2. Academic Validation
  3. Antibody-mediated depletion of CCR10+EphA3+ cells ameliorates fibrosis in IPF

Antibody-mediated depletion of CCR10+EphA3+ cells ameliorates fibrosis in IPF

  • JCI Insight. 2021 Jun 8;6(11):e141061. doi: 10.1172/jci.insight.141061.
Miriam S Hohmann 1,  David M Habiel 1,  Milena S Espindola 1,  Guanling Huang 1,  Isabelle Jones 1,  Rohan Narayanan 1,  Ana Lucia Coelho 1,  Justin M Oldham 2,  Imre Noth 3,  Shwu-Fan Ma 3,  Adrianne Kurkciyan 1,  Jonathan L McQualter 1,  Gianni Carraro 1,  Barry Stripp 1,  Peter Chen 1,  Dianhua Jiang 1,  Paul W Noble 1,  William Parks 1,  John Woronicz 4,  Geoffrey Yarranton 4,  Lynne A Murray 5,  Cory M Hogaboam 1
Affiliations

Affiliations

  • 1 Women's Guild Lung Institute, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • 2 Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of California, Davis, Sacramento, California, USA.
  • 3 Division of Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine, University of Virginia, Charlottesville, Virginia, USA.
  • 4 KaloBios Pharmaceuticals, Inc. (now Humanigen, Inc.), Burlingame, California, USA.
  • 5 MiroBio Ltd, Oxford, United Kingdom.
PMID: 33945505 DOI: 10.1172/jci.insight.141061
Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant repair that diminishes lung function via mechanisms that remain poorly understood. CC Chemokine Receptor (CCR10) and its ligand CCL28 were both elevated in IPF compared with normal donors. CCR10 was highly expressed by various cells from IPF lungs, most notably stage-specific embryonic antigen-4-positive mesenchymal progenitor cells (MPCs). In vitro, CCL28 promoted the proliferation of CCR10+ MPCs while CRISPR/Cas9-mediated targeting of CCR10 resulted in the death of MPCs. Following the intravenous injection of various cells from IPF lungs into immunodeficient (NOD/SCID-γ, NSG) mice, human CCR10+ cells initiated and maintained fibrosis in NSG mice. Eph receptor A3 (EphA3) was among the highest expressed Receptor Tyrosine Kinases detected on IPF CCR10+ cells. Ifabotuzumab-targeted killing of EphA3+ cells significantly reduced the numbers of CCR10+ cells and ameliorated pulmonary fibrosis in humanized NSG mice. Thus, human CCR10+ cells promote pulmonary fibrosis, and EphA3 mAb-directed elimination of these cells inhibits lung fibrosis.

Keywords

Fibrosis; Pulmonology.

Figures
Products