WO2009100035A2 - Modulation de lymphocytes t régulateurs et forkhead box p3 (foxp3) par des modulateurs de l’interleukine-21 (il-21) et du récepteur de l’il-21 (il-21r) - Google Patents

Modulation de lymphocytes t régulateurs et forkhead box p3 (foxp3) par des modulateurs de l’interleukine-21 (il-21) et du récepteur de l’il-21 (il-21r) Download PDF

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WO2009100035A2
WO2009100035A2 PCT/US2009/032894 US2009032894W WO2009100035A2 WO 2009100035 A2 WO2009100035 A2 WO 2009100035A2 US 2009032894 W US2009032894 W US 2009032894W WO 2009100035 A2 WO2009100035 A2 WO 2009100035A2
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cells
fragment
agonistic
fragments
polypeptide
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WO2009100035A3 (fr
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Fu-Dong Shi
Deborah A. Young
Mary Collins
Timothy Vollmer
Ruolan Liu
Wenhua Piao
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Wyeth
Catholic Healthcare West D/B/A St. Joseph's Hospital & Medical Center& Barrow Neurological Institute
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/75—Agonist effect on antigen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
    • C07K2319/74—Fusion polypeptide containing domain for protein-protein interaction containing a fusion for binding to a cell surface receptor

Definitions

  • the present invention relates to methods and compositions for modulating the levels and/or activity of regulatory T cells (Treg) and the forkhead box P3 (Foxp3) transcription factor, comprising interleukin-21 (IL-21) and/or interleukin-21 (IL-21 R) agonists and antagonists.
  • Treg regulatory T cells
  • Foxp3 forkhead box P3
  • IL-21 interleukin-21
  • IL-21 R interleukin-21 agonists and antagonists.
  • the methods and compositions disclosed herein are useful in, e.g., immunotherapy.
  • Human IL-21 is a cytokine that shows sequence homology to IL-2, IL-4 and IL-15 (Parrish-Novak et al. (2000) Nature 408:57-63). Despite low sequence homology among interleukin cytokines, cytokines share a common fold into a "four- helix-bundle" structure that is representative of the family. Most cytokines bind either class I or class II cytokine receptors.
  • Class II cytokine receptors include the receptors for IL-IO and the interferons, whereas class I cytokine receptors include the receptors for IL-2 through IL-7, IL-9, IL-1 1, IL- 12, IL-13, and IL- 15, as well as hematopoietic growth factors, leptin, and growth hormone (Cosman (1993) Cytokine 5:95-106).
  • Human IL-21 receptor (IL-2 IR) is a class I cytokine receptor that is expressed in lymphoid tissues, in particular by NK, B and T cells (Parrish-Novak et al. (2000) supra).
  • the nucleotide and amino acid sequences encoding human interleukin-21 (IL-21) and its receptor (IL-21R) are described in, e.g., WO 00/53761 ; WO 01/85792; Parrish-Novak et al. (2000) supra; and Ozaki et al. (2000) Proc. Natl. Acad. Sci. U.S.A. 97:11439-44.
  • IL-2 IR has the highest sequence homology to the IL-2 receptor ⁇ chain and the IL-4 receptor ⁇ chain (Ozaki et al. (2000) supra). Upon ligand binding, IL-2 IR associates with the common gamma cytokine receptor chain ( ⁇ c) that is shared by receptors for IL-2, IL-3, IL-4, IL-7, IL-9, IL- 13 and IL-15 (Ozaki et al. (2000) supra; Asao et al. (2001) J. Immunol. 167: 1-5). The widespread lymphoid distribution of IL-2 IR suggests that IL-21 plays an important role in immune regulation.
  • ⁇ c common gamma cytokine receptor chain
  • IL-21 significantly modulates the function of B cells, CD4 + and CD8 + T cells, and NK cells (e.g., Parrish-Novak et al. (2000) supra; Kasaian et al. (2002) Immunity. 16:559-69).
  • IL-2 IR is expressed in lymphoid tissues, particularly on T, B, NK, dendritic cells (DC) and macrophages (Parrish-Novak et al. (2000) supra), which allows these cells to respond to IL-21 (Leonard and Spolski (2005) Nat. Rev. Immunol. 5:688-98).
  • IL-21-mediated signaling can have antitumor activity (Sivakumar et al. (2004) Immunology 112:177-182), and that IL-21 can prevent antigen-induced asthma in mice (Shang et al. (2006) Cell. Immunol. 241 :66-74).
