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WO2000066632A1 - Agonistes ou antagonistes de facteurs de croissance hematopoietique - Google Patents

Agonistes ou antagonistes de facteurs de croissance hematopoietique Download PDF

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Publication number
WO2000066632A1
WO2000066632A1 PCT/AU2000/000394 AU0000394W WO0066632A1 WO 2000066632 A1 WO2000066632 A1 WO 2000066632A1 AU 0000394 W AU0000394 W AU 0000394W WO 0066632 A1 WO0066632 A1 WO 0066632A1
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agonist
antagonist
crd3
family
loop
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Richard D'andrea
Christopher Bagley
Mathew Alexander Vadas
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Medvet Science Pty Ltd
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Medvet Science Pty Ltd
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    • 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
    • C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • C07K14/7153—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for colony-stimulating factors [CSF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to agonists and antagonists to certain haemopoietic growth factors and to methods of isolating the agonists and antagonists and to therapeutic use of the agonists or antagonists.
  • Granulocyte-macrophage colony stimulating factor (GM-CSF), Interleukin-3 (IL-3) and Interleukin-5 (IL-5) are cytokines involved in hemopoiesis and inflammation and all three stimulate eosinophil production, function and survival and therefore have the ability to influence inflammatory diseases such as asthma, atopic dermatitis and allergic rhinitis where the eosinophil plays a major effector role.
  • GM-CSF and IL- 3 also stimulate the proliferation, differentiation and functional activity of a wider variety of haemopoieteic cells including neutrophils, monocytes and early progenitor cells.
  • GM-CSF, IL-3 and IL-5 have overlapping, pleiotropic effects on haemopoietic cells and these effects include mitogenesis, protection from apoptosis, differentiation and functional activation.
  • the overlapping activities observed with these cytokines is explained by the fact that the high affinity receptors for human GM-CSF, IL-3 and IL-5 share a common ⁇ -subunit (h ⁇ c ).
  • h ⁇ c ⁇ -subunit
  • IL5R which are discussed in detail by Miyajima et al.(l), are each comprised of unique ligand-specific subunits (GMR , IL3R or IL5R ⁇ ) and a shared subunit (h ⁇ c ), which appears to be the primary signalling subunit (2). While it is clear that h ⁇ c is required for signalling it is still uncertain whether the ⁇ subunits have a direct signalling role. Although their cytoplasmic segments are clearly required for the normal function of these receptors (4-7), as yet no signalling molecules have been detected that associate with ⁇ subunits, and it appears that under some circumstances, ⁇ subunit dimerisation is sufficient for signalling (8-10).
  • the receptor subunits for GM-CSF, IL-3 and IL-5 are all members of the cytokine receptor (CR) superfamily (12, 13) which is characterised by a two hundred amino acid, extracellular, CR module (CRM).
  • CR cytokine receptor
  • Each CRM comprises two fibronectin-like ⁇ barrel structures (CR domains, CRD (14)); the seven ⁇ -strands in the membrane-distal and -proximal CRDs are designated A to G and A v to G ⁇ respectively.
  • WSXWS box Within the membrane-distal CRD are two pairs of disulfide-linked cysteine residues, while the membrane-proximal CRD of nearly all CRs contains a motif with the consensus Trp- Ser-Xaa-Trp-Ser (where Xaa is any amino acid) - referred to as the "WSXWS box".
  • IL-3 and IL-5 receptor subunits include the receptor subunits for growth hormone (GH), prolactin (PRL), erythropoietin (Epo), thrombopoietin (Tpo), Interleukin-2 (IL-2), IL-4, IL-6, IL-7, IL- 9, IL-11, IL-13, IL-15, Granulocyte-colony stimulating factor (G-CSF), leukaemia inhibitory factor (LIF), oncostatin-M (OSM), ciliary neurotrophic factor (CNTF), the p40 subunit of IL-12 and most recently the leptin receptor (15).
