WO2007094776A1 - Compositions et procédés de suppression de la différenciation des fibrocytes - Google Patents

Compositions et procédés de suppression de la différenciation des fibrocytes Download PDF

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WO2007094776A1
WO2007094776A1 PCT/US2006/005229 US2006005229W WO2007094776A1 WO 2007094776 A1 WO2007094776 A1 WO 2007094776A1 US 2006005229 W US2006005229 W US 2006005229W WO 2007094776 A1 WO2007094776 A1 WO 2007094776A1
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antibody
fcγr
composition
igg
antibodies
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PCT/US2006/005229
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English (en)
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Richard Gomer
Darrell Pilling
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William Marsh Rice University
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Priority to PCT/US2006/005229 priority Critical patent/WO2007094776A1/fr
Priority to US11/535,649 priority patent/US8012472B2/en
Publication of WO2007094776A1 publication Critical patent/WO2007094776A1/fr
Priority to US13/224,959 priority patent/US8187599B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/283—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against Fc-receptors, e.g. CD16, CD32, CD64
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • the present invention relates to the ability of anti-Fc ⁇ R antibodies and cross-linked IgG to suppress differentiation of fibrocytes. Accordingly, it may include compositions and methods for suppressing such differentiation. These compositions and methods may be useful in a variety of applications in which decreased fibrocyte formation is beneficial, such as treatment of fibrosing diseases and asthma. BACKGROUND Fibrocytes
  • Inflammation is the coordinated response to tissue injury or infection.
  • the initiating events are mediated by local release of chemotactic factors, platelet activation, and initiations of the coagulation and complement pathways. These events stimulate the local endothelium, promoting the extravasation of neutrophils and monocytes.
  • the second phase of inflammation is characterized by the influx into the tissue of cells of the adaptive immune system, including lymphocytes.
  • the subsequent resolution phase when apoptosis of the excess leukocytes and engulfment by tissue macrophages takes place, is also characterized by repair of tissue damage by stromal cells, such as fibroblasts.
  • fibroblasts responsible for repair of wound lesions or in other fibrotic responses are controversial.
  • the conventional hypothesis suggests that local quiescent fibroblasts migrate into the affected area, produce extracellular matrix proteins, and promote wound contraction or fibrosis.
  • An alternative hypothesis is that circulating fibroblast precursors (called fibrocytes) present within the blood migrate to the sites of injury or fibrosis, where they differentiate and mediate tissue repair and other fibrotic responses .
  • Fibrocytes are fibroblast-like cells that appear to participate in wound healing and are present in pathological lesions associated with asthma, pulmonary fibrosis and scleroderma. Fibrocytes are known to differentiate from a CD14+ peripheral blood monocyte precursor population. Fibrocytes may also differentiate from other sources. Fibrocytes express markers of both hematopoietic cells (CD45, MHC class II, CD34) and stromal cells (collagen types I and III and fibronectin) . Fibrocytes at sites of tissue injury secrete inflammatory cytokines, extracellular matrix proteins and promote angiogenesis and wound contraction.
  • Fibrocytes are also associated with the formation of fibrotic lesions after infection or inflammation, and are implicated in fibrosis associated with autoimmune diseases. Fibrocytes are associated with a variety of processes and diseases including scleroderma, keloid scarring, rheumatoid arthritis, lupus, nephrogenic fibrosing dermopathy, and idiopathic pulmonary fibrosis. They play a role in the formation of fibrotic lesions after Schistosoma japonicum infection in mice and are also implicated in fibrosis associated . with autoimmune diseases. Fibrocytes have also been implicated in pathogenic fibrosis associated with radiation damage, Lyme disease and pulmonary fibrosis.
  • CD34+ fibrocytes have also been associated with stromal remodeling in pancreatitis and stromal fibrosis, whereas lack of such fibrocytes is associated with pancreatic tumors and adenocarcinomas.