  • IL-21 can promote Th2 cell function (Pesce et al. (2006) J. Clin. Invest. 1 16:2044-55; Strengell et al. (2002) J. Immunol. 169:3600-05; Wurster et al. (2002) J. Exp. Med. 196:969-77), can cooperate with IL-15 in enhancing the expansion and activity of CD8 + T cells (Zeng et al. (2005) J.
  • IL-21 can induce B cell apoptosis or, along with IL-4, stimulate B cell proliferation to promote differentiation toward memory and/or plasma cells (Ettinger et al. (2005) J. Immunol. 175:7867-79; Mehta et al. (2003) J. Immunol. 170:41 11-18).
  • IL-21 and IL-21 R likely play a prominent role in inflammation and immune responses.
  • IL-21 R deficiency is associated with a temporary expansion of ThI and Th2 responses (particularly ThI), as shown by increased expression of IFN- ⁇ , IL-4, and IL-10 in CD4 + and CD8 + T cells of IL-21 R A mice.
  • IL-21 R ⁇ mice also showed reduced numbers of splenic NK cells in the early stage of EAE, and increased numbers of CNS NK cells during later stages of the disease. These data provide evidence that the IL-21 /IL-21 R pathway modulates Treg and NK cells and Foxp3 expression.
  • One aspect of the present invention provides a method of treating, ameliorating, or preventing an autoimmune disorder, an inflammatory disorder, transplant/graft rejection, lymphopenia, or graft-versus-host disease (GvHD) in a mammalian subject, comprising administering to the subject an IL-21/IL-21R agonist selected from the group consisting of agonistic IL-21 /IL-2 IR polynucleotides or fragments thereof, agonistic IL-21 /IL-2 IR polypeptides or fragments thereof, agonistic anti-IL-21/IL-21R antibodies or fragments thereof, and agonistic small molecules, in an amount sufficient to increase the level and/or activity of a Treg cell or a population of Treg cells in the mammalian subject, thereby treating, ameliorating, or preventing the autoimmune disorder, inflammatory disorder, transplant/graft rejection, lymphopenia, or GvHD in the mammalian subject.
  • the mammalian subject is a human.
  • the agonistic IL-21R polypeptide or fragment thereof comprises the amino acid sequence set forth in SEQ ID NO:2, or an amino acid sequence with at least 90% identity to the amino acid sequence set forth in SEQ ID NO:2, and is capable of binding an IL-21.
  • the antagonistic anti-IL-21R antibody or fragment thereof is capable of binding to an IL-21R comprised of an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO:2, wherein the IL-21R is capable of binding an IL-21.
  • Another aspect of the present invention provides a method of modulating the level and/or activity of a Treg cell or a population of Treg cells in a mammalian subject, comprising administering to the subject an IL-21/IL-21R agonist or an IL-21 /IL-21 R antagonist in an amount sufficient to modulate the level and/or activity of the Treg cell or population of Treg cells in the mammalian subject.
  • the mammalian subject is a human.
  • the IL-21/IL-21R agonist is an agonistic IL-21/IL-21R polynucleotide or fragments thereof, agonistic IL-21/IL-21R polypeptide or fragment thereof, agonistic anti-IL-21/IL-21R antibody or fragment thereof, or agonistic small molecule.
  • the agonistic IL-2 IR polypeptide or fragment thereof comprises the amino acid sequence set forth in SEQ ID NO:2, or an amino acid sequence with at least 90% identity to the amino acid sequence set forth in SEQ ID NO:2, and is capable of binding an IL-21.
  • the IL-2 l/IL-2 IR antagonist is an antagonistic IL-21 /IL-2 IR polynucleotide or fragment thereof, antagonistic IL-2 l/IL-2 IR polypeptide or fragment thereof, antagonistic anti-IL-2 l/IL-2 IR antibody or fragments thereof, or antagonistic small molecule.
  • Yet another aspect of the present invention provides a pharmaceutical composition useful as a vaccine, comprising an antigen from a pathogenic microorganism selected from the group consisting of a viral, bacterial and parasitic microorganism, and an effective adjuvanting amount of an IL-21/IL-21R antagonist, in a pharmaceutically acceptable carrier.
  • IL-21/IL-21R antagonist in a pharmaceutically acceptable carrier.
  • the subject can also be administered at least one additional therapeutic agent selected from the group consisting of cytokine inhibitors, growth factor inhibitors, immunosuppressants, anti-inflammatory agents, metabolic inhibitors, enzyme inhibitors, cytotoxic agents, and cytostatic agents.