  • GH growth hormone
  • PRL prolactin
  • Epo erythropoietin
  • Tpo thrombopoietin
  • IL-2 Interleukin-2
  • IL-4 Interleukin-2
  • IL-4 Interleukin-6
  • IL-7 Interleukin-2
  • IL-4 Interleuk
  • CRD3 and CRD4 In vitro, these mutants confer factor-independence only on myeloid (granulocyte-macrophage) cells (17), a restriction explained by the recent finding that in mouse cell lines the CRD4 mutants require and interact with the (murine) GM-CSF receptor ⁇ -subunit (mGMR ⁇ )(18). These mutants also have activity in a subset of human haemopoietic cell lines suggesting that cell type-specific interactions are also important for activity in human cells (18).
  • CRD4 acts as a conformational switch and that normally, in the absence of ligand, it is constrained in an inactive conformation which cannot form a functional complex with the mGMR ⁇ (16).
  • the extracellular mutations in CRD4 appear to act by inducing a conformational change that results in an association with a mGMR ⁇ subunit (18).
  • the maintenance of the inactive conformation may be mediated through an interaction involving CRD3 and CRD4 (16,26).
  • the structure of the inactive EPOR dimer provides a model for such a structure (25). It has been shown previously that truncation of the extracellular region of h ⁇ c can result in activation; for example, a truncation equivalent to that which generated an oncogenic form of Tpo receptor (v- Mpl; ie which leaves only part of CRD4, see below) was shown to allow factor- independent proliferation of FDC-Pl cells (24).
  • the critical event appears to be the loss of CRD3, since a truncation that retained all of CRD4, but removed CRDs 1 , 2 and 3 was also activating, whereas removal of only CRDs 1 and 2 was insufficient to promote factor-independent proliferation (24) (WO 97/07125 to D'Andrea et at).
  • EPO-R erythropoietin
  • arginine to cysteine susbstitution in the membrane proximal CRD at position 129
  • This R129C form of EPO-R forms disulphide linked homodimers in the absence of EPO suggesting that wild type EPO-R is activated by ligand induced homodimerisation (26).
  • the introduction of further cysteine residues into the EPO-R membrane proximal domain also leads to disulphide linked homodimers that are constitutively active (27).
  • v- mpl is a murine oncogene encoding an activated cytokine fusion protein v-MPL and is transduced by the murine myeloproliferative leukaemia virus (MPLV) (28).
  • MPLV murine myeloproliferative leukaemia virus
  • the v-mpl fusion was generated from the partially deleted and rearranged env gene fused with cellular sequences from the c-mpl proto-oncogene encoding the thrombopoietin (TPO) receptor (29).
  • HGF Haemopoietic Growth Factors
  • the present inventors have found a small deletion in CRD3 ( ⁇ G254, A255) which is predicted to shorten the A-B loop and which confers constitutive activation. Additionally the inventors have data regarding a mutation in the adjacent E-F loop of CRD3 ( ⁇ A314, T315).
  • the present invention is predicated on the proposal that these residues are involved in interactions that are critical in modulating receptor activity.
  • the A-B loop and the E-F loop of CRD3 are therefore both key regulatory loops in h ⁇ c and conservation in receptor structure throughout the CR family suggests a similar role throughout the superfamily.
  • Interaction of ligand with these key loops in CRD3 or CRD4 may perturb inhibitory interactions in the same way as truncation or small deletion. This would result in conversion of the inactive receptor structure to an active structure capable of intracellular signalling. In the alternative they may result in inhibitory reactions that antagonise the actions of the cytokines that usually bind the receptors concerned.
  • the invention could be said to reside in an agonist or antagonist of an haemopoietic growth factor, said agonist or antagonist capable of binding a region of the CRD3 of h ⁇ or analogous domain of a corresponding haemopoietic growth factor receptor to thereby impact on an interaction between CRD3 and CRD4 or analogous domains to thereby effect an agonist or antagonist property.
  • the membrane proximal CRD of nearly all CRs contain a motif with a consensus WSXWS sequence. It is also known that the CRs contain conserved VRVR and WSXWS motifs which flank regions of h ⁇ c and other receptors that are known to be important for binding (see Middleton et al. (40); Woodcock et al. (22); Rajotte et al. (41); Layton et al. (42); Horsten et al. (43); Kalai et al. (44)).
