Source: http://www.google.com/patents/US8012472?dq=6,123,819
Timestamp: 2014-03-17 00:49:24
Document Index: 195059795

Matched Legal Cases: ['Application No. 2005', 'Application No. 2003299873', 'art 1', 'Application No. 03', 'Application No. 03', 'Application No. 2004']

Patent US8012472 - Compositions and methods for suppressing fibrocytes - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inAdvanced Patent SearchPatentsThe present invention relates to the ability of anti-FcγR antibodies to suppress fibrocytes. Methods and compositions for suppressing fibrocytes are provided. These methods are useful in a variety of applications including treatment and prevention of conditions resulting from fibrosis in the liver,...http://www.google.com/patents/US8012472?utm_source=gb-gplus-sharePatent US8012472 - Compositions and methods for suppressing fibrocytesAdvanced Patent SearchPublication numberUS8012472 B2Publication typeGrantApplication numberUS 11/535,649Publication dateSep 6, 2011Filing dateSep 27, 2006Priority dateDec 23, 2002Also published asUS20070065866Publication number11535649, 535649, US 8012472 B2, US 8012472B2, US-B2-8012472, US8012472 B2, US8012472B2InventorsRichard Gomer, Darrell PillingOriginal AssigneeWilliam Marsh Rice UniversityExport CitationBiBTeX, EndNote, RefManPatent Citations (37), Non-Patent Citations (135), Classifications (10), Legal Events (1) External Links: USPTO, USPTO Assignment, EspacenetCompositions and methods for suppressing fibrocytesUS 8012472 B2Abstract The present invention relates to the ability of anti-FcγR antibodies to suppress fibrocytes. Methods and compositions for suppressing fibrocytes are provided. These methods are useful in a variety of applications including treatment and prevention of conditions resulting from fibrosis in the liver, kidney, lung, heart and pericardium, eye, skin, mouth, pancreas, gastrointestinal tract, brain, breast, bone marrow, bone, genitourinary system, a tumor, or a wound.
PRIORITY CLAIM The present application is a continuation-in-part under 35 U.S.C. �120 of PCT patent application serial number PCT/US2006/005229, filed Feb. 15, 2006 and titled �Methods and Conditions for Suppressing Fibrocyte Differentiation� and Ser. No. 11/158,966, now U.S. Pat. No. 7,666,432 U.S. Application No. 2005/0238620 filed Jun. 22, 2005, which is a continuation-in-part under 35 U.S.C. �120 of PCT patent application serial number PCT/US2003/040957, filed Dec. 22, 2003 and titled �Methods and Conditions for Suppressing Fibrocyte Differentiation�, published in English as WO 2004/058292 on Jul. 15, 2004; which claims priority to the following: U.S. Provisional Patent Applications 60/436,046, filed Dec. 23, 2002; U.S. 60/436,027, filed Dec. 23, 2002; U.S. 60/515,776, filed Oct. 30, 2003; U.S. 60/519,467, filed Nov. 12, 2003; and U.S. 60/525,175 filed Nov. 26, 2003. Pertinent parts of the application are incorporated by reference herein.
FIELD OF THE INVENTION The present invention relates to the ability of anti-FcγR antibodies, aggregated IgG, and/or cross-linked IgG to suppress fibrocytes. Accordingly, it may include compositions and methods for suppressing fibrocytes. These compositions and methods may be useful in a variety of applications, for example, those in which decreased fibrocyte formation is beneficial, such as treatment of fibrosing diseases and asthma.
BACKGROUND Fibrocytes
SUMMARY The present invention may include compositions and methods for suppressing fibrocytes. In the context of the present invention, the term �suppressing fibrocytes� refers to one or more of inhibiting the proliferation of fibrocytes, inhibiting the development of fibrocytes, including the development or differentiation of a cell into a fibrocyte, and promoting the development or differentiation of fibrocytes into non-fibrocytic cell types.
BRIEF DESCRIPTION OF THE DRAWINGS The following figures form part of the present specification and are included to further demonstrate certain aspects of the present invention.
FIG. 1 shows the effects of cross-linked and non-cross-linked anti-FcγR antibodies on fibrocyte differentiation from Peripheral Blood Mononuclear Cells (PBMC). PBMC at 2.5�105 cells per ml were cultured in serum-free medium for 5 days in the presence or absence of 1 μg/ml of the indicated F(ab′)2 anti-FcγR or control IgG1 antibodies, in the presence (black bars) or absence (white bars) of 500 ng/ml goat F(ab′)2 anti-mouse IgG, which cross-links the F(ab′)2. Cells were then air-dried, fixed, stained, and fibrocytes were enumerated by morphology.