  • Fibrosis additionally occurs in asthma patients and possibly other pulmonary diseases such as chronic obstructive pulmonary disease when fibrocytes undergo further differentiation into myofibroblasts.
  • Fibrocytes may also play a role in a variety of conditions, likely even some in which fibrocyte formation is not currently known. Some additional conditions may include congestive heart failure and other post-ischemic conditions, such as cardiac fibrosis, post-surgical scarring including abdominal adhesions, corneal refraction surgery, and wide angle glaucoma trabeculotomy.
  • Fibrocytes are important in the formation of tumors, particularly stromal tissue in tumors. Recent evidence also suggests that fibrocytes may further differentiate into adipocytes and thus play a role in obesity.
  • SAP serum amyloid P
  • FCYR Fc portion of IgG antibodies
  • Anti-Fc ⁇ R antibodies are IgG antibodies that bind to receptors for the Fc portion of IgG antibodies (Fc ⁇ R) .
  • the anti-Fc ⁇ R antibodies bind through their variable region, and not through their constant (Fc) region.
  • IgG from the appropriate source e.g. human IgG for human receptors
  • Fc ⁇ R are found on the surface of a variety of hematopoietic cells.
  • Fc ⁇ RI CD64
  • CD64 is expressed by peripheral blood monocytes and binds monomeric IgG with a high affinity.
  • Fc ⁇ RII CD32
  • Fc ⁇ RIII CD16
  • Fc ⁇ RII is expressed by peripheral blood B cells and monocytes
  • Fc ⁇ RIII is expressed by NK cells and a subpopulation of monocytes.
  • Fc ⁇ RIV was recently identified in mice and is present on murine peripheral blood monocytes and neutrophils, macrophages and dendritic cells and efficiently binds murine IgG2a and IgG2b antibodies.
  • There is a putative human Fc ⁇ RIV gene but the biological function of the protein, such as ligand specificity and cellular expression is, as yet unknown.
  • Peripheral blood monocytes express both Fc ⁇ RI and Fc ⁇ RII (a subpopulation of monocytes express Fc ⁇ RIII) , whereas tissue macrophages express all three classical Fc ⁇ R.
  • Fc ⁇ R activation and induction of intracellular signaling pathways may occur when multiple Fc ⁇ R are cross-linked or aggregated.
  • This Fc ⁇ R activation leads to a cascade of signaling events initiated by two main kinases.
  • the initial events following Fc ⁇ R activation involve the phosphorylation of intracellular immunoreceptor tyrosine activation motifs (ITAMs) present on the cytoplasmic tail of Fc ⁇ RII or the FcR- ⁇ chain associated with Fc ⁇ RI and Fc ⁇ RIII, by Src-related tyrosine kinases (SRTK) .
  • ITAMs immunoreceptor tyrosine activation motifs
  • SRTK Src-related tyrosine kinases
  • monocytes the main Src- kinases associated with Fc ⁇ RI and Fc ⁇ RII are hck and lyn.
  • the phosphorylated ITAM then recruit cytoplasmic SH2 -containing kinases, especially Sy
  • Anti-Fc ⁇ R antibodies for Fc ⁇ RI (anti-Fc ⁇ RI) and for Fc ⁇ RII (anti-Fc ⁇ RII) are able to bind to either
  • Fc ⁇ RI or Fc ⁇ RII may then be cross-linked by the binding of additional antibodies or other means. This process initiates intracellular signaling events consistent with Fc ⁇ R activation.
  • Scleroderma is a non-inherited, noninfectious disease that has a range of symptoms. It involves the formation of scar tissue containing fibroblasts in the skin and internal organs . The origin of the fibroblasts is unknown. In mild or early cases of scleroderma, there is a hardening of the skin, fatigue, aches and sensitivity to cold. In more severe and later stages, there is high blood pressure, skin ulcers, difficulty moving joints, and death from lung scarring or kidney failure. Approximately 300,000 people in the U.S. have scleroderma. The disease has similarities to lupus and rheumatoid arthritis. There is no cure or significant treatment for scleroderma and even diagnosis is difficult because there is no clinical test.