  • the agonist or antagonist may have agonist or antagonist properties to a member of the cytokine receptor family where the member is selected from any one of a group acting as a receptor for any one or more of the following cytokines IL-2, IL-4, IL-6, IL-7, IL- 9, IL-11, IL-13, IL-15, growth hormone (GH), prolactin (PRL), granulocyte colony stimulating factor (G-CSF), erythropoietin (EPO), thrombopoietin (TPO), leukaemia inhibitory factor (LIF), oncostatin-M (OSM), cilairy neurotrophic factor (CNTF), the p40 subunit of IL-12 and leptin.
  • cytokines IL-2, IL-4, IL-6, IL-7, IL- 9, IL-11, IL-13, IL-15 growth hormone (GH), prolactin (PRL), granulocyte colony stimulating factor (G-CSF), ery
  • the agent may be an agonist or antagonist of any one of GM-CSF, IL-5 and IL-3 or of a newly discovered cytokine that resembles other cytokines in structure or is known to bind to a receptor that has a predicted structure resembling that of a cytokine receptor. Further, the agent may function through a predicted cytokine receptor for which ligand is not yet identified.
  • the agonist or antagonist may be selected from any one of a number of classes of compounds including antibodies, fragments of antibodies (Fab, Fv or peptide fragments), peptides, oligosaccharides, oligonucleotides, or other organic or inorganic compounds.
  • Fab fragments of antibodies
  • Fv fragments of antibodies
  • peptides oligosaccharides
  • oligonucleotides or other organic or inorganic compounds.
  • the antagonist or agonist may be capable of binding to a region selected from a group comprising the A-B loop and the E-F loop.
  • the antagonist or agonist binds to the A-B loop of CRD 3 or an analogous domain within the family of haemopoietic growth factors.
  • the predicted A-B loop of CRD3 may be bounded by a cysteine residue at position 250 and 260 and having a tyrosine residue at position 262 (h ⁇ c numbering).
  • the sequence of the A-B loop in analogous domains of other cytokine receptors can be predicted using the sequences between these conserved cyteine residues.
  • the antagonist or agonist may bind any one or more of the sequences listed in Figure 2.
  • the antagonist or agonist binds to the E-F loop of CRD3 or an analogous domain within the family of haemopoietic growth factors.
  • the predicted E-F loop of CRD3 may be bounded by a conserved cysteine in the E strand at position 306 and by an alternating series of hydrophobic residues in the F strand (positions 316, 321 and 323; see Figure 6)
  • the antagonist or agonist may bind any one or more of the sequences listed in Figure 6.
  • the antagonist or agonist may interfere with the interaction of the A-B loop of CRD3 or an analogous region within the family of haemopoietic growth factors with the F'-G loop of CRD4 or an analogous domain within the family of cytokine receptors.
  • the antagonist or agonist may interfere with the interaction of the A-B loop of CRD3 or an analogous region within the family of cytokine receptors, with the B'-C loop of CRD4 or an analogous domain within the family of cytokine receptors.
  • the antagonist or agonist may interfere with the interaction of the E-F loop of CRD3, or an analogous domain within the family of cytokine receptors with the F'-G' loop of CRD4 or an analogous region within the family of cytokine receptors.
  • the antagonist or agonist may interfere with the interaction of the E-F loop of CRD3, or an analogous region within the family of cytokine receptors with the B'-C loop of CRD4 or an analogous domain within the family of cytokine receptors.
  • the invention could be said to reside in a method lor isolating an agonist or antagonist of an haemopoietic growth factor, said agonist or antagonist capable of binding a region of the CRD3 of h ⁇ c or analogous domain of a corresponding cytokine receptor to thereby impact on an interaction between CRD3 and CRD4 or analogous domains to thereby effect an agonist or antagonist property, said method including the steps of contacting candidate agonists or antagonists with CRD3 or fragments thereof, assaying candidate agents for their capacity to bind CRD3 or fragment thereof and testing for agonist or antagonist properties.
