Abstract
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 αv-containing integrins, in the 24 family members, have been a central target of fibrosis. Currently, a small molecule against αvβ1 is undergoing a clinical trial for NASH-associated fibrosis as a rare agent aiming at fibrogenesis. Latent TGFβ activation, a distinct talent of αv-integrins, has been intriguing as a therapeutic target. None of the αv-integrin inhibitors, however, has been in the clinical market. αv-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 αv-integrins. In fact, an almighty inhibitor for αv-integrins, pan-αv, 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: αIIbβ3 on platelets, α4β1, α4β7 and αLβ2 on leukocytes. Herein, “disease specific” integrins would serve as attractive targets. α8β1 and α11β1 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 α8β1 and α11β1 in preclinical examinations may illuminate the road to the first medical agents.
Highlights
Liver fibrosis is an intractable disease with high morbidity by advancing into liver cirrhosis that often causes organ failure, where the parenchymal cells are replaced with collagen species and other matrix proteins
Acta2, Col1A1 and extra domain-A of fibronectin (EDA), we found Acta2 was reduced by the anti-α8 monoclonal antibody (mAb)
Because results from preclinical consequences in clinical trials at all, one might doubt whether the gold standard for the studies do not assure the consequences in clinical trials at all, one might doubt whether severity holds good as the endpoint for drug efficacy in human fibrosis
Summary
Liver fibrosis is an intractable disease with high morbidity by advancing into liver cirrhosis that often causes organ failure, where the parenchymal cells are replaced with collagen species and other matrix proteins. Most drugs in clinical trials target the early steps of steatosis/hepatitis and few target fibrogenesis, itself, especially after simtuzumab (anti-LOXL2) [4] and seronsertive (ASK-1 inhibitor) [5] failed in phase II and III, respectively. In this situation, integrin inhibitors have an emerging therapeutic opportunity in fibrosis [6]. Integrins are receptors for matrix proteins that essentially consist of fibrosis tissues, and some integrins activate latent-TGFβ a central driver of fibrosis [7]. We revisit the developmental history of αv-inhibitors, and present evidence that two other integrins α8β1 [11] and α11β1 [12], which exhibit pathology-specific expression in fibrosis, merit consideration as targets for anti-fibrotic therapy
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