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

Abstract

Integrins are activatable adhesion and signaling molecules. Of the 24 known human integrins, three are currently targeted therapeutically by monoclonal antibodies, peptides or small molecules. The platelet αIIbβ3 integrin is targeted by Abciximab, Eptifibatide and Tirofiban, all with indications for preventing thrombotic complications after percutaneous coronary interventions. The lymphocyte α4β1 and α4β7 integrins are targeted by Natalizumab with indications in multiple sclerosis and Crohn’s disease. Although efficacious, use of this antibody is limited by a rare but serious complication, progressive multifocal leukoencephalopathy. Vedolizumab is an antibody to a combinatorial epitope in α4β7 that is approved for use in patients with Crohn’s disease or ulcerative colitis in the United States, Canada and Europe. Progressive multifocal leukoencephalopathy has not been observed in the clinical trials or clinical use of vedolizumab. New antibodies and small molecules targeting β7 integrins (α4β7 and αEβ7) and MAdCAM-1 are in clinical development for treatment of these inflammatory bowel diseases. Overall, 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 the ligand binding site, or the ligand itself.

Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis?

“…Especially important in this regard is the integrin family, which mediates strong adhesion between leucocytes and endothelial and mucosal epithelial cells by binding to extracellular matrix components and specific receptor molecules. Six integrins are expressed only on leucocytes: LFA-1 (αLβ2), Mac-1 (αMβ2), αxβ2, αdβ2, α4β7 and αEβ7 60. Especially notable are: LFA-1, which plays a key role in the formation of the immunological synapse; α4β7, which mediates gut-specific lymphocyte homing via binding to MAdCAM-1 on the surface of gastrointestinal endothelial cells; and αEβ7, which binds E-cadherin on gut epithelial cells and may be important for lymphocyte retention within the mucosa 60.…”

“…Six integrins are expressed only on leucocytes: LFA-1 (αLβ2), Mac-1 (αMβ2), αxβ2, αdβ2, α4β7 and αEβ7 60. Especially notable are: LFA-1, which plays a key role in the formation of the immunological synapse; α4β7, which mediates gut-specific lymphocyte homing via binding to MAdCAM-1 on the surface of gastrointestinal endothelial cells; and αEβ7, which binds E-cadherin on gut epithelial cells and may be important for lymphocyte retention within the mucosa 60. Inhibition of lymphocyte recruitment to end organs can thus be achieved by blocking these interactions, with a specificity determined by the cellular tropism of the target cellular adhesion molecule (figure 3).…”

Bupleurum chinense polysaccharide inhibit adhesion of human melanoma cells via blocking β1 integrin function

“…Currently available inhibitors of β1 integrin are functionally blocking monoclonal antibodies, peptide antagonists and cyclic peptides which mimic matrix, and some of them have been even tested in clinical patients (Desgrosellier & Cheresh, 2010;Ley, Rivera-Nieves, Sandborn, & Shattil, 2016;Millard, Odde, & Neamati, 28 2011;Tucker, 2002). Integrin inhibitors have not only revealed impressive therapeutical efficacy in tumor growth and metastasis but also represent an alternative strategy for targeting multidrug-resistant tumors that do not responded to conventional chemotherapy (Kuphal, Bauer, & Bosserhoff, 2005;Stupp, & Ruegg, 2007).…”

Integrin β3 Inhibition Enhances the Antitumor Activity of ALK Inhibitor in ALK-Rearranged NSCLC

“…With at least 80 clinical trials on the application of integrins ongoing, these proteins have long been the focus of the biotechnology and pharmaceutical industries as potential therapeutic targets, given their central roles in almost all aspects of human biology, as well as in the pathobiology of many diseases (16). In NSCLC, integrin expression has been reported Author Manuscript Published OnlineFirst on May 18, 2018; DOI: 10.1158/1078-0432.CCR- in tumor cells and the cellular matrix, and has been found to accompany angiogenesis (17).…”