¹⁸F-FPP-RGD₂ PET Imaging for Interrogating Target Engagement and Antifibrotic Activity of an Integrin Antagonist in a Mouse Model of Metabolic Dysfunction-Associated Steatohepatitis.

Abstract

Patient outcomes in metabolic dysfunction-associated steatohepatitis (MASH) are associated with the presence and stage of liver fibrosis. Activated hepatic stellate cells are a key mediator of MASH fibrogenesis and show increased expression of integrin α_vβ₃, making it a promising target for imaging and treatment of liver fibrosis. The ability to noninvasively measure target engagement of integrin inhibitors is key to understanding their chances of success in clinical development. <b>Methods:</b> Target engagement was assessed using PET imaging of an arginine-glycine-aspartic acid (RGD)-based integrin-binding tracer ¹⁸F-FPP-RGD₂ Mice were fed a choline-deficient, ʟ-amino acid-defined, high-fat diet (CDAHFD) or control diet for 2, 6, 10, or 14 wk to induce fibrosis (<i>n</i> = 6/time point). PET was conducted on subsequent days without and with an oral dose of integrin α_vβ₃ antagonist IDL-2965 (10 mg/kg). The antifibrotic activity was evaluated in mice fed CDAHFD for 12 wk and treated with daily oral IDL-2965 (10 mg/kg) or vehicle in weeks 5-12. Integrin β₃ expression was evaluated in liver biopsies from patients with varying degrees of fibrosis. <b>Results:</b> Significantly higher liver uptake of the integrin-binding PET tracer was found in MASH mice than in age-matched controls and increased with the duration of CDAHFD up to 10 wk. At each stage of fibrotic progression, a single oral dose of IDL-2965 significantly reduced hepatic ¹⁸F-FPP-RGD₂ uptake, consistent with strong IDL-2965 target engagement. In a separate study, therapeutic administration of IDL-2965 significantly reduced multiple measures of CDAHFD-induced liver fibrosis, including histologic fibrosis scores, Sirius Red-stained area, hydroxyproline content, Col1α1 messenger RNA expression, and plasma cytokeratin-18. In human liver biopsies, integrin β₃ expression increased with increasing fibrosis score. <b>Conclusion:</b> Increased expression of integrin α_vβ₃ and strong target engagement by IDL-2965 in the CDAHFD-induced MASH model can be detected in vivo using the integrin-binding PET tracer ¹⁸F-FPP-RGD₂ Consistent with strong target engagement, therapeutic administration of IDL-2965 significantly reduced multiple measures of CDAHFD-induced hepatic fibrosis.