  • additional therapeutic agent selected from the group consisting of cytokine inhibitors, growth factor inhibitors, immunosuppressants, anti-inflammatory agents, metabolic inhibitors, enzyme inhibitors, cytotoxic agents, and cytostatic agents.
  • FIG. 8 depicts IL-21 blockade modifying the number of CD4 + CD25 + T cells and decreasing expression of Foxp3 in CD4 + CD25 + T cells.
  • FIG. 8 A depicts representative plots from individual mice showing the percentage of CD4 + CD25 +
  • FIG. 8C depicts the expression of Foxp3 in relation to CD25 + cells gated on CD4 + cells.
  • FIG. 8D depicts the mean percentage of Foxp3 and CD25 double-positive cells gated on CD4 + cells in control (IgG2a Ab) and IL-21 R Fc-treated mice.
  • FIG. 8E depicts blockade of IL-21 reducing the frequency and expression of Foxp3 in Treg cells of naive Foxp3 GFP/GFP mice.
  • FIG. 9A depicts blockade of IL-21 altering the encephalitogenic potential of
  • FIG. 9B depicts cotransfer of CD4 + CD25 + cells from IL-21 R-blockaded mice failing to protect recipients from EAE.
  • FIG. 10 depicts the influence of IL-21 R deficiency on the development of EAE.
  • FIG. 1OA depicts the clinical course of active EAE in B6 and IL-21 R ' ' ' mice.
  • FIG. 1OB depicts mononuclear cell infiltration and demyelination in the CNS of B6 and IL-21R " ⁇ mice with EAE.
  • FIG. 11 depicts the effects of IL-21R deficiency on T cell proliferation in EAE.
  • FIG. 12 depicts levels of intracellular cytokines (IFN- ⁇ (FIGs. 12A, 12B,
  • FIG. 13 depicts IL- 17 production in IL-21R "A and B6 mice with EAE.
  • FIG. 14 depicts peripheral Treg cells of B6 and IL-21R " ⁇ mice with EAE.
  • FIGs. 14A and 14B depict CD4 + CD25 + Treg cells.
  • FIGs. 14C and 14D depict CD4 + CD25 + Treg cells.
  • CD25 + Foxp3 + cells on a CD4 + gated subpopulation CD25 + Foxp3 + cells on a CD4 + gated subpopulation.
  • FIG. 15 depicts a comparison of suppressor activity of Treg cells from
  • FIG. 16 depicts the response to IL-2 of Treg cells from B6 and IL-21R " ⁇ mice with EAE.
  • FIG. 16A depicts the kinetics of IL-21 production in B6 and
  • FIG. 16C depicts CD4 + CD25 + cells of IL-2 cultures from B6 and IL-21R " ⁇ mice with EAE.
  • FIG. 16D depicts Foxp3 expression of IL-2 cultures by CD4 + cells (upper panel) in relation to CD25 + cells gated on
  • FIG. 17 shows that IL-21R " ' " NK cells do not expand early in EAE, but have suppressive activity on disease.
  • Methods and compositions for modulating the level, activity, and/or signal transduction of an IL-21 and/or an IL-2 IR, and/or an interaction between an IL-21 and an IL-21R e.g., using agonists (also referred to herein as an "IL-21/IL-21R agonists"), which increase the level, activity, and/or signal transduction of an IL-21 and/or an IL-21 R, and/or an interaction between an IL-21 and an IL-21 R, or antagonists of IL-21 and/or IL-21 R (also referred to herein as an "IL-21 /IL-21 R antagonists”), which decrease the level, activity, and/or signal transduction of an IL-21 and/or an IL-21 R, and/or an interaction between an IL-21 and an IL-21 R, are disclosed herein.
  • agonists also referred to herein as an "IL-21/IL-21R agonists”
  • antagonists of IL-21 and/or IL-21 R also referred to herein
  • IL-2 IR deficiency similarly increases the severity of EAE and enhances the influx of inflammatory cells into the CNS. Additionally, IL-2 IR deficiency is associated with a temporary expansion of ThI and Th2 responses (particularly ThI), as shown by increased expression of IFN- ⁇ , IL-4, and IL-10 in CD4 + and CD8 + T cells of IL-2 IR "7" mice.
  • agents that agonize the activity, levels and/or signal transduction of IL-21 /IL-2 IR and/or enhance the interaction of IL-21 with IL-2 IR can be used to decrease immune activity in vivo, ex vivo, and/or in vitro, e.g., for treating, ameliorating, or preventing inflammatory or autoimmune disorders (e.g., multiple sclerosis (MS), glomerulonephritis, transplant/graft rejection, psoriasis, atopic disorders, asthma, rheumatoid arthritis, IBD (e.g., Crohn's disease, ulcerative colitis), and systemic lupus erythematosus (SLE)).
