Chest Imaging with a Collagen-Binding Probe—A Human Hydroxyproline Assay?

Idiopathic pulmonary fibrosis (IPF), as suggested by its name, has an incompletely understood pathophysiology that makes developing novel therapies challenging (1). The mechanisms that give rise to IPF involve lung injury and aging with aberrant healing; sustained release of proinflammatory and profibrotic factors; and, ultimately, collagen deposition in previously healthy lung tissue (2). Although transforming growth factor β (TGF-β) is central to the pathogenesis of pulmonary fibrosis, it is also an essential cytokine with roles in immune regulation and tissue homeostasis, so direct inhibition poses the risk of serious adverse effects (3). Therefore, the search for therapeutic targets has shifted to tissue-specific or selective inhibitors of TGF-β by means of the integrins, which bind the latency-associated peptide and can liberate and activate latent TGF-β (3–5).

In this issue of the Journal, Montesi and colleagues (pp. 1229–1240) present the results of a Phase-2 placebo-controlled trial of a novel drug, bexotegrast, for IPF (6). Bexotegrast is an oral, once-daily inhibitor of the αvβ6 and αvβ1 integrins, which showed promise in reducing fibrosis in a study of lung tissue explants from patients with IPF and had a favorable side effect profile in the INTEGRIS-IPF trial (5, 7). The trial described in the article published in this issue was small—only 10 patients were enrolled at a single center—but with a primary endpoint focused on quantifying collagen deposition in the lungs by measuring the change in lung uptake of a collagen-binding probe, ⁶⁸Ga-CBP8, on positron emission tomography (PET) (8, 9). The other endpoints evaluated included changes in lung dynamic contrast-enhanced magnetic resonance imaging, forced vital capacity (FVC), cough severity, and biomarkers of collagen synthesis. Although the very small size of the treatment and placebo groups (7 and 3 patients, respectively) precluded any statistical inferences, the patients who received bexotegrast had a mean decrease in ⁶⁸Ga-CBP8 detection by PET of −1.2% over 12 weeks, compared with 6.6% for the patients who received placebo. The other outcomes, including change in FVC, also appeared to improve in the treatment group. Enthusiasm for these preliminary results are tempered by Pliant Therapeutics’s announcement that the Phase-2b/3 BEACON-IPF clinical trial was halted because of an imbalance in IPF-related adverse events in the bexotegrast and placebo groups (10). We will have to await the results from the company’s final analysis of the complete data before we know the future of bexotegrast and other TGF-β inhibitors in clinical trials of patients with pulmonary fibrosis.

The small but positive changes in FVC for the subjects treated with bexotegrast are the rationale for the more novel aspect of the study by Montesi and colleagues: Can imaging techniques be used to quantify and localize collagen in the lungs? In the current therapeutic landscape in which the medications available to treat IPF each have significant side effects, there has been a recent call for clinical trials to focus their endpoints on how patients “feel, function, and survive” (11, 12). However, these patient-centered outcomes—symptoms, functional limitation, and mortality—typically reflect the end results of pulmonary fibrosis, so emerging techniques that quantify collagen deposition are enticing, as they give a sense that we are nipping the underlying pathology in the proverbial bud. Or to basic fibrosis researchers, could this be the human equivalent of the hydroxyproline assay? The hydroxyproline assay, which quantifies hydroxyproline—the specially modified and essential amino acid in collagen—has been used widely by fibrosis researchers worldwide, including the team that established the essential role of TGF-β in pulmonary fibrosis (13). If ⁶⁸Ga-CBP8 PET imaging represents the human hydroxyproline assay, this technique could have far-reaching implications for how we monitor the progression of fibrosis both in humans and in experimental animals. These and other questions remain about whether changes in ⁶⁸Ga-CBP8 intensity on PET truly reflect areas of improving or worsening pulmonary fibrosis and, if they do, what degree of change is clinically relevant. How does this test perform in non-IPF interstitial lung disease? How sensitive is the test to longitudinal changes in fibrosis? The changes in FVC observed by the team could support the idea that ⁶⁸Ga-CBP8 detection by PET can monitor fibrosis. Currently, ⁶⁸Ga-CBP8 detection by PET has been shown to correlate with the degree of pulmonary fibrosis and collagen deposition seen on histopathology both in a mouse model of pulmonary fibrosis and in lung explants from patients with IPF (8). Furthermore, Montesi and colleagues previously compared ⁶⁸Ga-CBP8 PET between patients with IPF and healthy volunteers and showed that patients with IPF had more intense ⁶⁸Ga-CBP8 signals and that the regions of greatest intensity were distributed along the areas of lung with the most IPF-related changes on chest computed tomography (14). Although further work is needed to demonstrate the clinical relevance of ⁶⁸Ga-CBP8 PET imaging, its potential for evaluating fibrotic disease activity, progression, and response to therapy for both research and clinical purposes is appealing.

We congratulate the authors on their innovative study. The imaging techniques used in this study may allow us to detect subclinical changes in pulmonary fibrosis before they become symptomatically or functionally apparent. We look forward to future work that establishes and validates the clinical relevance of changes in ⁶⁸Ga-CBP8 PET with great anticipation.