  • NFD Nephrogenic fibrosing dermopathy
  • Asthma affects more than 100 million people worldwide, and its prevalence is increasing. Asthma appears to be caused by chronic airway inflammation.
  • One of the most destructive aspects of asthma is ' remodeling of the airways in response to chronic inflammation. This remodeling involves thickening of the lamina reticularis (the subepithelial reticular basement membrane surrounding airways) due to fibrosis. The airway passages then become constricted due to the thickened airway walls.
  • the thickened lamina reticularis in asthma patients contains abnormally high levels of extracellular matrix proteins such as collagen I, collagen III, collagen V, fibronectin and tenascin.
  • extracellular matrix proteins such as collagen I, collagen III, collagen V, fibronectin and tenascin.
  • the source of these proteins appears to be a specialized type of fibroblast called myofibroblasts.
  • myofibroblasts In asthma patients, CD34+/collagen 1+ fibrocytes accumulate near the basement membrane of the bronchial mucosa within 4 hours of allergen exposure. 24 hours after allergen exposure, labeled monocytes/fibrocytes have been observed to express ⁇ -smooth muscle actin, a marker for myofibroblasts.
  • Thickening of the lamina reticularis distinguishes asthma from chronic bronchitis or chronic obstructive pulmonary disease and is found even when asthma is controlled with conventional medications. An increased extent of airway wall thickening is associated with severe asthma. No medications or treatments have been found to reduce thickening of the lamina reticularis. However, it appears likely that reducing the number of myofibroblasts found in the airway walls may reduce thickening or help prevent further thickening.
  • Idiopathic pulmonary fibrosis is a unique type of chronic fibrosing lung disease of unknown etiology.
  • the sequence of the pathogenic mechanisms is unknown, but the disease is characterized by epithelial injury and activation, the formation of distinctive subepithelial fibroblast/myofibroblast foci, and excessive extracellular matrix accumulation.
  • These pathological processes usually lead to progressive and irreversible changes in the lung architecture, resulting in progressive respiratory insufficiency and an almost universally terminal outcome in a relatively short period of time.
  • While research has largely focused on inflammatory mechanisms for initiating the fibrotic response, recent evidence strongly suggests that disruption of the alveolar epithelium is an underlying pathogenic event. Given the role played by fibrocytes in wound healing and their known role in airway wall thickening in asthma, it appears likely that overproduction of fibrocytes may be implicated in IPF.
  • the present invention may include compositions and methods for suppressing fibrocyte differentiation. It may particularly relate to suppressing fibrocyte differentiation from monocytes.
  • fibrocyte differentiation in a target location may be suppressed by providing anti-Fc ⁇ RI antibodies and/or anti-Fc ⁇ RII antibodies that are able to cross-link Fo ⁇ R.
  • the target location may be located in vitro or in vivo. Specifically, the target location may be located in a mammal, such as a human patient.
  • the target location may include an entire organism or a portion thereof and the composition may be administered systemically or it may be confined to a particular area, such as an organ or tissue.
  • a decrease in or suppression of differentiation of fibrocytes may alleviate symptoms of numerous fibrosing diseases or other disorders caused by fibrosis.
  • administration of anti-Fc ⁇ R antibodies may be used to treat the effects of unwanted differentiation of fibrocytes. For example, it may be used to treat fibrosis in the kidney, liver, lung, heart, eye, uterus, tumors, and wounds.
  • FIGURE 1 shows the effects of cross-linked and non-cross-linked anti-Fc ⁇ R antibodies on fibrocyte differentiation from Peripheral Blood Mononuclear Cells (PBMC) .
  • PBMC Peripheral Blood Mononuclear Cells
  • FIGURE 1 shows the effects of cross-linked and non-cross-linked anti-Fc ⁇ R antibodies on fibrocyte differentiation from Peripheral Blood Mononuclear Cells (PBMC) .
