Abstract
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.
Highlights
Inflammatory and autoimmune diseases impose an enormous socio-economic burden on Western countries [1,2,3], with ~ 50–70 million people suffering an inflammatory disease and many patients finding little relief with current therapies [3,4,5,6]
Evaluation of anti-folate receptor β (FR-β) monoclonal antibody (mAb) efficacy in a thioglycollate model of inflammatory disease As an initial test to determine whether Mouse anti-mouse FR-β specific monoclonal antibody (F3) promotes elimination of FR-β-positive macrophages in vivo, we examined the impact of F3 administration on a general model of inflammation in which thioglycollate was injected into the peritoneal cavities of mice to induce infiltration of immune cells [37, 38]
Murine model of RA exhibits similar FR-β expression to human RA Because rheumatoid arthritis (RA) was found to be the inflammatory disease characterized by the largest infiltration of FR-β-positive macrophages in humans (Fig. 1b), we examined whether the collagen-induced model of RA in mice might be characterized by infiltration of FR-β expressing macrophages
Summary
Inflammatory and autoimmune diseases impose an enormous socio-economic burden on Western countries [1,2,3], with ~ 50–70 million people suffering an inflammatory disease and many patients finding little relief with current therapies [3,4,5,6]. The design of new medicines to treat these autoimmune diseases has focused largely on suppression of cytokine signaling with the expectation that inhibition of an essential cytokine’s function will disrupt a signaling network required for maintenance of the inflammatory state. Because activated monocytes/macrophages constitute the main source of these cytokines [7], the concept that eliminating/suppressing these activated myeloid cells might allow control of disease symptoms has often been entertained [8,9,10,11,12,13]. Animal studies suggest that nonspecific suppression of phagocytes with clodronate liposomes can mitigate symptoms of autoimmune and inflammatory diseases [9,10,11], albeit with toxic side effects. No strategy for safely suppressing the activated subset of macrophages has ever been described in the literature
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