WO2004007682A2 - Methods and compositions for modulating t helper (th) cell development and function - Google Patents
Methods and compositions for modulating t helper (th) cell development and function Download PDFInfo
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- WO2004007682A2 WO2004007682A2 PCT/US2003/021975 US0321975W WO2004007682A2 WO 2004007682 A2 WO2004007682 A2 WO 2004007682A2 US 0321975 W US0321975 W US 0321975W WO 2004007682 A2 WO2004007682 A2 WO 2004007682A2
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Definitions
- the contacting step is carried out ex vivo, in vitro or in vivo.
- the contacting step can be carried out in a mammalian subject, for example, the mammalian subject is a human.
- FIG. 1 A is a representation of a Northern blot hybridization analysis examining expression of IL-21, IL-4, IFN ⁇ , and ⁇ actin under the various Thl and Th2 skewing conditions described in the appended Examples.
- FIG. IB is a histogram showing the level of IL-21 mRNA relative to GAPDH mRNA in Thl and Th2 cells following primary and secondary stimulation.
- FIG. IC is a histogram showing the level of IL-21 mRNA relative to GAPDH mRNA in primary and secondary Thl and Th2 cells cultured in the presence or absence of LL-4 and IFN ⁇ .
- FIG. ID is a histogram showing the level of IL-21 mRNA, EL-4 mRNA, and IFN ⁇ mRNA relative to GAPDH mRNA in C57BL/g and BALB/c mice following infection with L. major.
- FIG. 2 A is a graphic representation of IL-4 and IL-21 cytokine production in Thp cells cultured under neutral conditions, or Thl skewing conditions.
- FIG. 2B is a histogram showing IFN ⁇ production in IL-21 treated or mock treated Thp cells.
- FIG. 3 A is a graphic representation of IL-4 and IFN ⁇ production in Thp cells cultured under Thl skewing conditions in the presence or absence of EL-22.
- FIG. 3B is a graphic representation of IL-4 and IFN ⁇ production in LL-21 treated or mock treated Thp cells treated in Thl skewing conditions from wild-type and Stat ⁇ -/- mice.
- FIG. 3C is a graphic representation of IFN ⁇ , IL-2, and TNF ⁇ expression in IL-21 treated or mock treated Thl cells from wild-type and Stat ⁇ -/- mice.
- FIG. 4A is a representation of a western blot analysis of T-bet and actin protein levels in Thp cells cultured under Thl or Th2 skewing conditions.
- FIG. 4B is a histogram showing relative levels of IL-12R ⁇ 2 mRNA relative to levels in Thl cells.
- FIG. 4C is a representation of a western blot analysis of phosphorylated Stat4, Stat4, Statl, and IL-12 polypeptide levels in Thp cells stimulated with anti-CD3 in the presence of LL- 21 or mock supernatants.
- FIG. 4D is a histogram showing levels of Stat4 mRNA relative to GAPDH mRNA in mock treated and IL-21 Thp cells stimulated with anti-CD3 for 48 hours in the presence of IL-21 or mock supernatants.
- IL-4 mRNA and IFN ⁇ are examples
- FIG. 5 A is a graph showing specific swelling in TNP-KLH-immunized wild type and IL21-21R-/- mice subsequently injected with TNP-KLH or PBS.
- FIG.5B is a histogram showing LFN ⁇ production in CD4+ T cells purified from draining lymph nodes of TNP-KLH-immunized wild type and IL21-21R-/- mice restimulated by antigen.
- the invention provides methods and compositions for modulating T helper cell differentiation, development and activity by modulating the interaction between IL-21 and an IL- 21 receptor.
- LL-21 or agents that increase IL-21 or IL-21 receptor levels in a cell population, are added to a population of T helper cells to suppress FN ⁇ levels in a population of Thp or Thl cells.
- IL-21, or agents that increase IL-21 levels can also be used to promote Th2 development, or to potentiate Th2-mediated immune responses and/or to suppress Thl development.
- a method for modulating one or more of: IFN ⁇ activity, expression, secretion, or processing, in a T cell e.g., a T cell precursor cell (a Thp cell), or a Thl cell (e.g., a differentiating Thl cell or an effector Th cell), or a T cell population thereof, is provided.
- a T cell e.g., a T cell precursor cell (a Thp cell), or a Thl cell (e.g., a differentiating Thl cell or an effector Th cell), or a T cell population thereof.