  • PBMC Peripheral Blood Mononuclear Cells
  • FIGURE 2 shows the effects of SRTK and Syk inhibitors on the ability of anti-Fc ⁇ R antibodies on fibrocyte differentiation from PBMC.
  • PBMC were incubated for 60 minutes at 4°C with 10 nM PP2 , PP3 , or Syk inhibitor.
  • PBMC at 2.5 x 10 5 cells per ml were then cultured in serum-free medium for 5 days in the presence or absence of 1 ⁇ g/ml of the indicated murine F(ab') 2 anti-Fc ⁇ R antibodies, in the presence or absence of 500 ng/ml goat F(ab')2 anti-mouse IgG. Results are expressed as the mean ⁇ SD of the number of fibrocytes per 2.5 x 10 5 cells (one of two separate donors) .
  • FIGURE 3 shows the effects of FcyR aggregation and the effects of SRTK and Syk on fibrocyte differentiation from monocytes.
  • PBMC peripheral blood mononuclear cells
  • Non-adherent cells were then removed by pipetting, resulting in a substantially monocyte cell sample.
  • the adherent monocytes were incubated for 60 minutes at 4 0 C in the presence or absence of 10 nM PP2 , PP3 or Syk inhibitor.
  • Monocytes were then washed twice and cultured in the presence or absence of heat-aggregated human IgG for 60 minutes at 4 0 C.
  • This IgG was not an anti-Fc ⁇ R IgG, but instead was able to bind through its Fc region.
  • FIGURE 4 shows the effects of cross-linking IgG and other antibody isotypes and on fibrocyte differentiation.
  • PBMC peripheral blood monomeric human IgG for 60 seconds.
  • PBMC peripheral blood monomeric human IgG were then washed and incubated in the presence (white boxes) or absence (black boxes) of 500 ng/ml goat F(ab ' )2 anti-human IgG.
  • PBMC were then cultured at 2.5 x 10 5 cells per ml in serum-free medium for 5 days.
  • PBMC peripheral blood mononuclear cells
  • Fibrocytes are a distinct population of fibroblast-like cells derived from peripheral blood monocytes that normally enter sites of tissue injury to promote angiogenesis and wound healing. Fibrocytes differentiate from CD14+ peripheral blood monocytes, and may differentiate from other PBMC cells. The presence of anti-Fc ⁇ RI and anti-Fc ⁇ RII antibodies may inhibit or at least partially delay this process.
  • Anti-Fc ⁇ R antibodies are IgG antibodies that bind to specifically to Fc ⁇ R through their F(ab) (variable) region.
  • Compositions containing anti-Fc ⁇ RI antibodies and/or anti-Fc ⁇ RII antibodies, and/or cross-linked or aggregated IgG, which may bind to Fc ⁇ R through the Fc region, may be used to suppress the differentiation of fibrocytes in inappropriate locations and in fibrosing disorders and chronic inflammatory conditions, inter alia.
  • compositions may be applied locally or systemically.
  • compositions containing approximately 1 ⁇ g/ml anti-Fc ⁇ R antibodies may be effective to inhibit fibrocyte differentiation by approximately 50%.
  • compositions may contain an amount sufficient to deliver 1 ⁇ g/ml anti-Fc ⁇ R antibodies to the target tissue.
  • compositions may contain as little as 0.1 ⁇ g ml cross-linked or aggregated IgG.
  • Anti-Fc ⁇ R antibodies used in examples of the present disclosure include anti-Fc ⁇ RI antibodies and anti-Fc ⁇ RII antibodies.
  • Cross-linked or aggregated IgG may include any IgG able to bind the target Fc ⁇ R through its Fc region, provided that at least two such IgG antibodies are physically connected to one another.
