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 PDF

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Publication number
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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WIPO (PCT)
Prior art keywords
cell
cell population
cells
thp
thl
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PCT/US2003/021975
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English (en)
French (fr)
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WO2004007682A3 (en
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Michael Grusby
Andrea Wurster
Deborah A. Young
Mary Collins
Matthew J. Whitters
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Wyeth LLC
Harvard University
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Wyeth LLC
Harvard University
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Priority to AU2003251900A priority Critical patent/AU2003251900B2/en
Priority to MXPA05000655A priority patent/MXPA05000655A/es
Priority to JP2004521793A priority patent/JP4776228B2/ja
Priority to EP03764624A priority patent/EP1553982A4/en
Priority to CA002491320A priority patent/CA2491320A1/en
Priority to EA200500206A priority patent/EA011686B1/ru
Priority to BRPI0312738-9A priority patent/BR0312738A/pt
Application filed by Wyeth LLC, Harvard University filed Critical Wyeth LLC
Publication of WO2004007682A2 publication Critical patent/WO2004007682A2/en
Priority to IL16599004A priority patent/IL165990A0/xx
Publication of WO2004007682A3 publication Critical patent/WO2004007682A3/en
Anticipated expiration legal-status Critical
Priority to NO20050717A priority patent/NO20050717L/no
Priority to IL195769A priority patent/IL195769A0/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • 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
    • C07K14/7155—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for interleukins [IL]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0636—T lymphocytes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/20—Cytokines; Chemokines
    • C12N2501/23—Interleukins [IL]

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.

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PCT/US2003/021975 2002-07-15 2003-07-15 Methods and compositions for modulating t helper (th) cell development and function Ceased WO2004007682A2 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
BRPI0312738-9A BR0312738A (pt) 2002-07-15 2003-07-15 processos e composições para a modulação do desenvolvimento e da função de células t auxiliares (th)
JP2004521793A JP4776228B2 (ja) 2002-07-15 2003-07-15 Ｔヘルパー（ｔｈ）細胞の発生および機能を調節するための方法および組成物
EP03764624A EP1553982A4 (en) 2002-07-15 2003-07-15 METHOD AND COMPOSITIONS FOR MODULATING THE DEVELOPMENT AND FUNCTION OF T-HELPER CELLS (T sb H / sb)
CA002491320A CA2491320A1 (en) 2002-07-15 2003-07-15 Methods and compositions for modulating t helper (th) cell development and function
EA200500206A EA011686B1 (ru) 2002-07-15 2003-07-15 Способ модуляции развития и функций т-клеток-хелперов
AU2003251900A AU2003251900B2 (en) 2002-07-15 2003-07-15 Methods and compositions for modulating T helper (Th) cell development and function
MXPA05000655A MXPA05000655A (es) 2002-07-15 2003-07-15 Metodos y composiciones para modular el desarrollo y la funcion de las celulas t helper (th).
IL16599004A IL165990A0 (en) 2002-07-15 2004-12-26 Methods and compositions for modulating T helper (TH) cell development and function
NO20050717A NO20050717L (no) 2002-07-15 2005-02-10 Metode og sammensetninger for modulering av T hjelpe (TH) celleutvikling og funksjon
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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US39616002P 2002-07-15 2002-07-15
US60/396,160 2002-07-15
US40300102P 2002-08-12 2002-08-12
US60/403,001 2002-08-12

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WO2004007682A3 WO2004007682A3 (en) 2004-12-29

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EP (1) EP1553982A4 (enExample)
JP (2) JP4776228B2 (enExample)
KR (1) KR20050037552A (enExample)
CN (1) CN1688340A (enExample)
AU (1) AU2003251900B2 (enExample)
BR (1) BR0312738A (enExample)
CA (1) CA2491320A1 (enExample)
EA (1) EA011686B1 (enExample)
IL (2) IL165990A0 (enExample)
MX (1) MXPA05000655A (enExample)
NO (1) NO20050717L (enExample)
WO (1) WO2004007682A2 (enExample)
ZA (1) ZA200500480B (enExample)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1608315A4 (en) * 2003-03-21 2008-07-16 Wyeth Corp TREATMENT OF IMMUNOLOGICAL DISORDERS USING INTERLEUKIN-21 / INTERLEUKIN-21 RECEPTOR
WO2009092087A2 (en) 2008-01-18 2009-07-23 The Brigham And Women's Hospital, Inc. Selective differentiation, identification, and modulation of human th17 cells
US7705123B2 (en) 1998-03-17 2010-04-27 Genetics Institute, Llc MU-1, member of the cytokine receptor family
US7731946B2 (en) 2002-07-15 2010-06-08 Wyeth Llc Methods and compositions for modulating T helper (TH) cell development and function
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
US7959908B2 (en) 2002-06-07 2011-06-14 Zymogenetics, Inc. Methods of treating viral infections using IL-21
US8143385B2 (en) 2003-03-14 2012-03-27 Wyeth Llc Nucleic acids coding for antibodies against human IL-21 receptor and uses therefor
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

Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007506789A (ja) * 2003-09-25 2007-03-22 ザイモジェネティクス， インコーポレイテッド Ｉｌ−２１を用いた自己免疫疾患の治療方法
CA2574848A1 (en) * 2004-08-05 2006-12-21 Wyeth Antagonizing interleukin-21 receptor activity
EP2805971A1 (en) * 2005-11-28 2014-11-26 ZymoGenetics, Inc. IL-21 antagonists
JP2009517406A (ja) * 2005-11-28 2009-04-30 ザイモジェネティクス， インコーポレイテッド Ｉｌ−２１受容体アンタゴニスト
AU2006342792A1 (en) * 2005-12-02 2007-11-08 Genentech, Inc. Compositions and methods for the treatment of diseases and disorders associated with cytokine signaling involving antibodies that bind to IL-22 and IL-22R
EP3103813A1 (en) * 2007-12-07 2016-12-14 ZymoGenetics, Inc. Anti-human il-21 monoclonal antibodies
AR071885A1 (es) * 2008-05-23 2010-07-21 Wyeth Corp Proteinas de union al receptor de interleuquina 21
RU2010152689A (ru) * 2008-05-23 2012-06-27 УАЙТ ЭлЭлСи (US) Способы лечения с применением белков, связывающих рецептор интерлейкина-21
NZ772688A (en) 2010-06-03 2022-09-30 Pharmacyclics Llc 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
ES2778053T3 (es) 2011-01-18 2020-08-07 Bioniz Llc Composiciones para modular la actividad de la citocina gamma-c
US9920932B2 (en) 2011-01-26 2018-03-20 United Technologies Corporation Mixer assembly for a gas turbine engine
KR20130011056A (ko) * 2011-07-20 2013-01-30 주식회사에이앤알쎄라퓨틱스 염증표적 수용체 및 염증 질환 치료용 약물 운반체
AU2013293087B2 (en) 2012-07-24 2017-08-31 Pharmacyclics Llc Mutations associated with resistance to inhibitors of Bruton's tyrosine kinase (BTK)
EP2914263A4 (en) 2012-11-02 2016-04-27 Pharmacyclics Inc ADJUVANT THERAPY WITH TEC FAMILY KINASE INHIBITOR
US20140170727A1 (en) * 2012-12-19 2014-06-19 Nanomr, Inc. Affinity medium using fixed whole cells
CA2942528A1 (en) 2014-03-20 2015-09-24 Pharmacyclics Inc. Phospholipase c gamma 2 and resistance associated mutations
EP3359556B1 (en) 2015-10-09 2021-05-26 Bioniz, LLC Modulating gamma - c -cytokine activity
KR20240142577A (ko) 2017-04-07 2024-09-30 바이오니즈 테라퓨틱스, 아이엔씨. 감마-c-사이토카인 활성의 안정한 조절자
JP2022530677A (ja) 2019-05-03 2022-06-30 バイオニズ リミテッド ライアビリティー カンパニー 脱毛症および脱毛症関連障害の治療ための、γｃサイトカインのシグナル伝達の効果の調節
GB201910605D0 (en) * 2019-07-24 2019-09-04 Immetacyte Ltd Tumour infltracting lymphocyte therapy amd uses thereo
JP7217071B2 (ja) 2019-09-30 2023-02-02 エルジー・ケム・リミテッド 高吸水性樹脂およびその製造方法
US12012441B2 (en) 2020-10-26 2024-06-18 Neptune Biosciences Llc Engineered human IL-21 cytokines and methods for using the same

Family Cites Families (65)

