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

Yingwen Hu, Bingbing Wang, Jiayin Shen, Stewart A. Low, Karson S. Putt, Hans W.M. Niessen, Eric Lawrence Matteson, Linda Murphy, Clemens Ruppert, Gerrit Jansen, Stephen J. Oliver, Yang Feng, Dimiter S. Dimitrov, Cheryl Nickerson-Nutter, Philip S. Low

Research output: Contribution to journalArticle

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Abstract

Objectives: Most 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. Methods: First, 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. Results: Human 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. Conclusions: These 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.

Original languageEnglish (US)
Article number143
JournalArthritis Research and Therapy
Volume21
Issue number1
DOIs
StatePublished - Jun 7 2019

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Folate Receptor 2
Rheumatoid Arthritis
Macrophages
Antibodies
Monoclonal Antibodies
Peritonitis
Autoimmune Diseases
Animal Models
Antibody-Dependent Cell Cytotoxicity
Idiopathic Pulmonary Fibrosis
Interleukin-17
Interstitial Lung Diseases
Granulocyte-Macrophage Colony-Stimulating Factor
Interleukin-1
Ulcerative Colitis
Psoriasis
Crohn Disease
Systemic Lupus Erythematosus
Dendritic Cells
Chronic Obstructive Pulmonary Disease

Keywords

  • Activated macrophages
  • Autoimmune disease
  • Folate receptor beta
  • Inflammatory disease
  • Rheumatoid arthritis

ASJC Scopus subject areas

  • Rheumatology
  • Immunology and Allergy
  • Immunology

Cite this

Depletion of activated macrophages with a folate receptor-beta-specific antibody improves symptoms in mouse models of rheumatoid arthritis. / Hu, Yingwen; Wang, Bingbing; Shen, Jiayin; Low, Stewart A.; Putt, Karson S.; Niessen, Hans W.M.; Matteson, Eric Lawrence; Murphy, Linda; Ruppert, Clemens; Jansen, Gerrit; Oliver, Stephen J.; Feng, Yang; Dimitrov, Dimiter S.; Nickerson-Nutter, Cheryl; Low, Philip S.

In: Arthritis Research and Therapy, Vol. 21, No. 1, 143, 07.06.2019.

Research output: Contribution to journalArticle

Hu, Y, Wang, B, Shen, J, Low, SA, Putt, KS, Niessen, HWM, Matteson, EL, Murphy, L, Ruppert, C, Jansen, G, Oliver, SJ, Feng, Y, Dimitrov, DS, Nickerson-Nutter, C & Low, PS 2019, 'Depletion of activated macrophages with a folate receptor-beta-specific antibody improves symptoms in mouse models of rheumatoid arthritis', Arthritis Research and Therapy, vol. 21, no. 1, 143. https://doi.org/10.1186/s13075-019-1912-0
Hu, Yingwen ; Wang, Bingbing ; Shen, Jiayin ; Low, Stewart A. ; Putt, Karson S. ; Niessen, Hans W.M. ; Matteson, Eric Lawrence ; Murphy, Linda ; Ruppert, Clemens ; Jansen, Gerrit ; Oliver, Stephen J. ; Feng, Yang ; Dimitrov, Dimiter S. ; Nickerson-Nutter, Cheryl ; Low, Philip S. / Depletion of activated macrophages with a folate receptor-beta-specific antibody improves symptoms in mouse models of rheumatoid arthritis. In: Arthritis Research and Therapy. 2019 ; Vol. 21, No. 1.
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abstract = "Objectives: Most 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. Methods: First, 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. Results: Human 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. Conclusions: These 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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AU - Hu, Yingwen

AU - Wang, Bingbing

AU - Shen, Jiayin

AU - Low, Stewart A.

AU - Putt, Karson S.

AU - Niessen, Hans W.M.

AU - Matteson, Eric Lawrence

AU - Murphy, Linda

AU - Ruppert, Clemens

AU - Jansen, Gerrit

AU - Oliver, Stephen J.

AU - Feng, Yang

AU - Dimitrov, Dimiter S.

AU - Nickerson-Nutter, Cheryl

AU - Low, Philip S.

PY - 2019/6/7

Y1 - 2019/6/7

N2 - Objectives: Most 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. Methods: First, 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. Results: Human 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. Conclusions: These 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.

AB - Objectives: Most 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. Methods: First, 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. Results: Human 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. Conclusions: These 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.

KW - Activated macrophages

KW - Autoimmune disease

KW - Folate receptor beta

KW - Inflammatory disease

KW - Rheumatoid arthritis

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