  • Antibodies of both types may include whole antibodies or a portion thereof, preferably the portion functional in suppression of fibrocyte differentiation. For example, they may include any antibody portion able to cross-link Fc ⁇ R. This may include aggregated or cross-linked antibodies or fragments thereof, such as aggregated or cross-linked whole antibodies, F(ab')2 fragments, and possible even Fc fragments.
  • Aggregation or cross-linking of antibodies may be accomplished by any known method, such as heat or chemical aggregation. Any level of aggregation or cross-linking may be sufficient, although increased aggregation may result in increased fibrocyte suppression.
  • Antibodies may be polyclonal or monoclonal, such as antibodies produced from hybridoma cells. Compositions and methods may employ mixtures of antibodies, such as mixtures of multiple monoclonal antibodies, which may be cross-linked or aggregated to like or different antibodies.
  • Anti-Fc ⁇ R antibodies may include any isotype of antibody.
  • compositions of the present invention may be supplied to a target location from an exogenous source, or they may be made in vivo by cells in the target location or cells in the same organism as the target location.
  • compositions of the present invention may be in any physiologically appropriate formulation. They may be administered to an organism by injection, topically, by inhalation, orally or by any other effective means.
  • the same compositions and methodologies described above to suppress differentiation of fibrocytes may also be used to treat or prevent conditions resulting from inappropriate fibrocyte differentiation. For example, they may treat or prevent a condition occurring in the kidney, liver, lung, heart, eye, uterus, a tumor, or a wound.
  • fibrosis resulting from conditions including but not limited to: scleroderma, keloid scarring, rheumatoid arthritis, lupus, nephrogenic fibrosing dermopathy, renal interstitial fibrosis, such as that resulting from immune complex disease, FSGS, HIV nephritis, or Lupus nephritis, fibrotic lesions such as those formed after Schistosoma japonicum infection, autoimmune diseases, pathogenic fibrosis, Lyme disease, stromal remodeling in pancreatitis and stromal fibrosis, asthma, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, pulmonary fibrosis, post trabeculectomy fibrosis, neonatal bronchopulmonary dysplasia, diabetic nephropathy, uterine fibroids, ovarian fibrosis, other fibrocystic formations, corneal fibrosis or other
  • fibrocytes may not represent an end-stage of fibrosis.
  • fibrocytes further differentiate into myofibroblasts, which persist in thickened airway walls.
  • fibrocytes further differentiate into adipocytes and thus cause or exacerbate the condiction.
  • the invention also includes a method of inhibiting or suppressing fibrocyte differentiation or treating or preventing a condition by cross-linking FcyRI and/or Fc ⁇ RII through the use of anti-Fc ⁇ R antibodies and/or through aggregated or cross-linked IgG.
  • Anti-Fc ⁇ R antibodies may be administered in a dose of approximately 1.0 ⁇ g/mL, in an amount sufficient to deliver 1 ⁇ g/ml anti-Fc ⁇ R antibodies to the target tissue, or in another dose sufficient to inhibit fibrocyte differentiation without causing an undesirable amount of cell death in the patient.
  • Aggregated or cross-linked IgG may be administered in an amount sufficient to deliver at least 0.1 ⁇ g/ml IgG to the target tissue, or in another dose sufficient to inhibit fibrocyte differentiation without causing an undesirable amount of cell death in the patient.
  • pulmonary fibrosis or other pulmonary fibrosing diseases may be treated by administration of anti-Fc ⁇ R antibodies and/or aggregated or cross-linked IgG. Treatment may reduce cellular growth associated with fibrosis and also collagen deposition. Treatment may prevent further fibrosis or reduce the effects of current fibrosis.
  • PBMC peripheral blood mononuclear cells
  • SFM serum-free medium
  • RPMI Human peripheral blood mononuclear cells
  • HEPES Invitrogen
  • 2 mM glutamine 100 U/ml penicillin, 100 ⁇ g/ml streptomycin
  • 1 x ITS-3 500 ⁇ g/ml bovine serum albumin, 10 ⁇ g/ml insulin, 5 ⁇ g/ml transferrin, 5 ng/ml sodium selenite, 5 ⁇ g/ml linoleic acid, and 5 ⁇ g/ml oleic acid; Sigma-Aldrich, St.