FIG. 2 shows the effects of SRTK and Syk inhibitors on the ability of anti-FcγR 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�105 cells per ml were then cultured in serum-free medium for 5 days in the presence or absence of 1 μg/ml of the indicated murine F(ab′)2 anti-FcγR 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�105 cells (one of two separate donors).
FIG. 3 shows the effects of FcγR aggregation and the effects of SRTK and Syk on fibrocyte differentiation from monocytes. PBMC were at 2.5�105 cells per ml were incubated for 60 minutes at 37� C. 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� 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� C. This IgG was not an anti-FcγR IgG, but instead was able to bind through its Fc region. The monocytes were then washed twice, and the non-adherent cells were replaced to a final concentration of 2.5�105 cells per ml and then cultured for 5 days at 37� C. in serum-free medium. Results are expressed as the mean�SEM of the number of fibrocytes per 2.5�105 cells (n=3 separate donors.
In FIG. 4A, PBMC were incubated with the indicated concentrations of monomeric human IgG for 60 minutes. PBMC 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�105 cells per ml in serum-free medium for 5 days. PBMC were then air-dried, fixed, stained, and fibrocytes were enumerated by morphology. Results are expressed as the mean�SEM of number of fibrocytes per 2.5�105 cells (n=4 separate donors).
In FIG. 4B, PBMC were cultured as in FIG. 4A in the presence of the indicated concentrations of heat-aggregated human IgG or heat-aggregated human F(ab′)2. Results are expressed as the �SEM of number of fibrocytes per 2.5�105 cells (n=3 separate donors).
DETAILED DESCRIPTION The regulation of events leading to fibrosis involves the proliferation and differentiation of fibrocytes. 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-FcγR antibodies, aggregated IgG, and/or cross-linked IgG may inhibit or at least partially delay this process.
EXAMPLES Example 1 Fibrocyte Differentiation Assay Human peripheral blood mononuclear cells (PBMC) were isolated from buffy coats (Gulf Coast Regional Blood Center, Houston, Tex.) by Ficoll-Paque Plus (Amersham Biosciences, Piscataway, N.J.). Cells were incubated in serum-free medium (SFM), which consists of RPMI (Invitrogen, Carlsbad, Calif.) supplemented with 10 mM HEPES (Invitrogen), 2 mM glutamine, 100 U/ml penicillin, 100 μg/ml streptomycin, and 1�ITS-3 (500 μg/ml bovine serum albumin, 10 μg/ml insulin, 5 μg/ml transferrin, 5 ng/ml sodium selenite, 5 μg/ml linoleic acid, and 5 μg/ml oleic acid; Sigma-Aldrich, St. Louis, Mo.). Normal human serum (Sigma-Aldrich) was added at 1%. PBMC were cultured in flat-bottomed 96 well tissue culture plates (Type 353072, BD Biosciences Discovery Labware, Bedford, Mass.) in 200 μl volumes at 2.5�105 cells per ml in a humidified incubator containing 5% CO2 at 37� C. for 5 days. 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. Cells were air dried, fixed in methanol and stained with eosin and methylene blue (Hema 3 Stain, Fisher Scientific, Hampton, N.H.). Fibrocytes from duplicate wells were counted in five different 900 μm diameter fields per well, using the above criteria of an elongated spindle-shape and the presence of an oval nucleus. All cultures were counted by at least two independent observers. The number of fibrocytes observed was 1.2�0.6�104 (mean�SD, n=12 healthy individuals) fibrocytes per ml of peripheral blood, with a range of 3.7�103 to 2.9�104 fibrocytes per ml. These results indicate that fibrocyte precursors account for approximately 1% of the total peripheral blood mononuclear cells.
Example 2 Antibodies, Proteins, and Inhibitors 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 IgG1, whole mouse IgG2a and mouse F(ab′)2 IgG1 isotype control antibodies were from Southern Biotechnology Associates Inc., Birmingham, Ala. Sheep red blood cells (SRBC) and rabbit anti-SRBC were from ICN, Irvine, Calif. F(ab′)2 fragments of the blocking monoclonal antibodies to FcγRI (clone 10.1, IgG1 isotype) and FcγRII (clone 7.3, IgG1 isotype) were from Ancell, Bayport, Minn. The following primary monoclonal antibodies were used for immunohistochemistry: anti-CD14 (clone M5E2, IgG2a, BD-Biosciences, San Diego, Calif.), anti-CD34 (clone QBend10, IgG1, GeneTex, San Antonio, Tex.), CD 43 (clone IG10, IgG1, BD), pan-CD45 (clone H130, IgG1, BD), anti-prolyl 4-hydrolase (clone 5B5, IgG1, Dako, Carpinteria, Calif.), and 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) and the Syk inhibitor (3-(1-Methyl-1H-indol-3-yl-methylene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide) were from Calbiochem, EMD Biosciences, San Diego, Calif.
