WO2001026675A9 - FcηRIA - Google Patents
FcηRIAInfo
- Publication number
- WO2001026675A9 WO2001026675A9 PCT/US2000/028321 US0028321W WO0126675A9 WO 2001026675 A9 WO2001026675 A9 WO 2001026675A9 US 0028321 W US0028321 W US 0028321W WO 0126675 A9 WO0126675 A9 WO 0126675A9
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- fcγria
- cytoplasmic domain
- inflammatory condition
- cell
- cytokine
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/70535—Fc-receptors, e.g. CD16, CD32, CD64 (CD2314/705F)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6854—Immunoglobulins
- G01N33/6857—Antibody fragments
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2500/00—Screening for compounds of potential therapeutic value
- G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
Definitions
- the present invention relates, in general, to Fc ⁇ RI and, in particular, to methods of modulating the signaling of the Fc ⁇ RI- ⁇ -chain receptor complex and to compounds suitable for use in such methods.
- Fc ⁇ receptors play a central role in the handling of immune complexes, regulation of inflammatory responses, antibody secretion and T cell activity (Kimberly et al, Arthritis Rheum. 38:306-314 (1995), McKenzie et al, Curr. Opin. Hermatol. 5:16-21 (1998), Ravetch et al, Ann. Rev. Immunol. 16:421-432 (1998) and Sutterwala et al, J. Exp. Med. 188:217-222 (1998)). Common to each of these functions is the initiation of tyrosine phosphorylation following receptor crosslinking (Daeron, Ann. Rev. Immunol.
- Fc receptors serve redundant signaling functions.
- Fc ⁇ RIIIa appears necessary for initiating the Arthus inflammatory reaction (Hazenbos et al, Immunity 5:181-188 (1996), Syvestre et al, Immunity 5:387-390 (1996))
- Fc ⁇ RIa and Fc ⁇ RI can down regulate inflammatory responses by initiating the secretion of EL- 10 and EL- lra respectively
- the basis for these differences are unknown.
- Fc ⁇ RI is expressed on the cell surface in association with the ⁇ -chain (Ernst et al, Proc. Natl. Acad. Sci. USA 90:6023-6027 (1993), Scholl et al, Proc. Natl. Acad. Sci. USA 90:8847-8850 (1993)).
- This association is not a prerequisite for transient receptor expression but is necessary for stable expression (Takai et al, Cell 76:510-529 (1994), van Vugt et al, Blood 87:3593-3599 (1996)).
- the ⁇ -chain cytoplasmic domain contains an immunoreceptor tyrosine activation motif (isoleucme-threonine-alanine-methionme-(ITAM) and current data suggest that the ⁇ -chain cytoplasmic domain is both necessary and sufficient for Fc ⁇ RIa induced functions
- ITAM immunoreceptor tyrosine activation motif
- Fc ⁇ RIa and ⁇ -chain may also be important in the formation of a higher affinity receptor complex through the recruitment of two ligand binding chains to the ⁇ homodimer (Miller et al, J. Exp. Med. 183:2227-2233 (1996)).
- the cytoplasmic domain of Fc ⁇ RI does not contain an IT AM or other tyrosine containing signaling motifs. Nonetheless, murine Fc ⁇ RI on J774 cells is constitutively phosphorylated on serine and, after phorbol myristate acetate (PMA) stimulation, the level of phosphorylation increases (Quilliam et al, Immunol. 78:358-363 (1993)).
- the cytoplasmic domain of Fc ⁇ RI may also associate with actin binding protein-280 (ABP-280, also known as non- muscle filamin) in the absence of ligand (Ohta et al, Cell 67:275-282 (1991)).
- Fc ⁇ RIa in the absence of the ⁇ - chain can signal for calcium in COS-1 cells and the transmission of this calcium signal requires the Fc ⁇ RIa cytoplasmic domain (Indik et al, Immunobiology 185:183-192 (1992)).
