Source: http://www.google.com/patents/US7763256?dq=7,444,563
Timestamp: 2017-11-25 01:07:53
Document Index: 108298369

Matched Legal Cases: ['§120', 'Application No. 2003299873', 'Application No. 03', 'Application No. 03', 'Application No. 03', 'Application No. 2003300266', 'Application No. 03', 'Application No. 2003300266', 'Application No. 03', 'Application No. 03']

Patent US7763256 - Compositions and methods for suppressing fibrocytes and for detecting ... - Google Patents
The present invention relates to the ability of SAP to suppress fibrocytes. It also relates to the ability of IL-12, laminin-1, cross-linked IgG and IgG aggregates to suppress fibrocytes. Methods and compositions for suppressing fibrocytes using these proteins are provided. These methods are useful in...http://www.google.com/patents/US7763256?utm_source=gb-gplus-sharePatent US7763256 - Compositions and methods for suppressing fibrocytes and for detecting fibrocyte differentiation
Publication number US7763256 B2
Application number US 11/535,636
Also published as US8057802, US8187608, US20070065368, US20100221208, US20120009146
Publication number 11535636, 535636, US 7763256 B2, US 7763256B2, US-B2-7763256, US7763256 B2, US7763256B2
Inventors Richard Gomer, Darrell Pilling
Patent Citations (30), Non-Patent Citations (125), Referenced by (9), Classifications (29), Legal Events (4)
US 7763256 B2
6. The method of claim 5, wherein the biocompatible polymer is selected from the group consisting of PEG, a poly(amino acid), and a polysaccharide; or copolymers and combinations thereof.
7. The method of claim 1, further comprising administering a composition selected from the group consisting of IL-12, Laminin-1, IgG aggregates, cross-linked IgG and combinations thereof.
8. The method of claim 1, wherein administering comprises administering approximately 1.6 μg SAP or a portion thereof per gram of bodyweight of the mammal.
9. The method of claim 1, wherein administering comprises administering an amount of SAP or a portion thereof sufficient to approximately double the normal serum concentration of SAP or a portion thereof similar to the portion thereof administered in the mammal.
10. The method of claim 1, wherein administering comprises administering an amount of SAP sufficient to increases the normal serum concentration of SAP or the a portion thereof similar to the portion thereof administered in the mammal by approximately 25%.
12. The method of claim 1, wherein administering comprises administering the SAP protein or a portion thereof an amount of approximately 600 μg or more.
13. The method of claim 1, wherein pulmonary fibrosis comprises a condition selected from the group consisting of: Adalimumab-associated pulmonary fibrosis, pulmonary interstitial fibrosis, sarcoidosis, idiopathic pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, diffuse alveolar damage disease, pulmonary hypertension, neonatal bronchopulmonary dysplasia, and emphysema.
The present application is a continuation-in-part of U.S. application Ser. No. 11/158,966 filed Jun. 22, 2005, and now U.S. Pat. No. 7,666,432; 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: U.S. 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 all above applications are incorporated by reference herein.
FIG. 13 shows the effects of SAP on fibrosis in rat lungs. Intra-tracheal injection of bleomycin (Bleo) was used to induce fibrosis. Control rats had saline injected into their tracheas. “+SAP” indicates that rats were given an intravenous injection of 240 μg of rat SAP on days 1, 3, 5, 7 and 9. The animals were euthanized on day 14. Lung tissues were removed and fibrosis was assessed using a modified Ashcroft score containing 5 fields per section, and from three separate areas of lung. Zero is a normal lung, 1 is minimal thickening of the alveolar wall, 2 and 3 are increased levels of fibrosis, and 4 is severe distortion of the lung structure with large areas of fibrosis. Values are means+/−SEM (n=4). *** indicates p<0.001 as determined by ANOVA.
These data suggest that the inhibitory factor is a protein. As the inhibitory factor was present in human serum, it indicated that the activity was unlikely to be involved with the coagulation system. The inhibitory factor also appeared to be an evolutionary conserved protein as bovine, equine, caprine, and rat sera were also able to inhibit the appearance of these fibroblast-like cells (data not shown).
Recovery of protein and fibrocyte inhibitory activity from
fractionated human plasma
Maxisorb 96 well plates (Nalge Nunc International, Rochester, N.Y.) were coated overnight at 4° C. with monoclonal anti-SAP antibody (SAP-5, Sigma) in 50 mM sodium carbonate buffer pH 9.5. Plates were then incubated in Tris buffered saline pH 7.4 (TBS) containing 4% BSA (TBS-4% BSA) to inhibit non-specific binding. Serum and purified proteins were diluted to 1/1000 in TBS-4% BSA, to prevent SAP from aggregating and incubated for 60 minutes at 37° C. Plates were then washed in TBS containing 0.05% Tween-20. Polyclonal rabbit anti-SAP antibody (BioGenesis) diluted 1/5000 in TBS-4% BSA was used as the detecting antibody. After washing, 100 pg/ml biotinylated goat F(ab)2 anti-rabbit (Southern Biotechnology Inc.) diluted in TBS-4% BSA was added for 60 minutes. Biotinylated antibodies were detected by ExtrAvidin peroxidase (Sigma). Undiluted peroxidase substrate 3,3,5,5-tetramethylbenzidine (TMB, Sigma) was incubated for 5 minutes at room temperature before the reaction was stopped by 1N HCl and read at 450 nm (BioTek Instruments, Winooska, Vt.). The assay was sensitive to 200 pg/ml.