- the method includes:
- the subject method can be used on cells in culture, e.g. in vitro or ex vivo.
- immune cells e.g., T cells as described herein
- the contacting step can be effected by adding one or more LL-21 modulators (e.g., an IL-21 agonist or antagonist), to the culture medium.
- the method is performed on cells (e.g., immune or T cells as described herein) present in a subject, e.g., as part of an in vivo (e.g., therapeutic or prophylactic) protocol.
- a method for reducing or inhibiting the activity or level of IFN ⁇ in a cell e.g., a T cell (e.g., a T cell precursor cell (a Thp cell), or a Thl cell (e.g., a differentiating Thl cell or an effector Th cell)), or a cell population thereof is provided.
- the method includes (optionally) identifying a cell, e.g., a T cell, or a cell population, e.g., a T cell population, in which reduction or inhibition of the activity or level of IFN ⁇ is desired; and contacting said cell or cell population with an amount of an IL-21 agonist, sufficient to reduce or inhibit the activity or level of IFN ⁇ in said cell or cell population.
- the 11-21 agonist specifically inhibits IFN ⁇ levels or activity, e.g., it does not reduce or inhibit the activity or level of other cytokines such IL-2 or TNF ⁇ .
- the IL-21 agonist inhibits production of IFN ⁇ by an IFN ⁇ -producing cell, e.g., an IFN ⁇ -producing Thl cell.
- the invention provides a method for reducing IFN ⁇ levels or activity in a subject. The method includes (optionally) identifying a subject in which reduction of IFN ⁇ levels or activity is desired; and administering to said subject an amount of an EL-21 agonist sufficient to reduce the levels or activity IFN ⁇ .
- IFN ⁇ can be measured using techniques known in the art, for example, intracellular cytokine staining, or an ELISA technique to determine levels in cell supernatants.
- the IL-21 agonist can be an IL-21 polypeptide, a human LL-21 polypeptide, or an active fragment thereof (e.g., a human IL-21 polypeptide comprising the amino acid sequence shown as SEQ ID NO:2, or encoded by a nucleotide sequence shown as SEQ ID NO: 1, or a sequence substantially homologous thereto).
- the IL-21 agonist is a fusion protein comprising an IL-21 polypeptide, e.g., human IL-21 polypeptide, or a fragment thereof fused to another polypeptide, e.g., an immunoglobulin polypeptide or a portion thereof (e.g., an Fc region of an immunoglobulin polypeptide); an agonist antibody to the IL-21 receptor; or a small molecule agonist.
- the IL-21 agonist is an agent that increases the activity or level of IL-21 by, e.g., increasing expression, processing and or secretion of functional IL-21.
- the invention additionally features a method of increasing IFN ⁇ levels or activity in a cell, e.g., a T-cell, or a cell population, e.g., a T cell population.
- a cell e.g., a T-cell
- a cell population e.g., a T cell population.
- the invention includes method for increasing EFN ⁇ activity, expression, secretion, or processing, in a T cell, e.g., a T cell precursor cell (a Thp cell), or a Thl cell (e.g., a differentiating Thl cell or an effector Th cell), or a T cell population thereof.
- a T cell precursor cell e.g., a Thp cell
- Thl cell e.g., a differentiating Thl cell or an effector Th cell
- the IL-21 antagonist can be, e.g., an antibody (e.g., a monoclonal or single specificity antibody) to IL-21, e.g., human LL-21, or an LL-21 receptor, e.g., human IL-21 receptor polypeptide.
- the antibody is a human, humanized, chimeric, or in vitro generated antibody to human IL-21 or human IL-21 receptor polypeptide.
- the antagonist includes a fragment of an IL-21 polypeptide, e.g., an IL-21 receptor binding domain of an IL-21 polypeptide.
- the antagonist includes a fragment of an IL-21 receptor polypeptide, e.g., an IL-21 binding domain of an IL-21 receptor polypeptide.
- the antagonist is a fusion protein comprising the aforesaid LL-21 or 11-21 receptor polypeptides or fragments thereof fused to a second moiety, e.g., a polypeptide (e.g., an immunoglobulin chain).
- a method of increasing Th2 cell activity and/or cell number is provided.
- the method includes (optionally) identifying a cell, e.g., a T cell (e.g., a Thp or a Th2 cell), or a cell population, where increased proliferation, survival and/or differentiation is desired; and contacting said cell or cell population with an IL-21 agonist in an amount sufficient to increase one or more of proliferation, survival and/or differentiation into, (e.g., increase differentiation of said Thp cell into a Th2 cell) a Th2 cell, thereby increasing Th2 cell activity and/or cell number.