- the present invention is based, at least in part, on the realization that the Fc ⁇ RIa cytoplasmic domain serves to modify the signaling of the Fc ⁇ RI- ⁇ -chain receptor complex. This realization makes possible the identification of compounds that can be used to modulate the effects of such signaling.
- the present invention relates to methods of modulating the signaling of the Fc ⁇ RI- ⁇ -chain receptor complex and to compounds suitable for use in such methods.
- FIG. 1 Expression of human wild type (WT) and mutant (MUT) Fc ⁇ RIa on the surface of stably transfected P388D1 cells. Cells were incubated with a saturating concentration of the anti-human Fc ⁇ RIa mAb 22.2-FITC and analyzed by flow cytometry.
- FIGs 2 A and 2B Receptor-specific phagocytosis by WT and MUT human Fc ⁇ RIa.
- parental non-transfected cells were analyzed. Phagocytosis was performed and quantitated by light microscopy. Data are expressed as the mean phagocytic index ⁇ SD.
- FIG. 3 Receptor-specific endocytosis by WT and MUT human Fc ⁇ RIa in P388D1 stable transfectants and of murine Fc ⁇ RI in non-transfected P388D1 cells.
- FIGs 4A and 4B Differential sensitivity to pre-treatment with BAPTA.
- WT (open bars) and MUT (hatched bars) P388D1 stable transfectants incubated with E-22.2 were prepared at maximal mAb conjugation ratios (prepared as in Figure 2A).
- IL-6 release but not DL-l ⁇ release, requires the cytoplasmic domain of Fc ⁇ RIa.
- FIGS. 6 A and 6B Substitution of serines in the cytoplasmic domain of Fc ⁇ RI with alanines increases the phagocytic index of P388D1 transfectants.
- the present invention results, at least in part, from the demonstration that the cytoplasmic domain Fc ⁇ RIa alters the biological properties of the Fc ⁇ RIa- ⁇ - chain receptor complex.
- the cytoplasmic domain of Fc ⁇ RIa directly contributes to the functional properties of the receptor complex. Deletion of the Fc ⁇ RIa cytoplasmic domain leads to slower kinetics of receptor specific phagocytosis and endocytosis as well as lower total phagocytosis despite identical levels of receptor expression. Deletion of the cytoplasmic domain also converts the phenotype of calcium independent Fc ⁇ RIa specific phagocytosis to a calcium dependent phenotype.
- deletion of the cytoplasmic domain abrogates Fc ⁇ RIa specific secretion of IL-6 (but does not affect production of FL-I ⁇ ) and allows substantial levels of phagocytosis.
- the invention provides a method of inhibiting the release of cytokines (e.g., IL-6 or other macrophage or granulocyte-derived interleukins, and TNF- ⁇ ) and other biologically active molecules (e.g., reactive oxygen species) from cells such as macrophages and granulocytes.
- cytokines e.g., IL-6 or other macrophage or granulocyte-derived interleukins, and TNF- ⁇
- other biologically active molecules e.g., reactive oxygen species
- the method of the present invention can be used to prevent or treat inflammation of any of a variety of tissues including the lung (in the case of, for example, asthmatics and patients suffering from ARDS), the joints (e.g., in the case of patients suffering from arthritis), the gastrointestinal tract (e.g., in the case of patients suffering from inflammatory bowel disease) and the kidney (e.g., in the case of patients suffering from glomerulonephritis).
- the present methods can be used to prevent or treat any disease or disorder resulting from the proinflammatory effects of the cytoplasmic domain of Fc ⁇ RI.
- Compounds suitable for use in the present methods include agents that bind the Fc ⁇ RI cytoplasmic domain and thereby inhibit its proinflammatory activity, agents that inhibit an interaction of the cytoplasmic domain with another cellular component(s), which interaction results, directly or indirectly, in cytokine release, and agents that otherwise inhibit the proinflammatory effect of the Fc ⁇ RIa cytoplasmic domain.
