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.

Automated summary

Extensive efforts have been made to develop drugs targeting integrins, particularly the alpha v-containing integrins. Despite the lack of alpha v-integrin inhibitors on the market, research in this area continues to advance.