  • MS multiple sclerosis
  • IBD e.g., Crohn's disease, ulcerative colitis
  • SLE systemic lupus erythematosus
  • interleukin-21 receptor and the term “IL-2 IR” as used herein, refer to a class I cytokine family receptor, also known as NILR or Zalphall
  • IL-2 IR is capable of interacting with a common ⁇ cytokine receptor chain ( ⁇ c) and inducing the phosphorylation of STATl and STAT3 (Asao et al. (2001) supra) or
  • IL-21R refers to a polypeptide (preferably of mammalian origin, e.g., murine or human IL-21R), or as context requires, a polynucleotide encoding such a polypeptide, that is capable of interacting with, e.g., binding to, an IL-21 (preferably an IL-21 of mammalian origin, e.g., murine or human IL-21) and having one of the following features: (i) an amino acid sequence of a naturally occurring mammalian IL-21 R polypeptide or a fragment thereof, e.g., an amino acid sequence set forth in SEQ ID NO:2 (human - corresponding to GENBANK® Accession No.
  • NP_068570 or SEQ ID NO:4 (murine - corresponding to GENBANK® Ace. No. NP_068687) or a fragment thereof;
  • an amino acid sequence that is encoded by a naturally occurring mammalian IL-21 R nucleotide sequence or fragment thereof e.g., SEQ ID NO: 1 (human - corresponding to GENBANK Accession No.
  • a "soluble IL-21 R” is an IL-21 R polypeptide incapable of being anchored to a cell membrane.
  • soluble polypeptides include, for example, IL-21 R polypeptides that lack a sufficient portion of their membrane-spanning domain or are modified such that the membrane-spanning domain is nonfunctional (e.g., a fragment of an IL-21R, comprising the extracellular domain of murine or human IL-21R, which includes an amino acid sequence from about amino acids 1-235, 1-236, 20-235, 20-236 of SEQ ID NO:2 (human), or from about amino acids 1-236, 20-236 of SEQ ID NO:4 (murine)).
  • the term "antibody” refers to a protein comprising at least one, and optionally two, heavy (H) chain variable regions (abbreviated herein as VH), and at least one, and optionally two, light (L) chain variable regions (abbreviated herein as VL).
  • VH and VL regions can be further subdivided into regions of hypervariability, termed “complementarity determining regions” (CDRs), interspersed with regions that are more conserved, termed “framework regions” (FRs).
  • CDRs complementarity determining regions
  • FRs framework regions
  • the extent of the FRs and CDRs has been precisely defined (see, e.g., Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S.
  • amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared.
  • a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein amino acid or nucleic acid "identity” is equivalent to amino acid or nucleic acid "homology”).
  • the percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.
  • IL-21 /IL-21 R antagonists and agonists for use in the disclosed methods may have additional conservative or nonessential amino acid substitutions relative to naturally occurring IL-21/IL-21R polypeptides, which do not have a substantial effect on their functions.
  • a "conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art.
  • the fusion protein includes a heterologous signal sequence (i.e., a polypeptide sequence that is not present in a polypeptide encoded by an IL-21/IL-21R nucleic acid) at its N-terminus.
  • a heterologous signal sequence i.e., a polypeptide sequence that is not present in a polypeptide encoded by an IL-21/IL-21R nucleic acid
  • the native IL-21R signal sequence can be removed and replaced with a signal sequence from another protein.
  • expression and/or secretion of IL-21/IL-21R can be increased through use of a heterologous signal sequence.
  • An IL-21 R for use in the disclosed methods is of mammalian, preferably, human origin.
  • the nucleotide sequence and the predicted amino acid sequence of human IL-21 R are shown in SEQ ID NO:1 and SEQ ID NO:2, respectively.
  • the isolated IL-21/IL-21R polypeptide or fragment or fusion thereof is purified so that it is substantially free of other mammalian proteins.
  • IL-21/IL-21R polypeptides or fragments or fusions thereof of the invention may also be used to screen for agents that are capable of binding to IL-21/IL-21R. Binding assays involving a desired binding protein, immobilized or not, are well known in the art and can be used for this purpose with an IL-21/IL-21R. Purified cell-based or protein-based (cell-free) screening assays may be used to identify such agents. For example, an IL-21 or IL-21R polypeptide may be immobilized in purified form on a carrier, and binding of potential ligands to purified IL-21 or IL-21 R may be measured.