- a cell e.g., a T cell (e.g., a Thp or a Th2 cell)
- an IL-21 agonist in an amount sufficient to increase one or more of proliferation, survival and/or differentiation into, (e.g., increase differentiation of said Thp cell into a Th2 cell) a Th2 cell, thereby increasing Th2 cell activity and/or cell number.
- the IL-21 agonist is a fusion protein comprising an IL-21 polypeptide, e.g., human IL-21 polypeptide, or a fragment thereof fused to another polypeptide, e.g., an immunoglobulin polypeptide or a portion thereof (e.g., an Fc region of an immunoglobulin polypeptide); an agonist antibody to the LL-21 receptor; or a small molecule agonist.
- an IL-21 polypeptide e.g., human IL-21 polypeptide, or a fragment thereof fused to another polypeptide, e.g., an immunoglobulin polypeptide or a portion thereof (e.g., an Fc region of an immunoglobulin polypeptide); an agonist antibody to the LL-21 receptor; or a small molecule agonist.
- a method for modulating e.g., increasing or decreasing, Thl cell number and/or activity is provided.
- a method of modulating, e.g., promoting or inhibiting, one or more of proliferation, survival and/or differentiation into e.g., differentiation of a T cell precursor, e.g., a Th precursor (Thp), into
- a Thl cell e.g., differentiation of a T cell precursor, e.g., a Th precursor (Thp), into
- immune cells e.g., T cells as described herein
- the contacting step can be effected by adding one or more IL-21 modulators (e.g., an IL-21 agonist or antagonist), to the culture medium.
- the method can be performed on cells (e.g., immune or T cells as described herein) present in a subject, e.g., as part of an in vivo (e.g., therapeutic or prophylactic) protocol.
- Thl cell activity and/or cell number can be increased by increasing one or more of proliferation, survival and/or differentiation into (e.g., differentiation of a T cell precursor, e.g., a Th precursor (Thp), into), a Thl cell.
- the method includes:
- identifying a cell e.g., a T cell (e.g., a Thp or a Thl cell), or a cell population, where increased proliferation, survival and/or differentiation is desired; and contacting said cell or cell population with an IL-21 antagonist in an amount sufficient to increase one or more of proliferation, survival and/or differentiation into, (e.g., increase differentiation of said Thp cell into a Thl cell) a Thl cell, thereby increasing Thl cell activity and/or cell number.
- a T cell e.g., a Thp or a Thl cell
- an IL-21 antagonist in an amount sufficient to increase one or more of proliferation, survival and/or differentiation into, (e.g., increase differentiation of said Thp cell into a Thl cell) a Thl cell, thereby increasing Thl cell activity and/or cell number.
- the clones can be subcloned by limiting dilution procedures and grown by standard methods. Suitable culture media for this purpose include, for example, Dulbecco's Modified Eagle's Medium and RPMI-1640 medium. Alternatively, the hybridoma cells can be grown in vivo as ascites in a mammal.
- the monoclonal antibodies secreted by the subclones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxyapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.
- Fully human antibodies relate to antibody molecules in which essentially the entire sequences of both the light chain and the heavy chain, including the CDRs, arise from human genes. Such antibodies are termed "human antibodies", or “fully human antibodies” herein.
- Human monoclonal antibodies can be prepared by the trioma technique; the human B-cell hybridoma technique (see Kozbor, et al. (1983) Immunol Today 4: 72) and the EBV hybridoma technique to produce human monoclonal antibodies (see Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp. 77-96).
- human antibodies can be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire.
- transgenic animals e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated.
- human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire.
- This approach is described, for example, in U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, and in Marks et al. (Bio/Technology 10, 779-783 (1992)); Lonberg et al.
- Example 5 IL-21 inhibition of IFN ⁇ is independent of Stat6.
- RNA from na ⁇ ve Thp cells cultured under Thl and Th2 skewing conditions in the presence and absence of IL-21 was analyzed for 12R ⁇ 2 expression by RealTime PCR.
- Thp cells were cultured under Th 1 or Th2 skewing conditions for one week.
- IL-21 or mock supernatant was included in indicated cultures.