  • the method may include the step of isolating a monoclonal antibody to CRD3 using methods that are well known to those skilled in the art (Zola et al. (45)).
  • the method may include fixing CRD3 or a fragment thereof to a substrate, contacting the fixed CRD3 or fragment with candidate antagonists or agonists, washing away material not bound to the fixed CRD3 or fragment, identifying the bound candidate antagonists or agonists, and testing the bound candidate antagonists or agonists for antagonist or agonist properties.
  • libraries of candidate antagonists or agonists are well known to those skilled in the art, and may include preparation of diversity libraries, such as random combinatorial peptide or nonpeptide libraries, that can be screened for molecules that specifically bind to CRD3 or a fragment thereof.
  • diversity libraries such as random combinatorial peptide or nonpeptide libraries, that can be screened for molecules that specifically bind to CRD3 or a fragment thereof.
  • Many libraries are known in the art that can be used, e.g., chemically synthesized libraries, recombinant (e.g., phage display libraries), natural products libraries, and in vitro translation-based libraries.
  • Screening the libraries can be accomplished by any of a variety of commonly known methods such as those found in PCT Publication No. WO 94/18318, for example.
  • screening can be carried out by contacting the library members with CRD3 or a fragment thereof (or nuclei acid or derivative) immobilized on a solid phase and harvesting those library members that bind to the protein (or nucleic acid or derivative). Examples of such screening methods, termed "panning" techniques are described by way of example in Parmley and Smith, 1988, Gene 73:305-318; Fowlkes et al., 1992, BioTechniques 13:422-427; PCT Publication No. WO 94/18318.
  • the agonist or antagonist properties of candidate agonists or antagonists may be tested using methods known in the art. Such methods may include monitoring the growth of factor-dependent cell lines in the absence of growth factor and the presence of a candidate molecule.
  • Alternative approaches may include a biochemical assay to detect signalling, which assays might include any one of the following: tyrosine phosphorylation status of the receptor, the levels of phosphorylation on ERK1 and ERK2 MAP kinases, JAK and STAT tyrosine phosphorylation, STAT DNA binding activity, and activation of reporter genes induced by specific signalling pathways.
  • the invention could be said to reside in a pharmaceutical composition, said composition including an agonist or antagonist as described or defined herein, and a suitable excipient.
  • compositions are well known in the art as reference can be made to Remington's Pharmaceutical Sciences, Mack Publishing Company, Eaton, Pa., USA and may also include one or more pharmaceutically acceptable carriers and/or diluents.
  • the invention could be said to reside in a method of treating a condition in a human or animal by administering an agonist or antagonist of a member of the cytokine receptor family as described or defined herein in a pharmaceutically acceptable form, in a suitable carrier and in a therapeutically effective dose.
  • Conditions that may be treated include those that are currently treated by GM-CSF, IL-3 and IL-5 as well as those in which other members of the family of haemopoietic growth factors are used in treatment.
  • the antagonists of the present invention may be useful inter alia in the treatment of myeloid and lymphocyte leukemias, tumors of non-haempoeitic origins and acute and chronic inflammation such as asthma, rheumatoid arthritis and atherosclerosis. These and other conditions are considered herein to result from or be facilitated by the aberrant effects of an endogenous HGF such as GM-CSF, IL-3 or IL-5.
  • an endogenous HGF such as GM-CSF, IL-3 or IL-5.
  • the treatment may be preventative and reduce the risk of contracting the condition or it may be used to alleviate or obviate the condition.
  • the administration of the therapeutic agent can be in any pharmaceutically acceptable form in a suitable carrier, and in a therapeutically acceptable dose.
  • FIG. 1 Model of CRD3 and CRD4 of h ⁇ c .
  • the spheres indicate the ⁇ -carbon atoms of residues Glycine 254 and Alanine 255 in the A-B loop.
  • the arrows indicate the B -C and F - G loops of CRD4 which have been shown to be important in ligand contact (see text and 20).