Peripheral blood mononuclear cells were isolated from buffy coats (Gulf Coast Regional Blood Center, Houston, Tex.) by Ficoll-Paque (Amersham Biosciences, Piscataway, N.J., USA) centrifugation for 40 minutes at 400×g. Depletion of specified leukocyte subsets was performed using negative selection using magnetic Dynabeads (Dynal Biotech Inc., Lake Success, N.Y.). Briefly, PBMC were incubated with primary antibodies for 30 minutes at 4° C. Cells were then washed and incubated with Dynabeads coated with goat anti-mouse IgG for 30 minutes, before removal of antibody-coated cells by magnetic selection. This process was repeated twice. The negatively selected cells were routinely in excess of 98% pure as determined by monoclonal antibody labeling.
PBMC were cultured in 24 or 96 well tissue culture plates in 2 ml or 200 μl volumes respectively (Becton Dickinson, Franklin Lakes, N.J.) at 2.5×105 cells per ml in a humidified incubator containing 5% CO2 at 37° C. for the indicated times. Fibrocytes in 5 different 900 μm diameter fields of view were enumerated by morphology in viable cultures as adherent cells with an elongated spindle-shaped morphology as distinct from small lymphocytes or adherent monocytes. Alternatively cells were air dried, fixed in methanol and stained with hematoxylin and methylene blue (Hema 3 Stain, VWR, Houston, Tex.). Fibrocytes were counted using the above criterion and the presence of an oval nucleus. Enumeration of fibrocytes was performed on cells cultured for 6 days in flat-bottomed 96 well plates, with 2.5×104 cells per well. In addition, fibrocyte identity was confirmed by immunoperoxidase staining (see below). The fibrocyte inhibitory activity of a sample was defined as the reciprocal of the dilution at which it inhibited fibrocyte differentiation by 50%, when added to serum-free medium.
The process of crossing the endothelium and basement membrane induces activation and differentiation signals for monocytes. Therefore, experiments were performed to determine if extracellular matrix proteins had an effect on the differentiation of fibrocytes. Extracellular matrix proteins were bound to 96 well tissue culture plates for 18 hours at 4° C. in 50 mM carbonate buffer pH 9.5. ProNectin-F and ProNectin-L were diluted in PBS. Plates were washed in PBS, and incubated for 60 minutes at 37° C. in PBS containing 2% bovine serum albumin, to prevent non-specific binding. Plates were washed with PBS and then tissue culture medium. PBMC were then added and cultured for 4 days. Differentiation of fibrocytes was unaffected by culturing on a wide variety of ECM proteins, including collagens, fibronectin and vitronectin. However, culturing PBMC with either laminin-1 (Sigma-Aldrich, St. Louis, Mo.) or ProNectin-F (Sanyo Chemical Industries Inc, Kyoto, Japan) led to a significant reduction in the number of fibrocytes (See FIG. 7A) (p<0.0001). ProNectin-F is a construct of silk protein and repeats of the canonical RGD adhesion sequence from fibronectin. ProNectin-L is a similar construct to ProNectin-F, with the amino acid sequence IKVAV, from the α1 chain of laminin.
Additional experiments were performed to determine whether other laminin proteins could suppress fibrocyte differentiation. Laminin 10/11 (Chemicon, Temecula, Calif.) a second commercially available laminin, was not capable of inhibiting fibrocyte differentiation, compared to laminin-1. (See FIG. 7B) This data suggests that sequences specific to laminin-1, outside the IKVAV region, and absent from laminin-10 and -11, may be responsible for the suppressive effect on fibrocyte differentiation.
To determine whether ligation and cross-linking of Fc receptors could also influence monocyte to fibrocyte differentiation, three test samples were used; soluble immune complexes (ovalbumin-antibody), particulate immune complexes, including opsonised SRBC and heat-aggregated IgG. PBMC cultured for 4 days with ovalbumin or anti-ovalbumin mAb showed that the two proteins alone had a modest effect on the differentiation of monocytes compared to cultures where no reagent was added. (See FIG. 9A.) However, the addition of ovalbumin:anti-ovalbumin immune complexes led to a significant reduction in the number of differentiated fibrocytes (See FIG. 9A). A similar effect was observed when PBMC were cultured with opsonised SRBC. SRBC opsonised with rabbit anti-SRBC at 20:1 and 40:1 SRBC:monocyte ratios significantly suppressed fibrocyte differentiation as compared to cells cultured with SRBC alone (See FIG. 9B). Finally, PBMC cultured with heat-aggregated IgG, but not heat-aggregated F(ab)2, also showed potent inhibition of fibrocyte differentiation (See FIG. 9C.) Together these data suggest that ligation and cross-linking linking of Fc receptors is suppressor of monocyte to fibrocyte differentiation.
Group Day 0 1 Day 3 5 Day 7 Day 9 Day 14
3 Bleomycin Inject Inject Inject Inject Inject sacrifice
4 Bleomycin Inject Inject Inject Inject Inject sacrifice
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U.S. Classification 424/198.1, 530/350, 514/1.5
International Classification C07K7/00, C07K14/00, A61K38/00
Cooperative Classification Y10S514/885, A61K31/13, A61K38/39, G01N33/505, A61K31/66, C07K2317/70, G01N33/5047, A61K38/208, C07K16/283, C07K16/06, C07K2317/76, A61K38/1709, A61K31/729
European Classification A61K38/17A2, A61K31/729, A61K38/39, G01N33/50D2F2B, A61K31/13, A61K31/66, G01N33/50D2F2, C07K16/28A26, C07K16/06, A61K38/20M
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