  • PNAs peptide nucleic acids
  • aptamers are synthetic homologs of nucleic acids in which the phosphate-sugar polynucleotide backbone is replaced by a flexible pseudo-peptide polymer to which the nucleobases are linked. This structure gives PNAs the capacity to hybridize with high affinity and specificity to complementary sequences of DNA and RNA, and also confers remarkable resistance to DNAses and proteinases. These unique features of PNAs make them apt to agonize or antagonize an IL-21 /IL-21 R pathway.
  • small molecules use the phrase small molecule to indicate folates, methotrexate, and neuropeptides
  • Halpin and Harbury ((2004) PLoS Biology 2:1022-30) use the phrase to indicate small molecule gene products, e.g., DNAs, RNAs, and peptides.
  • small molecules include, but are not limited to, cholesterols, neurotransmitters, aptamers, and siRNAs.
  • the vaccine adjuvant composition of the invention can be administered to a human or nonhuman mammal or other vertebrate by a variety of routes, including, but not limited to, intranasal, oral, vaginal, rectal, parenteral, intradermal, transdermal (see, e. g., International application WO 98/20734, which is hereby incorporated by reference herein), intramuscular, intraperitoneal, subcutaneous, intravenous, and intraarterial.
  • the amount of the antigen component(s) of the antigenic composition will vary depending in part upon the identity of the antigen, as well as upon the age, weight, and medical condition of the host, as well as on the method of administration. Again, suitable doses are readily determined by persons skilled in the art.
  • the combinations of adjuvants of this invention are suitable for use in combination with a wide variety of antigens from a wide variety of pathogenic microorganisms, including but not limited to those from viruses, bacteria, fungi, or parasitic microorganisms that infect humans and nonhuman mammals or other vertebrates, or from a cancer cell or tumor cell (e.g., sarcoma, melanoma, lymphoma, leukemia, neuroblastoma, carcinoma).
  • a cancer cell or tumor cell e.g., sarcoma, melanoma, lymphoma, leukemia, neuroblastoma, carcinoma.
  • IL-6 modulators include antibodies (or antigen-binding fragments thereof) against IL-6 or its receptor, e.g., chimeric, humanized, human, or in v#r ⁇ -generated antibodies to human IL-6 or its receptor, soluble fragments of the IL-6 receptor, and IL-6-binding proteins.
  • IL-15 modulators include antibodies (or antigen-binding fragments thereof) against IL- 15 or its receptor, e.g., chimeric, humanized, human, or in vitro- generated antibodies to human IL-15 or its receptor, soluble fragments of the IL-15 receptor, and IL-15-binding proteins.
  • Additional examples of therapeutic agents that can be combined with an IL-21/IL-21R agonist or antagonist include one or more of: 6-mercaptopurines (6-MP); azathioprine sulphasalazine; mesalazine; olsalazine chloroquine/ hydroxychloroquine; pencillamine; aurothiornalate (intramuscular and oral); azathioprine; colchicine; beta-2 adrenoreceptor agonists (salbutamol, terbutaline, salmeterol); xanthines (theophylline, aminophylline); cromoglycate; nedocromil; ketotifen; ipratropium and oxitropium; mycophenolate mofetil; adenosine agonists; antithrombotic agents; complement inhibitors; and adrenergic agents.
  • 6-MP 6-mercaptopurines
  • Nonlimiting examples of agents for treating, ameliorating, or preventing multiple sclerosis (MS) with which an IL-21/IL-21R agonist can be combined include the following: interferons, e.g., interferon-alphala (e.g., AVONEXTM; Biogen) and interferon-lb (BETASERONTM; Chiron/Berlex); Copolymer 1 (Cop-1 ; COPAXONETM; Teva Pharmaceutical Industries, Inc.); hyperbaric oxygen; intravenous immunoglobulin; cladribine; TNF antagonists as described herein; corticosteroids; prednisolone; methylprednisolone; azathioprine; cyclophosphamide; cyclosporine; methotrexate; 4-aminopyridine; and tizanidine.
  • interferons e.g., interferon-alphala (e.g., AVONEXTM; Biogen) and interferon-lb (
  • Nonlimiting examples of agents for treating, ameliorating, or preventing psoriasis and other skin conditions with which an IL-21/IL-21R modulator can be combined include one or more of the following: inhibitors of CD2 or LFA-3 interactions (e.g., soluble CD2- or LFA-polypeptides, such as Fc fusions, or antibodies against CD2 or LFA-3), cyclosporin A, anti-TNF, prednisone, FK506, anti-IL-12, anti-p40, anti-IL-23, methotrexate, PUVA, UV light, steroids, retinoids, interferon, or nitrogen mustard.