- the compounds can be peptides (e.g., peptide fragments of the cytoplasmic domain of Fc ⁇ RIa), or mimetics thereof, or other nonpeptidic agents.
- the peptide itself can be introduced into target cells directly, for example, using liposomes.
- a DNA sequence encoding the peptide can be introduced using gene therapy protocols so that the peptide is produced intracellularly.
- the mode of administration will, of course, depend on the compound, the patient and the effect sought.
- the peptide, or encoding sequence, or non-peptidic agent can be administered by inhalation.
- the compound can be administered, for example, by direct injection into the joint.
- the compounds can be administered by any route (e.g., intravenously, orally or as per rectum) that will ensure that the amount that reaches the target site is sufficient to inhibit the proinflammatory effect of the cytoplasmic domain of Fc ⁇ RIa.
- Compounds suitable for use in the present invention can be identified using any of a variety of art-recognized techniques.
- test compounds can be contacted with the cytoplasmic domain of Fc ⁇ RIa, or portion thereof, and the determination made as to whether or not binding of the test compound to the cytoplasmic domain occurs, test compounds that bind the cytoplasmic domain being potential inhibitors of the proinflammatory effect of the cytoplasmic domain of Fc ⁇ RIa.
- Compound screens can also be used that are based on the ability of a compound to effect cytokine release. For example, test compounds can be contacted with cells capable of releasing IL-6 and the amount of IL-6 released in the presence and absence of the test compound determined. Cells suitable for use in such screens include cells that naturally express Fc ⁇ receptors and cells that do not.
- cells such as mouse fibroblast NIH3T3 cells transfected with a Fc ⁇ RIa encoding sequence can be used.
- Other cell types can also be used.
- Compounds that inhibit cytokine release in such systems can be expected to be suitable for use in the present invention.
- test compounds can be labeled with a detectable label or unlabeled.
- the cytoplasmic domain which also can be labeled or unlabeled, can be present in isolation or in a cell, as appropriate depending on the nature of the screen. Either the test compound or the cytoplasmic domain, or portion thereof, can be bound to a solid support.
- compositions can be formulated as pharmaceutical compositions.
- Such compositions comprise the compound and a pharmaceutically acceptable carrier.
- the amount of the compound administered will depend on the compound, the patient and the effect sought. Optimum dosing can be readily determined by one skilled in the art. The sequence of Fc ⁇ RIa is disclosed in Porges et al, J. Clin. Invest.
- the murine macrophage cell line P388D1 stably transfected with a cDNA encoding human Fc ⁇ RIa or a mutant form of Fc ⁇ RIa containing a stop codon after the first amino acid of the cytoplasmic domain (K31519Stop 315) were prepared as previously described (Indik et al, Exp. Hematol. 22:599-606 (1994)).
- P388D1 cells transfected with human Fc ⁇ PJIa were previously described (Edberg et al, J. Biol. Chem. 270:22301-22307 (1995)).
- Human and mouse IgG were obtained from Sigma (St. Louis, MO).
- Mouse F(ab') 2 fragments and F(ab ! ) 2 goat anti-mouse IgG (G ⁇ M) were obtained from Jackson ImmunoResearch (West Grove, PA).
- F(ab') 2 fragments of the anti- Fc ⁇ RIa mAbs 22.2 and 32.2 were obtained from Medarex (Annandale, NJ).
- lgM anti-H-2D d (clone 3-25.4) was obtained from Pharmingen (San Diego, CA).
- the hybridoma line expressing the rat anti-murine Fc ⁇ RII/Fc ⁇ RIII mAb 2.4G2 was obtained from ATCC (Manassas, VA).
- polyclonal anti- ⁇ -chain Ab was provided by Dr. Jean-Pierre Kinet (Letourneur et al, J. Immunol. 147:2652-2656 (1991)).
- polyclonal anti- ⁇ -chain Abs were prepared in rabbits immunized with a C-terminal peptide sequence that is shared by both human and murine ⁇ -chain exactly as described (Letourneur et al, J. Immunol. 147:2652-2656 (1991)).
