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Depletion of activated macrophages with a folate receptor-beta-specific antibody improves symptoms in mouse models of rheumatoid arthritis

  • Hu, Yingwen1
  • Wang, Bingbing1
  • Shen, Jiayin1
  • Low, Stewart A.1
  • Putt, Karson S.2
  • Niessen, Hans W. M.3
  • Matteson, Eric L.4
  • Murphy, Linda5
  • Ruppert, Clemens6
  • Jansen, Gerrit7
  • Oliver, Stephen J.8
  • Feng, Yang9
  • Dimitrov, Dimiter S.10
  • Nickerson-Nutter, Cheryl11
  • Low, Philip S.1, 2
  • 1 Purdue University, Department of Chemistry, 560 Oval Drive, West Lafayette, IN, 47907, USA , West Lafayette (United States)
  • 2 Purdue University, Institute for Drug Discovery, West Lafayette, IN, 47907, USA , West Lafayette (United States)
  • 3 Amsterdam UMC, Department of Pathology and Cardiac Surgery, ACS, location VUMC, Amsterdam, The Netherlands , Amsterdam (Netherlands)
  • 4 Mayo Clinic, Division of Rheumatology, and Department of Health Sciences Research, Rochester, MN, USA , Rochester (United States)
  • 5 Mayo Clinic College of Medicine, Department of Biochemistry and Molecular Biology, Rochester, MN, USA , Rochester (United States)
  • 6 Biomedizinisches Forschungszentrum Seltersberg, Justus-Liebig University Giessen, Department of Internal Medicine, Giessen, Germany , Giessen (Germany)
  • 7 VU University Medical Center, Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, Amsterdam, The Netherlands , Amsterdam (Netherlands)
  • 8 New York University School of Medicine, Department of Medicine, New York, NY, USA , New York (United States)
  • 9 National Institutes of Health, Protein Interactions Section, Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer, National Cancer Institute-Frederick, Frederick, MD, 21702, USA , Frederick (United States)
  • 10 University of Pittsburgh, Center for Antibody Therapeutics, Pittsburgh, PA, 15216, USA , Pittsburgh (United States)
  • 11 HuLow Medical, Northbrook, IL, USA , Northbrook (United States)
Published Article
Arthritis Research & Therapy
Springer Science and Business Media LLC
Publication Date
Jun 07, 2019
DOI: 10.1186/s13075-019-1912-0
Springer Nature


ObjectivesMost therapies for autoimmune and inflammatory diseases either neutralize or suppress production of inflammatory cytokines produced by activated macrophages (e.g., TNFα, IL-1, IL-6, IL-17, GM-CSF). However, no approved therapies directly target this activated subset of macrophages.MethodsFirst, we undertook to examine whether the folate receptor beta (FR-β) positive subpopulation of macrophages, which marks the inflammatory subset in animal models of rheumatoid arthritis, might constitute the prominent population of macrophages in inflamed lesions in humans. Next, we utilized anti-FR-β monoclonal antibodies capable of mediating antibody-dependent cell cytotoxicity (ADCC) to treat animal models of rheumatoid arthritis and peritonitis.ResultsHuman tissue samples of rheumatoid arthritis, Crohn’s disease, ulcerative colitis, idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, chronic obstructive pulmonary disease, systemic lupus erythematosus, psoriasis, and scleroderma are all characterized by dramatic accumulation of macrophages that express FR-β, a protein not expressed on resting macrophages or any other healthy tissues. A monoclonal antibody to FR-β accumulates specifically in inflamed lesions of murine inflammatory disease models and successfully treats such models of rheumatoid arthritis and peritonitis. More importantly, elimination of FR-β-positive macrophages upon treatment with an anti-FR-β monoclonal antibody promotes the departure of other immune cells, including T cells, B cells, neutrophils, and dendritic cells from the inflamed lesions.ConclusionsThese data suggest that specific elimination of FR-β-expressing macrophages may constitute a highly specific therapy for multiple autoimmune and inflammatory diseases and that a recently developed human anti-human FR-β monoclonal antibody (m909) might contribute to suppression of this subpopulation of macrophages.

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