New Therapeutic Targets for Hepatic Fibrosis in the Integrin Family, α8β1 and α11β1, Induced Specifically on Activated Stellate Cells

A huge effort has been devoted to developing drugs targeting integrins over 30 years, because of the primary roles of integrins in the cell-matrix milieu. Five alpha v-containing integrins, in the 24 family members, have been a central target of fibrosis. Currently, a small molecule against alpha v beta 1 is undergoing a clinical trial for NASH-associated fibrosis as a rare agent aiming at fibrogenesis. Latent TGF beta activation, a distinct talent of alpha v-integrins, has been intriguing as a therapeutic target. None of the alpha v-integrin inhibitors, however, has been in the clinical market. alpha v-integrins commonly recognize an Arg-Gly-Asp (RGD) sequence, and thus the pharmacophore of inhibitors for the 5-integrins is based on the same RGD structure. The RGD preference of the integrins, at the same time, dilutes ligand specificity, as the 5-integrins share ligands containing RGD sequence such as fibronectin. With the inherent little specificity in both drugs and targets, "disease specificity " has become less important for the inhibitors than blocking as many alpha v-integrins. In fact, an almighty inhibitor for alpha v-integrins, pan-alpha v, was in a clinical trial. On the contrary, approved integrin inhibitors are all specific to target integrins, which are expressed in a cell-type specific manner: alpha IIb beta 3 on platelets, alpha 4 beta 1, alpha 4 beta 7 and alpha L beta 2 on leukocytes. Herein, "disease specific " integrins would serve as attractive targets. alpha 8 beta 1 and alpha 11 beta 1 are selectively expressed in hepatic stellate cells (HSCs) and distinctively induced upon culture activation. The exceptional specificity to activated HSCs reflects a rather "pathology specific " nature of these new integrins. The monoclonal antibodies against alpha 8 beta 1 and alpha 11 beta 1 in preclinical examinations may illuminate the road to the first medical agents.