- RNA was harvested 24 hours after secondary stimulation with anti-CD3 and assessed for LL-12R ⁇ 2 expression by RealTime PCR.
Abstract
Description
Claims
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EP03764624A EP1553982A4 (en) | 2002-07-15 | 2003-07-15 | METHODS AND COMPOSITIONS FOR MODULATING T HELPER (T sb H /sb ) CELL DEVELOPMENT AND FUNCTION |
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JP2004521793A JP4776228B2 (en) | 2002-07-15 | 2003-07-15 | Methods and compositions for modulating the development and function of T helper (TH) cells |
AU2003251900A AU2003251900B2 (en) | 2002-07-15 | 2003-07-15 | Methods and compositions for modulating T helper (Th) cell development and function |
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IL195769A IL195769A0 (en) | 2002-07-15 | 2008-12-07 | Methods and compositions for modulating t helper (th) cell development and function |
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CA2800913C (en) | 2010-06-03 | 2019-07-23 | Pharmacyclics, Inc. | The use of inhibitors of bruton's tyrosine kinase (btk) |
WO2015089217A2 (en) | 2013-12-10 | 2015-06-18 | Bionz, Llc | Methods of developing selective peptide antagonists |
PT2665486T (en) | 2011-01-18 | 2020-03-30 | Bioniz Llc | Compositions and mehthods for modulating gamma-c-cytokine activity |
US9920932B2 (en) | 2011-01-26 | 2018-03-20 | United Technologies Corporation | Mixer assembly for a gas turbine engine |
KR20130011056A (en) * | 2011-07-20 | 2013-01-30 | 주식회사에이앤알쎄라퓨틱스 | Receptors targeting inflammation and drug carriers for treatment of inflammatory diseases |
EP2877598A1 (en) | 2012-07-24 | 2015-06-03 | Pharmacyclics, Inc. | Mutations associated with resistance to inhibitors of bruton's tyrosine kinase (btk) |
KR20150080592A (en) | 2012-11-02 | 2015-07-09 | 파마시클릭스, 인코포레이티드 | Tec family kinase inhibitor adjuvant therapy |
US20140170727A1 (en) * | 2012-12-19 | 2014-06-19 | Nanomr, Inc. | Affinity medium using fixed whole cells |
WO2015143400A1 (en) | 2014-03-20 | 2015-09-24 | Pharmacyclics, Inc. | Phospholipase c gamma 2 and resistance associated mutations |
US10030058B2 (en) | 2015-10-09 | 2018-07-24 | Bioniz, Llc | Modulating gamma-C-cytokine activity |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6057128A (en) * | 1998-03-17 | 2000-05-02 | Genetics Institute, Inc. | MU-1, member of the cytokine receptor family |
US6307024B1 (en) * | 1999-03-09 | 2001-10-23 | Zymogenetics, Inc. | Cytokine zalpha11 Ligand |
Family Cites Families (63)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3710795A (en) * | 1970-09-29 | 1973-01-16 | Alza Corp | Drug-delivery device with stretched, rate-controlling membrane |
US4816567A (en) * | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US5225539A (en) * | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
US4946778A (en) * | 1987-09-21 | 1990-08-07 | Genex Corporation | Single polypeptide chain binding molecules |
US5011912A (en) * | 1986-12-19 | 1991-04-30 | Immunex Corporation | Hybridoma and monoclonal antibody for use in an immunoaffinity purification system |
ATE140963T1 (en) * | 1988-01-22 | 1996-08-15 | Zymogenetics Inc | METHOD FOR PRODUCING SECRETED RECEPTOR ANALOGUES |
US6018026A (en) * | 1988-01-22 | 2000-01-25 | Zymogenetics, Inc. | Biologically active dimerized and multimerized polypeptide fusions |
US5750375A (en) * | 1988-01-22 | 1998-05-12 | Zymogenetics, Inc. | Methods of producing secreted receptor analogs and biologically active dimerized polypeptide fusions |
US5567584A (en) * | 1988-01-22 | 1996-10-22 | Zymogenetics, Inc. | Methods of using biologically active dimerized polypeptide fusions to detect PDGF |
