Project Summary/Abstract Idiopathic Pulmonary Fibrosis (IPF) is a devastatingly progressive disease with median survival of 2-4 years post diagnosis. Three decades of research and over 20 clinical trials have resulted in only two approved treatments for IPF: pirfenidone and nintedanib. While both drugs slow disease progression, there are differences in treatment response for individual IPF patients and neither drug is curative suggesting that IPF may arise from different pathologic pathways resulting in disease heterogeneity. Drug development in IPF is hampered by poor patient phenotyping and a lack of tools to assess disease activity and early treatment response. As a result, clinical trials require large numbers of subjects to observe real efficacy signals. Multimodal molecular imaging offers to accelerate drug development and ultimately change IPF management. Molecular imaging of specific targets can stratify subjects, assess drug-target engagement and guide dose optimization for a new drug designed to bind to that target. Molecular imaging also can assess disease activity and monitor response to therapy. A comprehensive multimodal molecular imaging protocol would thus improve the probability for clinical trial success with smaller patient numbers in a shorter period of time. We propose to use multimodal imaging of αvβ3 integrin and oxidized collagen in mouse models of lung fibrosis to evaluate αvβ3 antagonism as a route to pathway-specific intervention. αvβ3 is implicated as a regulator of IPF development with αvβ3 expression elevated in preclinical models and in the lungs of IPF patients. Treatment with αvβ3 antagonists leads to reduction of lung fibrosis and enhanced survival in preclinical models of pulmonary fibrosis and several antagonists are entering clinical trials for IPF. The positron emission tomography (PET) probe 18F-FPP-RGD2 was used to image αvβ3 in (pre-)clinical studies of cancer. To assess disease activity, we’ve developed the allysine-binding magnetic resonance (MR) probe Gd-CHyd which reports on the oxidized collagen formed during fibrogenesis. We showed that imaging oxidized collagen predicts disease activity and treatment response. Because oxidized collagen is fundamental to fibrogenesis, Gd-CHyd can quantify pulmonary disease activity independent of cause and can be used generally to measure response to treatment. We will develop and optimize a multimodal 18F-FPP-RGD2 PET and Gd-CHyd MR imaging protocol in mouse models of pulmonary fibrosis, then use this to noninvasively quantify αvβ3 expression and fibrogenesis through the course of disease progression with validation by ex vivo measurements. We will then apply the protocol to confirm target engagement of an αvβ3 antagonist, determine optimal therapeutic dose, and use Gd-CHyd MR to measure therapeutic response. We hypothesize that molecular imaging will allow pre- clinical assessment of target relevance while simultaneously assessing disease activity and response to target inhibition, all of which will accelerate successful drug development for IPF.

Project Narrative Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease with highly variable clinical course and limited treatment options. This proposal aims to develop and validate a multimodal, noninvasive imaging protocol to investigate a pathway-specific route for IPF therapy. The outcomes of this work have the potential to accelerate development of IPF interventions.