  • FIG. 4 Proliferation of BaF-B03 cells infected with retroviruses encoding activated forms of h ⁇ c.
  • A Proliferation of BaF-B03 cells infected with the ⁇ GA mutant
  • B Proliferation of infected BaF-B03 expressing the murine GM-CSF ⁇ -subunit, infected with the ⁇ GA mutant.
  • Cells were grown in the presence (grey) or absence (black) of murine IL-3. Control cell populations infected with a wild type h ⁇ c retrovirus, or a retrovirus carrying the constitutive mutant V449E (16) are also shown.
  • FIG. 1 Proliferation of CTL-EN cells in response to hIL-3. Proliferation of CTL-EN cells expressing hIL3R ⁇ and h ⁇ c mutants. Cells were grown in the presence of the indicated concentrations of human IL-3. A control cell population expressing only hIL3R ⁇ is also shown.
  • FIG. 6 Alignment of E-F loop sequences of cytokine receptors.
  • the sequences of the predicted E-F loop for h ⁇ c and other related CRs are shown.
  • the alignment consists of the three known structures (Growth hormone receptor, GHR, EPOR and the IL-6 receptor ⁇ -chain, gpl30).
  • the ⁇ -strand structure is indicated below the alignment; E: conserved ⁇ -strand, e: ⁇ -strand observed in at least one structure.
  • TPOR and OBR sequences of thrombopoietin and the leptin receptors.
  • the conserved cysteine in strand E and the hydrophobic residues in strand F are boxed.
  • the mutant receptor cDNA was excised from pALTER and cloned into the retroviral expression vector pRUFNeo (35). Retroviral DNA was used to transfect the ecotropic packaging cell line, ⁇ 2 ⁇ Mann ⁇ , and virus from G418 resistant cells was used to infect the murine haemopoietic cell lines, FDC-Pl, BaF-B03 or CTL-EN by co-cultivation.
  • Murine myeloid, IL-3/GM-CSF dependent FDC-Pl cells and derived cell lines were maintained in Dulbecco's modified Eagle's medium (DMEM) supplemented with 7.5% fetal bovine serum and murine GM-CSF (80U/ml; gift from Dr. G. Begley, Walter and Eliza Hall Institute for Medical Research, Melbourne Australia).
  • Murine IL-3 dependent BaF-B03 cells were maintained in DMEM supplemented with 7.5% fetal bovine serum and murine IL-3 (300 U/ml; gift from Dr. A. Hapel, John Curtin School for Medical Research, Australia, Australia).
  • Murine IL-2 dependent CTL-EN cells 37 were maintained in RPMI supplemented with 10% bovine serum and murine IL-2 .
  • mGMR ⁇ human IL-3 receptor ⁇ - subunit
  • hIL3R ⁇ human IL-3 receptor ⁇ - subunit
  • FDC-Pl producer cells
  • BaF-B03 or CTL-EN cells were harvested and selected in the presence of appropriate antibiotic and growth factor.
  • Receptor expression was examined by flow cytometric analysis after staining with the FLAG-specific monoclonal antibody, M2 (Kodak/IBI). Briefly, cells were washed and resuspended in cold PBS supplemented with 5% BSA (PBSA).
  • PBSA BSA
  • infected cells FDC-Pl, BaF-B03 and CTL-EN were washed three times with PBS to remove growth factor and then assayed in triplicate (5000 cells per well) in a 96-well microtiter plate in the presence and absence of the appropriate growth factor.
  • Cell growth was determined after 72 hours using a Cell Titer 96 non- radioactive cell proliferation assay (Promega). Quantitation was performed using an automated plate reader (BioRad).
  • the A-B loop is of invariant size and lies between two highly conserved cysteine residues (39). Thus we can confidently predict the sequence of this loop in CRD3 (see Figure 2).
  • the E-F loop is less well defined, however, there is a conserved cysteine in the E-strand which can be use for alignment and the F-strand has an alternating series of hydrophobic residues (see figure 6).