  • inhibitors of CD2 or LFA-3 interactions e.g., soluble CD2- or LFA-polypeptides, such as Fc fusions, or antibodies against CD2 or LFA-3
  • cyclosporin A e.g., anti-TNF, prednisone, FK506, anti-IL-12, anti-p40, anti-IL-
  • Antibodies were directly labeled with one of the following fluorescent tags: FITC, PE, PerCP-Cy5.5, APC, Alexa-647, CD25 (7D4), CD4 (GKl.4), CD8 (53-6.7), IFN- ⁇ (XMGl.2), IL-IO (JESS-16E3) (BD Biosciences, San Jose, CA), Foxp3 (FJK- 16s) (eBioscience, San Diego, CA). Cells were harvested at the end of the incubation period and stained with a combination of anti-CD4-FITC, anti- CD8-PerCP-Cy5.5, and anti-CD25-PE.
  • mice were immunized with PLPi 3 ⁇ i 5 ] peptide/CFA/PT, as described above, and then injected with 250 ⁇ g of either IL-21R Fc or IgG2a Ab (control) seven days after immunization. Eleven days after immunization, mononuclear cells were obtained by mincing spleens through a wire mesh (BD Bioscience). CD4 + CD25 + T cells were isolated using a mouse CD4 + CD25 + regulatory T cell isolation kit (Miltenyi Biotec, Auburn, CA). Briefly, CD4 + T cells were first isolated through negative selection by removing all other cell types.

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Abstract

La présente invention concerne des méthodes permettant de moduler le niveau et l’activité de lymphocytes Tregs et du facteur de transcription FOXP3 à l’aide de modulateurs d’IL-21/IL-21 R, c’est-à-dire, des agonistes d’IL-21/IL-21 R (à savoir, des agonistes d’IL-21 et des agonistes d’IL-21 R) et des antagonistes d’IL-21/IL-21 R (à savoir, des antagonistes d’IL-21 et des antagonistes d’IL-21 R). Les agonistes et antagonistes d’IL-21/IL-21 R peuvent être utilisés pour accroître l’immunité ou induire une suppression immune in vivo, ex vivo et/ou in vitro, notamment, pour traiter, améliorer ou prévenir des troubles auto-immuns ou inflammatoires, des cancers et des troubles infectieux.
PCT/US2009/032894 2008-02-01 2009-02-02 Modulation de lymphocytes t régulateurs et forkhead box p3 (foxp3) par des modulateurs de l’interleukine-21 (il-21) et du récepteur de l’il-21 (il-21r) WO2009100035A2 (fr)

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Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2010104617A3 (fr) * 2009-01-23 2011-01-06 Salvatore Albani Nouveaux procédés destinés à induire un état de tolérance immunitaire
WO2011032119A1 (fr) 2009-09-14 2011-03-17 The Regents Of The University Of Colorado Modulation de produits d'immunothérapie à base de levure et réponses associées
US7910105B2 (en) 2005-04-14 2011-03-22 Wyeth Llc Methods for treating and preventing fibrosis
US8012475B2 (en) * 1994-03-14 2011-09-06 Genetics Institute, Llc Use of IL-12 and IL-12 antagonists in the treatment of autoimmune diseases
US8143385B2 (en) 2003-03-14 2012-03-27 Wyeth Llc Nucleic acids coding for antibodies against human IL-21 receptor and uses therefor
WO2011160043A3 (fr) * 2010-06-18 2012-05-31 Whitehead Institute For Biomedical Research Pla2g16 utilisé en tant que cible pour des composés antiviraux
CN102949722A (zh) * 2011-08-26 2013-03-06 中国医学科学院放射医学研究所 基于p38抑制剂和细胞生长因子的新颖药物组合物
US8455449B2 (en) 2011-01-18 2013-06-04 Bioniz, Llc Compositions and methods for modulating γ-c-cytokine activity
WO2014205501A1 (fr) 2013-06-27 2014-12-31 Monash University Protéines de liaison il-21 et leurs utilisations
WO2015054386A1 (fr) 2013-10-08 2015-04-16 Georgia State University Research Foundation, Inc Compositions comprenant il-18 et il-22 et leur utilisation dans des thérapies antivirales
WO2015110930A1 (fr) * 2014-01-24 2015-07-30 Pfizer Inc. Protéines de récepteur d'interleukine 21 modifiées
WO2016022465A1 (fr) * 2014-08-04 2016-02-11 Drexel University Nouveaux composés et procédés pour traiter ou atténuer un trouble ou une maladie à médiation par il-1r au moyen de ces composés
WO2016094962A1 (fr) 2014-12-19 2016-06-23 Monash University Anticorps il -21
US9959384B2 (en) 2013-12-10 2018-05-01 Bioniz, Llc Methods of developing selective peptide antagonists
US10030058B2 (en) 2015-10-09 2018-07-24 Bioniz, Llc Modulating gamma-C-cytokine activity
CN109125717A (zh) * 2017-09-08 2019-01-04 江苏苏博生物医学股份有限公司 一种治疗慢性病的自体全细胞疫苗配方及其制备方法
EP3458473B1 (fr) * 2016-05-16 2022-04-13 Checkmab S.R.L. Marqueurs sélectivement deregulés dans les cellules t régulatrices présentes dans les infiltrtions tumorales.