* Cited by examiner, † Cited by third party
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
EP0721983A1 (en) * 1988-01-22 1996-07-17 ZymoGenetics, Inc. Methods of producing biologically active peptide dimers
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
US5098833A (en) * 1989-02-23 1992-03-24 Genentech, Inc. DNA sequence encoding a functional domain of a lymphocyte homing receptor
US5116964A (en) * 1989-02-23 1992-05-26 Genentech, Inc. Hybrid immunoglobulins
US6406697B1 (en) * 1989-02-23 2002-06-18 Genentech, Inc. Hybrid immunoglobulins
US5216131A (en) * 1989-02-23 1993-06-01 Genentech, Inc. Lymphocyte homing receptors
US5225538A (en) * 1989-02-23 1993-07-06 Genentech, Inc. Lymphocyte homing receptor/immunoglobulin fusion proteins
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
ES2284161T3 (es) * 1990-01-12 2007-11-01 Amgen Fremont Inc. Generacion de anticuerpos xenogenicos.
AU8507191A (en) * 1990-08-29 1992-03-30 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5633425A (en) * 1990-08-29 1997-05-27 Genpharm International, Inc. 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
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
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
ES2301158T3 (es) 1992-07-24 2008-06-16 Amgen Fremont Inc. Produccion de anticuerpos xenogenicos.
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
WO1996034096A1 (en) 1995-04-28 1996-10-31 Abgenix, Inc. Human antibodies derived from immunized xenomice
FR2742156A1 (fr) 1995-12-06 1997-06-13 Sanofi Sa Polypeptide recepteur de l'il-13
US5710023A (en) 1996-03-01 1998-01-20 Genetics Institute, Inc. IL-13 cytokine receptor chain
WO1997033913A1 (en) 1996-03-13 1997-09-18 Zymogenetics, Inc. Cytokine-receptor expressed in testis cells
AU6450196A (en) 1996-06-12 1998-01-07 Human Genome Sciences, Inc. Hr-1 receptor
EP0812913A3 (en) 1996-06-12 1999-08-04 Smithkline Beecham Corporation HR-1 receptor, a receptor of the cytokine receptors family
AU6175696A (en) 1996-06-12 1998-01-07 Human Genome Sciences, Inc. 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
EP1005552A1 (en) 1997-01-16 2000-06-07 Genetics Institute, Inc. Member of the hematopoietin receptor superfamily
US6057128A (en) 1998-03-17 2000-05-02 Genetics Institute, Inc. MU-1, member of the cytokine receptor family
US7198789B2 (en) * 1998-03-17 2007-04-03 Genetics Institute, Llc Methods and compositions for modulating interleukin-21 receptor activity
US7189400B2 (en) * 1998-03-17 2007-03-13 Genetics Institute, Llc Methods of treatment with antagonists of MU-1
US20020029391A1 (en) 1998-04-15 2002-03-07 Claude Geoffrey Davis Epitope-driven human antibody production and gene expression profiling
WO1999067290A1 (fr) 1998-06-24 1999-12-29 Chugai Research Institute For Molecular Medicine, Inc. Nouvelles proteines receptrices d'hemopoïetine
AU5104799A (en) 1998-08-04 2000-02-28 Regeneron Pharmaceuticals, Inc. Novel orphan cytokine receptors
AU772172B2 (en) 1998-09-23 2004-04-08 Zymogenetics Inc. Cytokine receptor zalpha11
US6576744B1 (en) * 1998-09-23 2003-06-10 Zymogenetics, Inc. Cytokine receptor zalpha11
WO2000027882A1 (en) 1998-11-06 2000-05-18 Smithkline Beecham Corporation Hnovilr
DK1165791T3 (da) 1999-03-09 2008-02-11 Zymogenetics Inc Humant cytokin som zalpha-receptor-ligand og anvendelse deraf
US6307024B1 (en) * 1999-03-09 2001-10-23 Zymogenetics, Inc. Cytokine zalpha11 Ligand
US20020090680A1 (en) 1999-05-18 2002-07-11 Millennium Pharmaceuticals, Inc. Novel IL-9/IL-2 receptor-like molecules and uses thereof
DE60125543T2 (de) 2000-04-05 2007-10-04 Zymogenetics, Inc., Seattle Löslicher zytokinrezeptor zalpha11
DE60124954T2 (de) 2000-05-11 2007-09-20 Genetics Institute, LLC, Cambridge Mu-1, ein mitglied der cytokine rezeptor familie
US20060083713A1 (en) * 2000-10-13 2006-04-20 Eli Lilly And Company Methods of using a human il-17 related polypeptide to treat disease
ES2629395T3 (es) * 2001-10-04 2017-08-09 Genetics Institute, Llc Métodos y composiciones para modular la actividad de la interleucina-21
US20040016010A1 (en) * 2002-04-17 2004-01-22 Marion Kasaian IL-21 receptor knockout animal and methods of use thereof
CN1688340A (zh) 2002-07-15 2005-10-26 韦思公司 调节t辅助(th)细胞发育和功能的方法和组合物
DE602004025332D1 (de) 2003-03-14 2010-03-18 Wyeth Corp Antikörper gegen il21-rezeptor und deren verwendung
AU2004224277A1 (en) 2003-03-21 2004-10-07 Wyeth Treating immunological disorder using agonists of interleukin-21/ interleukin-21 receptor
US20060024268A1 (en) * 2004-05-19 2006-02-02 Wyeth Modulation of immunoglobulin production and atopic disorders
CA2574848A1 (en) 2004-08-05 2006-12-21 Wyeth Antagonizing interleukin-21 receptor activity
GT200600148A (es) * 2005-04-14 2006-11-22 Metodos para el tratamiento y la prevencion de 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)

Cited By (14)

* Cited by examiner, † Cited by third party
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 TREATMENT OF IMMUNOLOGICAL DISORDERS USING 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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