- Fura-2 (Molecular Probes, Eugene, OR), a fluorescent dye with spectral properties that change with the binding of free Ca 2+ , was used to measure changes in intracellular calcium concentrations as described (Edberg et al, J. Biol. Chem. 273:8071-8079 (1998)).
- P388D1 cells adhered to 25mm diameter round glass coverslips at 5 x 10 5 cells/ml, were incubated at 37°C for 15 min with 2 ⁇ M fura-2 AM. During the last 5 min, anti-Fc ⁇ RIa mAb 22.2 F(ab') 2 was added.
- BAPTA- AM was performed using Indo-1 (Molecular Probes) in an SLM Spectrofluorometer (Spectronics Instruments, Rochester, NY) exactly as previously described (Edberg et al, J. Biol. Chem. 270:22301-22307 (1995), Edberg et al, J. Biol. Chem. 273:8071-8079 (1998)).
- Endocytosis and Phagocytosis Endocytosis of transfected huFc ⁇ RIa was determined by monitoring the disappearance of cell surface associated anti-Fc ⁇ RI mAb 32.2 F(ab') 2 (Medarex) upon crosslinking with F(ab') 2 G ⁇ M (Odin et al, Science 254: 1785-1788 (1991)). Similarly, endocytosis of murine Fc ⁇ RIa on non-transfected cells was determined using mIgG2a (Sigma) and F(ab') ⁇ G ⁇ M. Cells (50 il, 5 x 10 6 /ml) were incubated with a saturating concentration mAb for 15 min at 4°C.
- Biotinylated mAb 22.2 F(ab') 2 and biotinylated bovine erythrocytes (E) were prepared as previously described (Edberg et al, J. Biol. Chem. 270:22301-22307 (1995)). Biotinylated E were saturated with streptavidin and washed. The resulting E were coated with biotinylated mAb and the level of mAb binding was' verified by flow cytometry.
- P388D1 cells adhered to round glass coverslips at 5 x 10 5 cells/ml, were incubated with anti-Fc ⁇ RIa mAb 22.2 F(ab') 2 coated E (E-22.2) in RPMI720% FCS (50 ⁇ l at 5 x 10 7 E/ml) for 1 hr at 37°C.
- E coated with an IgM anti-H2D d (Pharmingen) were used.
- Non-internalized E were lysed by brief immersion of the coverslip in dH 2 0 followed by immersion in buffer. Phagocytosis was quantitated by light microscopy and expressed as a phagocytic index (number of E internalized per 100 P388D1 cells).
- BAPTA- AM (Molecular Probes) to quench intracellular Ca 2+ levels was performed as previously described (Edberg et al, J. Biol. Chem. 270:22301-22307 (1995)). Briefly, coverslip adherent cells were incubated with varying concentrations of BAPTA-AM in RPMI/20% FCS for 30 min at 37°C followed by two washes. E-22.2 in RPMI/20% FCS were then added and handled as described above. Controls included loading cells with the BAPTA- AM solvent (1% DMSO) for the same period of time.
- the kinetics of transfected Fc ⁇ RIa specific phagocytosis was performed using a flow cytometric based assay (Pricop et al, J. Immunol. Methods 205:55-65 (1997)).
- the E-22.2 were labeled with the PKH26 Red Fluorescence Cell linker Kit (Sigma).
- Transfected P388D1 cells were mixed in suspension with labeled E-22.2 at a ratio of 50: 1 (E:P388D1) (both in RPMI/20% FCS), pelleted and incubated at 37°C for varying periods of time.
- Cytokine Analysis Cells were stimulated in 96 well tissue culture plates (Corning) with either PMA, surface absorbed rabbit IgG or surface absorbed F(ab') 2 G ⁇ M IgG + mAb 22.2 F(ab') 2 - Wells were coated with absorbed protein (20 ⁇ g/ml rabbit IgG or F(ab') 2 G ⁇ M) for 2 hrs at 37°C. For anti-Fc ⁇ Rl mAb 22.2 F(ab') 2 stimulation, mAb at 20 ⁇ g/ml was added to F(ab') 2 G ⁇ M coated wells for 1 hr at 37°C.
