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

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.

Figure 1

Integrin families. Integrins targeted for therapy circled in red; dotted red circle indicates past therapeutic use (for αLβ2) or unknown effects (antibodies to β7 integrins also target αEβ7, but α4β7 is believed to be the effective target). RGD-binding integrins circled in blue, I-domain containing integrin α subunits circled in green.

Figure 2

Inside-out activation of αIIbβ3 platelet integrin. Drawing of the bent (left), extended (middle) and extended-open (right) conformation of αIIbβ3. αIIb in blue, β3 in red. Ligand binding site indicated by black triangle in extended-open integrin. Note the movement of the transmembrane and cytoplasmic domains with integrin activation. Binding of cytoplasmic adaptor molecules (not shown here) are thought to drive the conformational changes in the ectodomains. Ligand binding affinity, conformation and outside-in signaling noted below each conformation.

Figure 3

The three integrins α4β1, α4β7 and αEβ7 targeted by therapeutic α4 and β7 antibodies. α4 (blue) and thus α4β1 and α4β7 are targeted by natalizumab. β7 (purple) and thus α4β7 and αEβ7 are targeted by etrolizumab. Vedalizumab and AMG-181 recognize an epitope formed by both α4 and β7 and thus is monospecific. The αE subunit (orange) contains an I domain (I). Main ligands for each integrin noted above. PML: progressive multifocal leukoencephalopathy.