Example 3 Inhibition of Fibrocyte Differentiation To determine if anti-FcγR antibodies activate FcγR to inhibit fibrocyte differentiation, PBMC at 2.5�105 per ml were cultured in serum-free medium for 5 days in the presence or absence of 1 μg/ml of free or cross-linked F(ab′)2 antibodies to FcγRI or FcγRII.
To crosslink individual FcγR, PBMC were incubated for 30 minutes at 4� C. with 1 μg/ml F(ab′)2 anti-FcγRI or F(ab′)2 anti-FcγRII, and receptors were then cross-linked by the addition of 500 ng/ml 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.
Example 4 Inhibition of Fibrocyte Differentiation is SYK- and SRC Kinase Dependent FcγR activation leads to a cascade of signaling events initiated by two main kinases. The initial events following FcγR aggregation involve the phosphorylation of intracellular immunoreceptor tyrosine activation motifs (ITAM) present on the cytoplasmic tail of FcγRII or the FcRγ chain associated with FcγRI, by src-related tyrosine kinases (SRTK). In monocytes, the main src-kinases associated with FcγRI and FcγRII are hck and lyn. The phosphorylated ITAM then recruits cytoplasmic SH2-containing kinases, especially Syk, to the ITAMs and Syk then activates a series of downstream signaling molecules.
Example 5 IgG Immune Complexes Inhibit Fibrocyte Differentiation In addition to FcγR, monocytes express IgA receptors, low numbers of IgE receptors, and the recently characterized IgM receptor. To determine if other immunoglobins inhibit fibrocyte differentiation, native or heat-aggregated IgA, IgE, IgG or IgM were added to PBMC. The results of this example are shown in FIG. 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 FcγR receptors is an inhibitory signal for fibrocyte differentiation, but that ligation of the other immunoglobin receptors has no effect on fibrocyte differentiation.
Example 6 Cross-Linked IgG Inhibits Fibrocyte Differentiation PBMC were incubated with the indicated various concentrations of monomeric human IgG for 60 minutes. PBMC were then washed and incubated in the presence or absence of 500 ng/ml goat F(ab′)2 anti-human IgG. PBMC were then cultured at 2.5�105 cells per ml in serum-free medium for 5 days. PBMC were then air-dried, fixed, stained, and fibrocytes were enumerated by morphology. Results are shown in FIG. 4A. Specifically, compared to monomeric IgG, cross-linked human IgG clearly inhibited fibrocyte differentiation as compared to non-cross-linked IgG at 0.1 μg/ml. At 10 and 100 μg/ml inhibition of differentiation was significant (p=0.03 and p=0.003, respectively, as determined by Student's t test. Additional experiments using sheep red blood cells (SRBC) either opsinized or not opsinized with rabbit anti-SRBC IgG indicated that the opsinized SRBC significantly inhibited fibrocyte differentiation (p=0.018) (data not shown).
Example 7 Antibody Studies SAP and CRP augment phagocytosis and bind to Fcγ receptors on a variety of cells. CRP binds with a high affinity to FcγRII (CD32), a lower affinity to FcγRI (CD64), but does not bind FcγRIII (CD16). SAP binds to all three classical Fcγ receptors, with a preference for FcγRI and FcγRII. Monocytes constitutively express FcγRI. Because this receptor binds monomeric IgG, it is saturated in vivo. In order to determine whether the presence of monomeric human IgG could prevent SAP from inhibiting fibrocyte differentiation, PBMC were cultured in serum-free medium in the presence of a range of concentrations of monomeric IgG for 60 minutes. SAP, at the concentrations indicated in FIG. 5, was then added and the cells were cultured for 4 days. As described in the above examples, 2.5 μg/ml SAP in the absence of IgG strongly inhibited fibrocyte differentiation. (See FIG. 5.) Monomeric IgG in a range from 0.1 to 1000 μg/ml, which corresponds to approximately 0.001 to 10% serum respectively, had little effect on the suppression of fibrocyte formation by SAP.
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