Multimodal Imaging Demonstrates Antifibrotic Effects of Targeting α v β 6 /α v β 1 Integrins in Biliary Fibrosis
Yingying Ning1, Iris Y Zhou, Johanna R Schaub
1Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (Y.N., I.Y.Z., N.J.R., A.B., I.A., P.C.); and Pliant Therapeutics, Inc., South San Francisco, CA (J.R.S., S.T.).
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 α v β 6 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 α v β 6 integrin-targeted positron emission tomography (PET) and collagen-specific magnetic resonance imaging (MRI) to measure target expression/engagement and liver fibrosis reduction with a α v β 6 integrin inhibitor.
Materials And Methods:
We conducted a treatment study in bile duct-ligated (BDL) rats using a small molecule inhibitor to α v β 6 /α v β 1 . 68 Ga-DOTA-R01-MG, an α v β 6 -specific PET probe, was used to noninvasively measure α v β 6 expression and target engagement in the liver. CM-101, a type I collagen MRI probe, was used to quantify fibrosis.
Results:
68 Ga-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 α v β 6 /α v β 1 inhibitor 1 hour before imaging significantly decreased liver PET uptake in BDL rats (31%, P = 0.012). Two weeks of daily dosing with an α v β 6 /α v β 1 inhibitor attenuated α v β 6 expression in BDL rat liver as assessed by α v β 6 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 ΔR 1 = 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.