  • PBMC peripheral blood mononuclear cells
  • PBMC peripheral blood mononuclear cells
  • tissue culture plates Type 353072, BD Biosciences Discovery Labware, Bedford, MA
  • Fibrocytes were identified by morphology in viable cultures as adherent cells with an elongated spindle-shaped morphology as distinct from lymphocytes or adherent monocytes. Enumeration of fibrocytes was performed on cells cultured for 5 days.
  • Human IgA, IgG, IgM, and IgG F(ab')2 fragments were from Jackson ImmunoResearch Laboratories, West Grove, PA. Goat F(ab') 2 anti-human IgG, goat F(ab')2 anti-murine IgG, goat F(ab')2 anti-rabbit IgG, and whole mouse IgGl, whole mouse IgG2a and mouse F(ab') 2 IgGl isotype control antibodies were from Southern Biotechnology Associates Inc., Birmingham, AL. Sheep red blood cells (SRBC) and rabbit anti-SRBC were from ICN, Irvine, CA.
  • SRBC Sheep red blood cells
  • anti- CD14 clone M5E2 , IgG2a, BD-Biosciences, San Diego, CA
  • anti-CD34 clone QBendlO, IgGl, GeneTex, San Antonio, TX
  • CD 43 clone IGlO, IgGl, BD
  • pan-CD45 clone H130, IgGl, BD
  • anti-prolyl 4-hydrolase clone 5B5, IgGl, Dako, Carpinteria, CA
  • anti-alpha smooth muscle actin clone 1A4, IgG2a, Sigma-Aldrich, St. Louis, MO
  • Collagen-I was detected using an affinity-purified rabbit polyclonal antibody from Rockland, Gilbertsville, PA.
  • PP2 AG 1879; 4-Amino-5- (4-chlorophenyl) -7- (t-butyl) pyrazolo [3 , 4-d] pyrimidine
  • PP3 4-Amino-7-phenylpyrazol [3, 4-d] pyrimidine
  • Syk inhibitor 3- (1-Methyl-lH-indol-3 -yl-methylene) -2- oxo-2 , 3-dihydro-lH-indole-5-sulfonamide
  • PBMC peripheral blood mononuclear cells
  • PBMC peripheral blood mononuclear cells
  • F(ab') 2 anti-Fc ⁇ RI or F(ab')2 anti-Fc ⁇ RII receptors were then cross- linked by the addition of 500 ng/tnl F(ab') 2 goat anti- mouse IgG for 30 minutes at 4°C .
  • PBMC were then warmed to 37°C and cultured for 5 days.
  • Fc ⁇ R activation leads to a cascade of signaling events initiated by two main kinases.
  • the initial events following Fc ⁇ R aggregation involve the phosphorylation of intracellular immunoreceptor tyrosine activation motifs (ITAM) present on the cytoplasmic tail of Fc ⁇ RII or the FcR ⁇ chain associated with Fc ⁇ RI, by src-related tyrosine kinases (SRTK) .
  • ITAM immunoreceptor tyrosine activation motifs
  • SRTK src-related tyrosine kinases
  • PBMC peripheral blood mononuclear cells
  • SRTK and Syk were pre- incubated with the specific SRTK inhibitor PP2, PP3 as a control for PP2, or the specific Syk inhibitor 3- (1- methyl -lH-indol -3-yl -methylene) -2 -oxo-2 , 3 -dihydro-lH- indole-5-sulfonamide, before the addition of anti-Fc ⁇ R antibodies.
  • This Syk inhibitor was used instead of the standard Syk inhibitor piceatannol, as piceatannol at concentrations used to inhibit Syk in whole cells (10 ⁇ M) also inhibits a variety of other enzymes and transcription factors.