GB8823869D0 (en) * | 1988-10-12 | 1988-11-16 | Medical Res Council | Production of antibodies |
US5116964A (en) * | 1989-02-23 | 1992-05-26 | Genentech, Inc. | Hybrid immunoglobulins |
US5225538A (en) * | 1989-02-23 | 1993-07-06 | Genentech, Inc. | Lymphocyte homing receptor/immunoglobulin fusion proteins |
US6406697B1 (en) * | 1989-02-23 | 2002-06-18 | Genentech, Inc. | Hybrid immunoglobulins |
US5098833A (en) * | 1989-02-23 | 1992-03-24 | Genentech, Inc. | DNA sequence encoding a functional domain of a lymphocyte homing receptor |
US5216131A (en) * | 1989-02-23 | 1993-06-01 | Genentech, Inc. | Lymphocyte homing receptors |
US5328470A (en) * | 1989-03-31 | 1994-07-12 | The Regents Of The University Of Michigan | Treatment of diseases by site-specific instillation of cells or site-specific transformation of cells and kits therefor |
ATE139258T1 (en) * | 1990-01-12 | 1996-06-15 | Cell Genesys Inc | GENERATION OF XENOGENE ANTIBODIES |
US5625126A (en) * | 1990-08-29 | 1997-04-29 | Genpharm International, Inc. | Transgenic non-human animals for producing heterologous antibodies |
US5545806A (en) * | 1990-08-29 | 1996-08-13 | Genpharm International, Inc. | Ransgenic non-human animals for producing heterologous antibodies |
US5633425A (en) * | 1990-08-29 | 1997-05-27 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
KR100272077B1 (en) * | 1990-08-29 | 2000-11-15 | 젠팜인터내셔날,인코포레이티드 | Transgenic non-human animals capable of producing heterologous antibodies |
US5661016A (en) * | 1990-08-29 | 1997-08-26 | Genpharm International Inc. | Transgenic non-human animals capable of producing heterologous antibodies of various isotypes |
US6136310A (en) * | 1991-07-25 | 2000-10-24 | Idec Pharmaceuticals Corporation | Recombinant anti-CD4 antibodies for human therapy |
WO1993008829A1 (en) | 1991-11-04 | 1993-05-13 | The Regents Of The University Of California | Compositions that mediate killing of hiv-infected cells |
US5447851B1 (en) * | 1992-04-02 | 1999-07-06 | Univ Texas System Board Of | Dna encoding a chimeric polypeptide comprising the extracellular domain of tnf receptor fused to igg vectors and host cells |
SG48760A1 (en) | 1992-07-24 | 2003-03-18 | Abgenix Inc | Generation of xenogenetic antibodies |
US5262564A (en) * | 1992-10-30 | 1993-11-16 | Octamer, Inc. | Sulfinic acid adducts of organo nitroso compounds useful as retroviral inactivating agents anti-retroviral agents and anti-tumor agents |
US5516964A (en) * | 1994-01-21 | 1996-05-14 | Sun Company, Inc. (R&M) | Hydrocarbon isomerization using solid superacid catalysts comprising platinum metal |
US5731168A (en) | 1995-03-01 | 1998-03-24 | Genentech, Inc. | Method for making heteromultimeric polypeptides |
EP0822830B1 (en) | 1995-04-27 | 2008-04-02 | Amgen Fremont Inc. | Human anti-IL-8 antibodies, derived from immunized xenomice |
EP0823941A4 (en) | 1995-04-28 | 2001-09-19 | Abgenix Inc | Human antibodies derived from immunized xenomice |
FR2742156A1 (en) | 1995-12-06 | 1997-06-13 | Sanofi Sa | IL-13 RECEPTOR POLYPEPTIDE |
US5710023A (en) | 1996-03-01 | 1998-01-20 | Genetics Institute, Inc. | IL-13 cytokine receptor chain |
AU2326097A (en) | 1996-03-13 | 1997-10-01 | Zymogenetics Inc. | Cytokine-receptor expressed in testis cells |
WO1997047741A1 (en) | 1996-06-12 | 1997-12-18 | Smithkline Beecham Corporation | Hr-1 receptor |
EP0812913A3 (en) | 1996-06-12 | 1999-08-04 | Smithkline Beecham Corporation | HR-1 receptor, a receptor of the cytokine receptors family |
WO1997047742A1 (en) | 1996-06-12 | 1997-12-18 | Smithkline Beecham Corporation | Hr-1 receptor |
WO1998010638A1 (en) | 1996-09-10 | 1998-03-19 | Amrad Operations Pty. Ltd. | Therapeutic molecules |