- EL-l ⁇ determination recombinant standard, capture ab (polyclonal rabbit Ab) and biotinylated detection and neutralization mAb (clone 1400.24.17) were obtained from Endogen (Woburn, MA).
- IL-6 determination recombinant standard, capture mAb (clone MP5-2- F3) and biotinylated detection mAb (clone MP5-32C11) were obtained from Pharmingen. HRP-conjugated streptavidin (Jackson) and then TMB substrate were added and the A 45 onm was determined.
- Fc ⁇ RIa and the ⁇ -chain mediate receptor complex assembly and twenty of the twenty-one amino acids in the transmembrane region are identical in murine and human ⁇ -chain with one conservative difference (I t_? V).
- the huFc ⁇ RIa CY domain alters the magnitude and kinetics of Fc ⁇ RIa internalization
- Phagocytosis by WT huFc ⁇ RIa also displayed more rapid kinetics (Fig. 2B). Similarly, while both WT and MUT huFc ⁇ RIa were capable of endocytosis, endocytosis by the WT receptor was more rapid than that mediated by the MUT receptor (Fig. 3). Endocytosis of endogenous murine Fc ⁇ RIa, assessed on non-transfected P388D1 cells, was indistinguishable from the transfected huFc ⁇ RIa.
- the CY domain of the -chain determines Ca sensitivity of Fc ⁇ RIa phagocytosis
- the ITAM has been shown to be both necessary and sufficient for Fc ⁇ R phagocytosis and the Fc ⁇ R Ca 2+ transient (Davis et al, EMBO J. 14:432-441 (1995), Lowry et al, J. Exp. Med. 187:161-176 (1998), Edberg et al, J. Biol. Chem. 270:22301-22307 (1995), Daeron et al, J. Immunol. 152:783-792 (1994), Mitchell et al, Blood 84: 1753- 1759 (1994), Park et al, Proc. Natl. Acad. Sci. USA 92:7381-7385 (1995)).
- WT huFc ⁇ RIa WT huFc ⁇ RIa
- phagocytosis by the WT huFc ⁇ RIa was performed with E-22.2 prepared with a lower mAb conjugation level resulting in a phagocytic index of 65.1 ⁇ 13.2 compared to a PI of 70.4+6.2 for MUT huFc ⁇ RIa and E-22.2 prepared at the maximal conjugation level.
- WT huFc ⁇ RI insensitivity to BAPTA was maintained under these reduced phagocytic conditions (Fig. 4A) indicating that the Ca 2+ insensitivity is a property of the cytoplasmic domain of huFc ⁇ RIa.
- WT huFc ⁇ RIa engages a Ca 2+ insensitive phagocytic pathway while MUT huFc ⁇ RIa with the associated ⁇ -chain engages a Ca 2+ sensitive phagocytic pathway.
- Fc ⁇ RIa can also modulate the immune response through the induction of cytokine secretion.
- activation of monocytes/macrophages by Fc ⁇ RIa can result in the secretion of IL- 6 and IL-l ⁇ (Krutmann et al, J. Immunol. 145:1337-1342 (1990), Simms et al, J. Immunol. 147:265-272 (1991)).
- P388D1 expressing the WT and MUT forms of huFc ⁇ RIa were stimulated with receptor specific mAb bound to surface absorbed F(ab') 2 -G ⁇ M.
- Fc ⁇ RIIa/Fc ⁇ R ⁇ ia and transfected human Fc ⁇ RIa to elicit IL-l ⁇ or IL-6 secretion was observed between the WT and MUT lines.