CN117904290A (zh) * 2023-12-13 2024-04-19 暨南大学 Il21r在制备非酒精性脂肪性肝炎相关肝癌诊断、预后预测产品及治疗药物中的应用
US12012441B2 (en) 2020-10-26 2024-06-18 Neptune Biosciences Llc Engineered human IL-21 cytokines and methods for using the same
US12030936B2 (en) 2020-04-30 2024-07-09 Bioniz Therapeutics, Inc. Modulating the effects of gamma-c-cytokine signaling for the treatment of alopecia and alopecia associated disorders

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004084835A2 (fr) * 2003-03-21 2004-10-07 Wyeth Traitement de troubles immunologiques a l'aide de l'interleukine-21/ du recepteur de l'interleukine-21
WO2005067956A2 (fr) * 2004-01-15 2005-07-28 Novo Nordisk A/S Traitement de maladies auto-immunes et du rejet d'allogreffes par l'il-21

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004084835A2 (fr) * 2003-03-21 2004-10-07 Wyeth Traitement de troubles immunologiques a l'aide de l'interleukine-21/ du recepteur de l'interleukine-21
WO2005067956A2 (fr) * 2004-01-15 2005-07-28 Novo Nordisk A/S Traitement de maladies auto-immunes et du rejet d'allogreffes par l'il-21

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
PELUSO ILARIA ET AL: "IL-21 counteracts the regulatory T cell-mediated suppression of human CD4(+) T lymphocytes" JOURNAL OF IMMUNOLOGY, vol. 178, no. 2, January 2007 (2007-01), pages 732-739, XP002528645 ISSN: 0022-1767 *
PIAO W -H ET AL: "IL-21 modulates CD4(+) CD25(+) regulatory t-cell homeostasis in experimental autoimmune encephalomyelitis" SCANDINAVIAN JOURNAL OF IMMUNOLOGY, vol. 67, no. 1, January 2008 (2008-01), pages 37-46, XP002528644 ISSN: 0300-9475 *
PIAO WEN-HUA ET AL: "IL-21 modulates CD4(+)CD25(+) regulatory T cell homeostasis in experimental autoimmune encephalomyelitis" NEUROLOGY, vol. 70, no. 11, Suppl. 1, March 2008 (2008-03), page A31, XP009116916 & 60TH ANNUAL MEETING OF THE AMERICAN-ACADEMY-OF-NEUROLOGY; CHICAGO, IL, USA; APRIL 12 -19, 2008 ISSN: 0028-3878 *

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US8012475B2 (en) * 1994-03-14 2011-09-06 Genetics Institute, Llc Use of IL-12 and IL-12 antagonists in the treatment of autoimmune diseases
US7705123B2 (en) 1998-03-17 2010-04-27 Genetics Institute, Llc MU-1, member of the cytokine receptor family
US7994292B2 (en) 1998-03-17 2011-08-09 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
US8143385B2 (en) 2003-03-14 2012-03-27 Wyeth Llc Nucleic acids coding for antibodies against human IL-21 receptor and uses therefor
US7910105B2 (en) 2005-04-14 2011-03-22 Wyeth Llc Methods for treating and preventing fibrosis
WO2010104617A3 (fr) * 2009-01-23 2011-01-06 Salvatore Albani Nouveaux procédés destinés à induire un état de tolérance immunitaire
WO2011032119A1 (fr) 2009-09-14 2011-03-17 The Regents Of The University Of Colorado Modulation de produits d'immunothérapie à base de levure et réponses associées
WO2011160043A3 (fr) * 2010-06-18 2012-05-31 Whitehead Institute For Biomedical Research Pla2g16 utilisé en tant que cible pour des composés antiviraux
US8455449B2 (en) 2011-01-18 2013-06-04 Bioniz, Llc Compositions and methods for modulating γ-c-cytokine activity
US11834519B2 (en) 2011-01-18 2023-12-05 Bioniz Therapeutics, Inc. Compositions and methods for modulating γ-c-cytokine activity
US11708392B2 (en) 2011-01-18 2023-07-25 Bioniz, Llc Peptide conjugates
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US9675672B2 (en) 2011-01-18 2017-06-13 Bioniz, Llc Compositions and methods for modulating gamma-C-cytokine activity