AUPO224696A0 (en) | 1996-09-11 | 1996-10-03 | Amrad Operations Pty. Limited | A novel haemopoietin receptor and genetic sequences encoding same |
US5916771A (en) * | 1996-10-11 | 1999-06-29 | Abgenix, Inc. | Production of a multimeric protein by cell fusion method |
JP2001508309A (en) | 1997-01-16 | 2001-06-26 | ジェネティックス・インスチチュート・インコーポレーテッド | Member of the hematopoietin receptor superfamily |
US7189400B2 (en) * | 1998-03-17 | 2007-03-13 | Genetics Institute, Llc | Methods of treatment with antagonists of MU-1 |
US7198789B2 (en) * | 1998-03-17 | 2007-04-03 | Genetics Institute, Llc | Methods and compositions for modulating interleukin-21 receptor activity |
US20020029391A1 (en) | 1998-04-15 | 2002-03-07 | Claude Geoffrey Davis | Epitope-driven human antibody production and gene expression profiling |
WO1999067290A1 (en) | 1998-06-24 | 1999-12-29 | Chugai Research Institute For Molecular Medicine, Inc. | Novel hemopoietin receptor proteins |
AU5104799A (en) | 1998-08-04 | 2000-02-28 | Regeneron Pharmaceuticals, Inc. | Novel orphan cytokine receptors |
CZ20011026A3 (en) | 1998-09-23 | 2001-08-15 | Zymogenetics, Inc. | Isolated polynucleotide, expression vector, cultivated cell, DNA construct, production process of protein, isolated polypeptide, production process of antibody, antibody per se and detection method |
US6576744B1 (en) * | 1998-09-23 | 2003-06-10 | Zymogenetics, Inc. | Cytokine receptor zalpha11 |
EP1124851A1 (en) | 1998-11-06 | 2001-08-22 | Smithkline Beecham Corporation | Hnovilr |
CN101575377B (en) | 1999-03-09 | 2012-12-26 | 津莫吉尼蒂克斯公司 | Human cytokine as ligand of zalpha receptor and use thereof |
US20020090680A1 (en) | 1999-05-18 | 2002-07-11 | Millennium Pharmaceuticals, Inc. | Novel IL-9/IL-2 receptor-like molecules and uses thereof |
EP1303602B1 (en) | 2000-04-05 | 2006-12-27 | ZymoGenetics, Inc. | Soluble zalpha11 cytokine receptors |
EP1353953B1 (en) | 2000-05-11 | 2006-11-29 | Genetics Institute, LLC | Mu-1, member of the cytokine receptor family |
ES2277947T3 (en) * | 2000-10-13 | 2007-08-01 | Eli Lilly And Company | PROCEDURES FOR USING A HUMAN IL-17 AFIN POLYPEPTIDE TO TREAT DISEASES. |
EP3254687A1 (en) * | 2001-10-04 | 2017-12-13 | Genetics Institute LLC | Methods and compositions for modulating interleukin-21 receptor activity |
US20040016010A1 (en) * | 2002-04-17 | 2004-01-22 | Marion Kasaian | IL-21 receptor knockout animal and methods of use thereof |
MXPA05000655A (en) | 2002-07-15 | 2006-02-22 | Harvard College | Methods and compositions for modulating t helper (th. |
DE602004025332D1 (en) | 2003-03-14 | 2010-03-18 | Wyeth Corp | ANTIBODY TO IL21 RECEPTOR AND ITS USE |
KR20060015482A (en) | 2003-03-21 | 2006-02-17 | 와이어쓰 | Treating immunological disorder using agonists of interleukin-21/interleukin-21 receptor |
EP1753458A4 (en) * | 2004-05-19 | 2009-07-22 | Wyeth Corp | Modulation of immunoglobulin production and atopic disorders |
WO2006135385A2 (en) * | 2004-08-05 | 2006-12-21 | Wyeth | Antagonizing interleukin-21 receptor activity |
GT200600148A (en) * | 2005-04-14 | 2006-11-22 | METHODS FOR THE TREATMENT AND PREVENTION OF FIBROSIS | |
WO2009100035A2 (en) | 2008-02-01 | 2009-08-13 | Wyeth | Interleukin-21 (il-21) and il-21 receptor (il-21r) modulation of regulatory t cells and forkhead box p3 (foxp3) |
-
2003
- 2003-07-15 MX MXPA05000655A patent/MXPA05000655A/en active IP Right Grant
- 2003-07-15 JP JP2004521793A patent/JP4776228B2/en not_active Expired - Fee Related
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- 2003-07-15 AU AU2003251900A patent/AU2003251900B2/en not_active Ceased
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-
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- 2005-02-10 NO NO20050717A patent/NO20050717L/en not_active Application Discontinuation
