Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic lung disease that is prevalent in individuals >50 years of age, with a median survival of 3–5 years and limited therapeutic options. The disease is characterized by collagen deposition and remodeling of the lung parenchyma in a process that is thought to be driven by collagen-expressing immune and structural cells. The G-protein coupled C-X-C chemokine receptor 4, CXCR4, is a candidate therapeutic target for IPF owing to its role in the recruitment of CXCR4+ fibrocytes from the bone marrow to fibrotic lung tissue and its increased expression levels by structural cells in fibrotic lung tissue. We have engineered a novel fully human single domain antibody “i-body” called AD-114 that binds with high affinity to human CXCR4. We demonstrate here that AD-114 inhibits invasive wound healing and collagen 1 secretion by human IPF fibroblasts but not non-diseased control lung fibroblasts. Furthermore, in a murine bleomycin model of pulmonary fibrosis, AD-114 reduced the accumulation of fibrocytes (CXCR4+/Col1+/CD45+) in fibrotic murine lungs and ameliorated the degree of lung injury. Collectively, these studies demonstrate that AD-114 holds promise as a new biological therapeutic for the treatment of IPF.
Highlights
IntroductionVarious studies have shown that inhibition of CXCR4 results in anti-fibrotic effects in vitro and ameliorated bleomycin induced lung fibrosis in vivo[22,23,24,25,26], suggesting that this chemokine receptor might be a therapeutic target in fibrotic lung diseases
AD-114-6H produced in P. pastoris had a lower affinity for human CXCR4, it still bound with a KD of 35 nM (Fig. 1A)
Mechanisms contributing to the progression of fibrosis in Idiopathic pulmonary fibrosis (IPF) remain elusive, various reports suggest that fibroblast invasion might play a major role in the spread of this disease[12,13]
Summary
Various studies have shown that inhibition of CXCR4 results in anti-fibrotic effects in vitro and ameliorated bleomycin induced lung fibrosis in vivo[22,23,24,25,26], suggesting that this chemokine receptor might be a therapeutic target in fibrotic lung diseases. In murine models of bleomycin-mediated lung injury and fibrosis[30,31,32], AD-114 treatment, especially by applying a half-life extended format[33], ameliorated lung remodeling as determined by histological, biochemical and transcriptomic quantification of collagen expression and deposition. Anti-fibrotic effects of AD-114 in the murine bleomycin model appear to be due to reduction of collagen transcript and protein expression and reduced migration of CXCR4+Col+CD45+ fibrocytes to the injured lung. Our results suggest that utilizing CXCR4 specific i-body AD-114 in IPF patients might reduce disease progression and prove beneficial in treating this disease
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