- P388D1 cells were transfected with constructs encoding wild type Fc ⁇ RIa or Fc ⁇ RIa mutants bearing alanines in place of serines in the cytoplasmic domain as indicated below:
- RI-SAS(400.1) The N-terminal two serine residues (Ser-328 and Ser- 331) in the cytoplasmic domain of human Fc ⁇ RI mutated to alanine (see Fig. 7).
- RI-SSA (400.1) The C-terminal two serines residues (Ser-339 and Ser- 340) in the cytoplasmic domain of human Fc ⁇ RI mutated to alanine (see Fig. 7).
- RI-dSdA 400.1: All four serine residues in the cytoplasmic domain of human Fc ⁇ RI mutated to alanine (see Fig. 7).
- constructs described above have C-terminal Myc and poly-histidine epitope tag derived from pCDNA3.1 -MycHis vector (Invitrogen). All the constructs were expressed under the control of human beta-actin promoter (Gunning et al,. Proc Nati Acad Sci U SA 84:483 (1987)). For culture, DMEM supplemented with L-glutamine (3 mM), penicillin (100 units/ml), streptomycin (100 jug/ml), 2-ME (50 ⁇ M) and 10% FCS was used.
- the phagocytic index of the transfectants is given in Fig. 6 (the "controls” are P388D1 cells transfected with wild type Fc ⁇ RI while the “experimentals” are P388D1 cells transfected, as indicated, with one of the above mutant forms of Fc ⁇ RI.
- the results from multiple experiments are shown.
- the data presented in Fig. 6 resulted from experiments in which the phagocytic index was determined using sheep erythrocytes coated with anti-sheep erythrocyte rabbit antibodies (designated "EA” in Fig. 6A) which engage all the Fc receptors present or using sheep erythrocytes coated with "E22.2 Fab” (see Fig. 6B), which engage only human Fc ⁇ RI.
- the data indicate that mutation of the serines in the cytoplasmic domain of Fc ⁇ RI increases phagocytosis generally and Fc ⁇ RI mediated phagocytosis in particular.
- cytoplasmic domain serines may bind a protein that leads to decreased Fc ⁇ RI signaling, and elimination of the serines leads to increasing signaling. All documents cited above are hereby incorporated in their entirety by reference.
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU80184/00A AU8018400A (en) | 1999-10-13 | 2000-10-13 | Fcgammaria |
EP00970865A EP1223967A4 (en) | 1999-10-13 | 2000-10-13 | Fc GAMMA RIA |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US15909699P | 1999-10-13 | 1999-10-13 | |
US60/159,096 | 1999-10-13 |
Publications (2)
Publication Number | Publication Date |
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WO2001026675A1 WO2001026675A1 (en) | 2001-04-19 |
WO2001026675A9 true WO2001026675A9 (en) | 2002-08-01 |
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Application Number | Title | Priority Date | Filing Date |
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PCT/US2000/028321 WO2001026675A1 (en) | 1999-10-13 | 2000-10-13 | FcηRIA |
Country Status (3)
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EP (1) | EP1223967A4 (en) |
AU (1) | AU8018400A (en) |
WO (1) | WO2001026675A1 (en) |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US5858981A (en) * | 1993-09-30 | 1999-01-12 | University Of Pennsylvania | Method of inhibiting phagocytosis |
US5650396A (en) * | 1994-03-15 | 1997-07-22 | Celtrix Pharmaceuticals, Inc. | Methods of modulating inflammatory cytokines in the CNS using TGF-β |
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2000
- 2000-10-13 EP EP00970865A patent/EP1223967A4/en not_active Withdrawn
- 2000-10-13 AU AU80184/00A patent/AU8018400A/en not_active Abandoned
- 2000-10-13 WO PCT/US2000/028321 patent/WO2001026675A1/en not_active Application Discontinuation
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Publication number | Publication date |
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WO2001026675A1 (en) | 2001-04-19 |
AU8018400A (en) | 2001-04-23 |
EP1223967A4 (en) | 2003-03-12 |
EP1223967A1 (en) | 2002-07-24 |
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