Anti-fibrotic Effects of CXCR4-Targeting i-body AD-114 in Preclinical Models of Pulmonary Fibrosis

K. Griffiths, D. M. Habiel, J. Jaffar, U. Binder, W. G. Darby, C. G. Hosking, A. Skerra, G. P. Westall, C. M. Hogaboam, M. Foley

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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.

Original languageEnglish
Article number3212
Number of pages15
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - 1 Dec 2018

Cite this

Griffiths, K., Habiel, D. M., Jaffar, J., Binder, U., Darby, W. G., Hosking, C. G., ... Foley, M. (2018). Anti-fibrotic Effects of CXCR4-Targeting i-body AD-114 in Preclinical Models of Pulmonary Fibrosis. Scientific Reports, 8(1), [3212]. https://doi.org/10.1038/s41598-018-20811-5
Griffiths, K. ; Habiel, D. M. ; Jaffar, J. ; Binder, U. ; Darby, W. G. ; Hosking, C. G. ; Skerra, A. ; Westall, G. P. ; Hogaboam, C. M. ; Foley, M. / Anti-fibrotic Effects of CXCR4-Targeting i-body AD-114 in Preclinical Models of Pulmonary Fibrosis. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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Griffiths, K, Habiel, DM, Jaffar, J, Binder, U, Darby, WG, Hosking, CG, Skerra, A, Westall, GP, Hogaboam, CM & Foley, M 2018, 'Anti-fibrotic Effects of CXCR4-Targeting i-body AD-114 in Preclinical Models of Pulmonary Fibrosis', Scientific Reports, vol. 8, no. 1, 3212. https://doi.org/10.1038/s41598-018-20811-5

Anti-fibrotic Effects of CXCR4-Targeting i-body AD-114 in Preclinical Models of Pulmonary Fibrosis. / Griffiths, K.; Habiel, D. M.; Jaffar, J.; Binder, U.; Darby, W. G.; Hosking, C. G.; Skerra, A.; Westall, G. P.; Hogaboam, C. M.; Foley, M.

In: Scientific Reports, Vol. 8, No. 1, 3212, 01.12.2018.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Griffiths, K.

AU - Habiel, D. M.

AU - Jaffar, J.

AU - Binder, U.

AU - Darby, W. G.

AU - Hosking, C. G.

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AU - Hogaboam, C. M.

AU - Foley, M.

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AB - 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.

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