm. Bowel Dis. 18, 1470–1479 (2011).

    PubMed  Google Scholar 

  122. 122

    Feagan, B. G. et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 369, 699–710 (2013).

    CAS  PubMed  Google Scholar 

  123. 123

    Sandborn, W. J. et al. Vedolizumab as induction and maintenance therapy for Crohn's disease. N. Engl. J. Med. 369, 711–721 (2013).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are supported by a grant from the National Institutes of Health (DK108670) and a Biomedical Laboratory Research and Development Vetrans Affairs Merit Review award (1I01BX001051) to J.R.-N., grants from the National Institutes of Health (HL 56595 and HL 78784) to S.S., and grants from the National Institutes of Health (DK091222 and HL078784) to K.L.

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Correspondence to Klaus Ley.

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W.J.S. participates in clinical trials in this area. The other authors declare no competing interests.

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Ley, K., Rivera-Nieves, J., Sandborn, W. et al. Integrin-based therapeutics: biological basis, clinical use and new drugs. Nat Rev Drug Discov 15, 173–183 (2016). https://doi.org/10.1038/nrd.2015.10

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