  • To assess the function of the A-B loop we deleted two residues ( ⁇ G254, A255) predicted to lie in the centre.
  • the modified h ⁇ c cDNAs were cloned into the retroviral expression vector pRUFNeo and introduced into the retroviral packaging cell line, ⁇ 2.
  • a stable pool of transfected ⁇ 2 cells was produced by antibiotic selection.
  • IL3R ⁇ (38). These cells therefore provide a useful system for analysing the ability of mutant h ⁇ c to interact with another ⁇ -subunit and ligand. These cells therefore provide a useful system for analysing the ability of mutant h ⁇ c to interact with another ⁇ - subunit and ligand.
  • Methods may include monitoring the growth of factor-dependent cell lines in the absence of growth factor and the presence of a candidate molecule (as described above).
  • Alternative approaches include a biochemical assay to detect signalling, which assays might include any one of the following: tyrosine phosphorylation status of the receptor, the levels of phosphorylation on ERK1 and ERK2 MAP kinases, JAK and STAT tyrosine phosphorylation, STAT DNA binding activity, and activation of reporteer genes induced by specific signalling pathways.
  • CRD3 antibodies to CRD3 or an fragment thereof may be carried out by any of the techniques familiar to those skilled in the art. For example, production of monoclonal antibodies involves immunisation of animals with recombinant CRD3 or CRD3-derived peptide coupled to carrier protein. Derived antibodies are then screened for ability to detect recombinant CRD3 and hbc (and truncated derivatives) expressed on the surface of cultured animal or human cells. Antibodies are tested for function as described in Example 1 above.
  • a diversity library such as a random combinatorial peptide or nonpeptide library is prepared according to any one or more of the following references.
  • a library of natural products may be screened according to the methods known in the art and discussed herein.
  • phage display libraries are described in Scott and Smith, 1990, Science 249:386-390; Devlin et al., 1990, Science, 249:404-406; Christian, R. B., et al., 1992, J. Mol. Biol. 227:711-718); Lenstra, 1992, J. Immunol. Meth. 152: 149-157; Kay et al., 1993, Gene 128:59-65; and PCT Publication No. WO 94/18318 dated Aug. 18, 1994.
  • In vitro translation-based libraries include but are not limited to those described in PCT Publication No. WO 91/0505 dated Apr. 18, 1991; and Mattheakis et al., 1994, Proc. Natl. Acad. Sci. USA 91:9022-9026.
  • a benzodiazepine library (see e.g., Bunin et al., 1994, Proc. Natl. Acad. Sci. USA 91:4708-4712) can be adapted for use.
  • Peptoid libraries (Simon et al., 1992, Proc. Natl. Acad. Sci. USA 89:9367-9371) can also be used.
  • the library can then be screened against CRD3 or fragment thereof using any of a variety of commonly known methods. See, e.g., the following references, which disclose screening of peptide libraries: Parmley and Smith, 1989, Adv. Exp. Med. Biol. 251:215-218; Scott and Smith, 1990, Science 249:386-390; Fowlkes et al., 1992; BioTechniques 13:422-427; Oldenburg et al., 1992, Proc. Natl. Acad. Sci.
  • the screening can be carried out by contacting the library members with CRD3 or fragment thereof immobilized on a solid phase and harvesting those library members that bind to the protein (or nucleic acid or derivative).
  • Examples of such screening methods termed “panning” techniques are described by way of example in Parmley and Smith, 1988, Gene 73:305-318; Fowlkes et al., 1992, BioTechniques 13:422-427; PCT Publication No. WO 94/18318; and in references cited hereinabove.