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-
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- 2008-12-07 IL IL195769A patent/IL195769A0/en unknown
-
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- 2009-11-27 JP JP2009270851A patent/JP2010090133A/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6057128A (en) * | 1998-03-17 | 2000-05-02 | Genetics Institute, Inc. | MU-1, member of the cytokine receptor family |
US6307024B1 (en) * | 1999-03-09 | 2001-10-23 | Zymogenetics, Inc. | Cytokine zalpha11 Ligand |
Non-Patent Citations (1)
Title |
---|
See also references of EP1553982A2 * |
Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7994292B2 (en) | 1998-03-17 | 2011-08-09 | Genetics Institute, Llc | MU-1, member of the cytokine receptor family |
US7705123B2 (en) | 1998-03-17 | 2010-04-27 | Genetics Institute, Llc | MU-1, member of the cytokine receptor family |
US7959908B2 (en) | 2002-06-07 | 2011-06-14 | Zymogenetics, Inc. | Methods of treating viral infections using IL-21 |
US7731946B2 (en) | 2002-07-15 | 2010-06-08 | Wyeth Llc | Methods and compositions for modulating T helper (TH) cell development and function |
US8143385B2 (en) | 2003-03-14 | 2012-03-27 | Wyeth Llc | Nucleic acids coding for antibodies against human IL-21 receptor and uses therefor |
EP1608315A4 (en) * | 2003-03-21 | 2008-07-16 | Wyeth Corp | Treating immunological disorder using agonists of interleukin-21/ interleukin-21 receptor |
EP1608315A2 (en) * | 2003-03-21 | 2005-12-28 | Wyeth | Treating immunological disorder using agonists of interleukin-21/ interleukin-21 receptor |
EP2263684A1 (en) | 2003-10-10 | 2010-12-22 | Novo Nordisk A/S | IL-21 derivatives |
US7910105B2 (en) | 2005-04-14 | 2011-03-22 | Wyeth Llc | Methods for treating and preventing fibrosis |
WO2009092087A2 (en) | 2008-01-18 | 2009-07-23 | The Brigham And Women's Hospital, Inc. | Selective differentiation, identification, and modulation of human th17 cells |
US9505748B2 (en) | 2012-11-08 | 2016-11-29 | Bristol-Myers Squibb Company | Amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23 and/or IFNα responses |
US10000480B2 (en) | 2012-11-08 | 2018-06-19 | Bristol-Myers Squibb Company | Amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23 and/or IFN alpha responses |
US10526321B2 (en) | 2012-11-08 | 2020-01-07 | Bristol-Myers Squibb Company | Amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23 and/or IFN alpha responses |
USRE47929E1 (en) | 2012-11-08 | 2020-04-07 | Bristol-Myers Squibb Company | Amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23 and/or IFNα responses |
US11021475B2 (en) | 2012-11-08 | 2021-06-01 | Bristol-Myers Squibb Company | Amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23 and/or IFN alpha responses |
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MXPA05000655A (en) | 2006-02-22 |
IL195769A0 (en) | 2009-09-01 |
EP1553982A2 (en) | 2005-07-20 |
EA200500206A1 (en) | 2006-06-30 |
JP4776228B2 (en) | 2011-09-21 |
ZA200500480B (en) | 2006-10-25 |
AU2003251900B2 (en) | 2008-12-18 |
KR20050037552A (en) | 2005-04-22 |
NO20050717L (en) | 2005-04-11 |
EP1553982A4 (en) | 2008-03-26 |
JP2010090133A (en) | 2010-04-22 |
JP2006507231A (en) | 2006-03-02 |
US20090197803A1 (en) | 2009-08-06 |
US20040136954A1 (en) | 2004-07-15 |
BR0312738A (en) | 2007-06-26 |
CN1688340A (en) | 2005-10-26 |
WO2004007682A3 (en) | 2004-12-29 |
AU2003251900A1 (en) | 2004-02-02 |
IL165990A0 (en) | 2006-01-15 |
US7731946B2 (en) | 2010-06-08 |
EA011686B1 (en) | 2009-04-28 |
US7314623B2 (en) | 2008-01-01 |
CA2491320A1 (en) | 2004-01-22 |
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