  • proteins include the catalytic subunit of protein kinase A, protein kinase C, myosin light chain kinase, TNF-induced NF-kB activation, and interferon ⁇ -mediated signaling via STAT proteins.
  • PBMC cultured with 500 ng/ml goat F(ab') 2 in addition to anti-mouse IgG anti-Fc ⁇ RI, anti-Fc ⁇ RII or both antibodies significantly inhibited fibrocyte differentiation (p ⁇ 0.05), as determined by ANOVA.
  • the presence of PP2 or Syk inhibitor, but not the control compound PP3 inhibited this inhibition.
  • EXAMPLE 5 IgG IMMUNE COMPLEXES INHIBIT FIBROCYTE DIFFERENTIATION
  • monocytes express IgA receptors, low numbers of IgE receptors, and the recently characterized IgM receptor.
  • native or heat-aggregated IgA, IgE, IgG or IgM were added to PBMC. The results of this example are shown in Figure 4C. Only heat-aggregated IgG, but not monomeric IgG or monomeric or heat-aggregated IgA, IgE or IgM, could inhibit fibrocyte differentiation. This suggests that ligation and cross-linking of Fo ⁇ R receptors is an inhibitory signal for fibrocyte differentiation, but that ligation of the other immunoglobin receptors has no effect on fibrocyte differentiation .
  • PBMC peripheral blood mononuclear cells
  • PBMC peripheral blood mononuclear cells
  • cross-linked human IgG clearly inhibited fibrocyte differentiation as compared to non-cross-linked IgG at 0.1 ⁇ g/ml .
  • Additional experiments using sheep red blood cells (SRBC) either opsinized or not opsonized with rabbit anti-SRBC IgG indicated that the opsonized SRBC significantly inhibited fibrocyte differentiation (p 0.018) (data not shown) .
  • SRBC sheep red blood cells
  • PBMC peripheral blood mononuclear cells
  • PBMC peripheral blood mononuclear cells
  • results of this example are shown in Figure 4B.
  • heat-aggregated whole IgG significantly inhibited fibrocyte differentiation at concentrations of 25 ⁇ g/ml and higher, as determined by Student's t test.

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Abstract

La présente invention concerne la capacité d'anticorps anti-FcγR et d'IgG agrégées ou réticulées à supprimer la différenciation des fibrocytes. L'invention concerne des procédés et des compositions de suppression de la différenciation des fibrocytes en utilisant ces anticorps. Ces procédés sont utiles dans diverses applications, parmi lesquelles le traitement et la prévention de maladies résultant d'une fibrose du rein, du foie, du poumon, du cœur, de l'œil, de l'utérus, ainsi que de tumeurs et de plaies.
PCT/US2006/005229 2002-12-23 2006-02-15 Compositions et procédés de suppression de la différenciation des fibrocytes WO2007094776A1 (fr)

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PCT/US2006/005229 WO2007094776A1 (fr) 2006-02-15 2006-02-15 Compositions et procédés de suppression de la différenciation des fibrocytes
US11/535,649 US8012472B2 (en) 2002-12-23 2006-09-27 Compositions and methods for suppressing fibrocytes
US13/224,959 US8187599B2 (en) 2002-12-23 2011-09-02 Compositions and methods for suppressing fibrocytes

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PCT/US2003/040957 Continuation-In-Part WO2004058292A2 (fr) 2002-12-23 2003-12-22 Methodes de detection de differenciation de fibrocytes, compositions et methodes pour supprimer une fibrose
US11/158,966 Continuation-In-Part US7666432B2 (en) 2002-12-23 2005-06-22 Methods of suppressing fibrosis and fibrocyte formation
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Cited By (1)

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CN115154606A (zh) * 2022-06-20 2022-10-11 中国医学科学院基础医学研究所 FcγRⅢ抑制剂作为新靶点在制备治疗肺纤维化药物中的应用

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