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Abstract

L'invention concerne un agoniste ou un antagoniste d'un facteur de croissance hématopoïétique, capable de se lier à une région du CRD3 de hβc ou un domaine analogue d'un récepteur correspondant de facteur de croissance hématopoïétique, afin d'influencer ainsi l'interaction entre le CRD3 et le CRD4 ou des domaines analogues et, de là, agir sur une propriété agoniste ou antagoniste. Les propriétés agonistes ou antagonistes peuvent appartenir à un membre de la famille des récepteurs de cytokine, le membre étant sélectionné dans le groupe servant de récepteur pour n'importe le(s)quel(s) des éléments suivants: IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-11, IL-13, IL-15, un facteur de stimulation des granulocytes et macrophages (GM-CSF), une hormone de croissance, la prolactine (PRL), un facteur stimulant les colonies de granulocytes (G-CSF), l'érythropoïétine, la thrombopoïétine, un facteur inhibant les cellules leucémiques (LIF), l'oncostatine M (OSM), un facteur neurotrophique ciliaire (CNTF), la sous-unité p40 de l'interleukine 12, la leptine et les membres de la famille du récepteur de cytokine, découverts récemment.
PCT/AU2000/000394 1999-04-29 2000-05-01 Agonistes ou antagonistes de facteurs de croissance hematopoietique Ceased WO2000066632A1 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005001478A1 (fr) * 2003-06-30 2005-01-06 Biovitrum Ab Procedes pour identifier des agents regulant les cytokines
EP1409543A4 (fr) * 2001-05-10 2005-04-20 Applera Corp Proteines receptrices humaines isolees, molecules d'acides nucleiques codant pour ces proteines receptrices humaines et leurs utilisations
EP1459762A4 (fr) * 2001-11-02 2005-11-16 Yoshiko Yasuda Agents prophylactiques/therapeutiques destines aux maladies des organes a evolution chronique, aux maladies arthritiques chroniques, aux cicatrices hypertrophiques ou cheloides
US7285392B2 (en) 2003-06-30 2007-10-23 Biovitrum Ab Methods for identifying active compounds
US7396913B2 (en) 2002-10-14 2008-07-08 Abbott Laboratories Erythropoietin receptor binding antibodies
WO2009006688A1 (fr) * 2007-07-11 2009-01-15 Medvet Science Pty Ltd Régulation des taux d'il-4 et d'il-13 par blocage de la liaison de haute affinité par l'il-3, l'il-5 et le gm-csf à leur récepteur commun
WO2010094068A1 (fr) * 2009-02-18 2010-08-26 Csl Limited Traitement d'affections inflammatoires chroniques
WO2013017830A1 (fr) * 2011-08-03 2013-02-07 University Of Sheffield Structure des récepteurs de leptine

Citations (4)

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EP1459762A4 (fr) * 2001-11-02 2005-11-16 Yoshiko Yasuda Agents prophylactiques/therapeutiques destines aux maladies des organes a evolution chronique, aux maladies arthritiques chroniques, aux cicatrices hypertrophiques ou cheloides
US7053050B2 (en) 2001-11-02 2006-05-30 Yoshiko Yasuda Preventives/remedies for proliferative organ diseases chronic arthritic diseases, hypertrophic scar or keloid
US7396913B2 (en) 2002-10-14 2008-07-08 Abbott Laboratories Erythropoietin receptor binding antibodies
WO2005001478A1 (fr) * 2003-06-30 2005-01-06 Biovitrum Ab Procedes pour identifier des agents regulant les cytokines
US7285392B2 (en) 2003-06-30 2007-10-23 Biovitrum Ab Methods for identifying active compounds
WO2009006688A1 (fr) * 2007-07-11 2009-01-15 Medvet Science Pty Ltd Régulation des taux d'il-4 et d'il-13 par blocage de la liaison de haute affinité par l'il-3, l'il-5 et le gm-csf à leur récepteur commun
WO2010094068A1 (fr) * 2009-02-18 2010-08-26 Csl Limited Traitement d'affections inflammatoires chroniques
US8535669B2 (en) 2009-02-18 2013-09-17 Csl Limited Methods of treating lupus by administering humanized anti-interleukin 3 receptor alpha chain antibodies
US9758585B2 (en) 2009-02-18 2017-09-12 Csl Limited Compositions and methods for targeting type 1 interferon producing cells
WO2013017830A1 (fr) * 2011-08-03 2013-02-07 University Of Sheffield Structure des récepteurs de leptine

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