US10227382B2 (en) 2011-01-18 2019-03-12 Bioniz, Llc Method of designing a peptide and/or peptide derivative for modulating gamma-c-cytokine activity
US9951105B2 (en) 2011-01-18 2018-04-24 Bioniz, Llc Methods of developing selective peptide antagonists
CN102949722A (zh) * 2011-08-26 2013-03-06 中国医学科学院放射医学研究所 基于p38抑制剂和细胞生长因子的新颖药物组合物
US10787510B2 (en) 2013-06-27 2020-09-29 Monash University Methods of treating cancer using an IL-21 agonist
US10077301B2 (en) 2013-06-27 2018-09-18 Monash University IL-21 binding proteins
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JP2016529213A (ja) * 2013-06-27 2016-09-23 モナッシュ ユニバーシティ Ｉｌ−２１結合タンパク質及びその使用
AU2014302028B2 (en) * 2013-06-27 2019-09-19 Monash University IL-21 binding proteins and uses thereof
US11517611B2 (en) 2013-10-08 2022-12-06 Georgia State University Research Foundation, Inc. Methods of treating viral infection with a composition comprising IL-18 and IL-22
WO2015054386A1 (fr) 2013-10-08 2015-04-16 Georgia State University Research Foundation, Inc Compositions comprenant il-18 et il-22 et leur utilisation dans des thérapies antivirales
EP3054978A4 (fr) * 2013-10-08 2017-05-10 Georgia State University Research Foundation, Inc. Compositions comprenant il-18 et il-22 et leur utilisation dans des thérapies antivirales
US10646548B2 (en) 2013-10-08 2020-05-12 Georgia State University Research Foundation, Inc. Compositions including IL-18 and IL-22 and their use in anti-viral therapies
US11462297B2 (en) 2013-12-10 2022-10-04 Bioniz, Llc Selective peptide antagonists
US9959384B2 (en) 2013-12-10 2018-05-01 Bioniz, Llc Methods of developing selective peptide antagonists
US10854312B2 (en) 2013-12-10 2020-12-01 Bioniz, Llc Selective peptide antagonists
WO2015110930A1 (fr) * 2014-01-24 2015-07-30 Pfizer Inc. Protéines de récepteur d'interleukine 21 modifiées
US11345696B2 (en) 2014-08-04 2022-05-31 Drexel University Compounds and methods of treating or ameliorating an IL-1R-mediated disease or disorder using same
US10428059B2 (en) 2014-08-04 2019-10-01 Drexel University Compounds and methods of treating or ameliorating an IL-1R-mediated disease or disorder using same
WO2016022465A1 (fr) * 2014-08-04 2016-02-11 Drexel University Nouveaux composés et procédés pour traiter ou atténuer un trouble ou une maladie à médiation par il-1r au moyen de ces composés
JP2017523211A (ja) * 2014-08-04 2017-08-17 ドレクセル ユニバーシティ 新規化合物およびそれを用いてｉｌ−１ｒ媒介性の疾患または障害を処置するかまたは寛解させる方法
US10940212B2 (en) 2014-12-19 2021-03-09 Monash University IL-21 agonist antibodies and methods of treatment using same
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US10030058B2 (en) 2015-10-09 2018-07-24 Bioniz, Llc Modulating gamma-C-cytokine activity
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EP3458473B1 (fr) * 2016-05-16 2022-04-13 Checkmab S.R.L. Marqueurs sélectivement deregulés dans les cellules t régulatrices présentes dans les infiltrtions tumorales.
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US12030936B2 (en) 2020-04-30 2024-07-09 Bioniz Therapeutics, Inc. Modulating the effects of gamma-c-cytokine signaling for the treatment of alopecia and alopecia associated disorders
US12012441B2 (en) 2020-10-26 2024-06-18 Neptune Biosciences Llc Engineered human IL-21 cytokines and methods for using the same
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