Multimodal Imaging Demonstrates Antifibrotic Effects of Targeting αvβ6/αvβ1 Integrins in Biliary Fibrosis.

Objectives: Development of molecular therapies for liver fibrosis is slowed by a lack of noninvasive methods addressing questions of target expression, target engagement, and treatment response. Integrin αvβ6 is a biomarker of liver fibrosis that is upregulated in livers of patients with primary sclerosing cholangitis. It activates latent TGF-β and plays a critical role in regulating extracellular matrix expression, especially collagen. In this study, our aim was to use combined αvβ6 integrin-targeted positron emission tomography (PET) and collagen-specific magnetic resonance imaging (MRI) to measure target expression/engagement and liver fibrosis reduction with a αvβ6 integrin inhibitor.

Materials and methods: We conducted a treatment study in bile duct-ligated (BDL) rats using a small molecule inhibitor to αvβ6/αvβ1. 68Ga-DOTA-R01-MG, an αvβ6-specific PET probe, was used to noninvasively measure αvβ6 expression and target engagement in the liver. CM-101, a type I collagen MRI probe, was used to quantify fibrosis.

Results: 68Ga-DOTA-R01-MG PET showed 3-fold higher liver uptake in BDL rats compared with sham rats at 17 days after surgery. Pretreatment with high dose αvβ6/αvβ1 inhibitor 1 hour before imaging significantly decreased liver PET uptake in BDL rats (31%, P = 0.012). Two weeks of daily dosing with an αvβ6/αvβ1 inhibitor attenuated αvβ6 expression in BDL rat liver as assessed by αvβ6 PET (0.27 ± 0.07 percent injected dose [%ID]/mL compared with 0.40 ± 0.09 %ID/mL in vehicle-treated group, P = 0.014) and reduced liver fibrosis as assessed by collagen MRI (liver relaxation rate change ΔR1 = 0.14 ± 0.11 vs 0.36 ± 0.06, P = 0.0037). Imaging findings were confirmed by histology (collagen proportionate area 10.7 ± 2.8% vs 22.5 ± 6.1%, P < 0.001).

Conclusions: A single imaging protocol combining molecular MRI and PET can be used to effectively monitor integrin inhibitor treatment by measuring target expression/engagement and treatment outcomes. Multimodality molecular imaging may be valuable in accelerating drug development in molecular therapies for liver fibrosis.