US20110274650A1 - Compositions and methods of treating inflammatory and autoimmune diseases - Google Patents

Compositions and methods of treating inflammatory and autoimmune diseases Download PDF

Info

Publication number
US20110274650A1
US20110274650A1 US13/145,537 US201013145537A US2011274650A1 US 20110274650 A1 US20110274650 A1 US 20110274650A1 US 201013145537 A US201013145537 A US 201013145537A US 2011274650 A1 US2011274650 A1 US 2011274650A1
Authority
US
United States
Prior art keywords
variant
foxp3
cells
seq
stat5
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US13/145,537
Other languages
English (en)
Inventor
Marc A. Gavin
Li Li
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Amgen Inc
Original Assignee
Amgen Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=42356180&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20110274650(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Amgen Inc filed Critical Amgen Inc
Priority to US13/145,537 priority Critical patent/US20110274650A1/en
Assigned to AMGEN INC. reassignment AMGEN INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GAVIN, MARC A., LI, LI
Publication of US20110274650A1 publication Critical patent/US20110274650A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/55—IL-2
    • 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
    • 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
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • IL-2 binds three transmembrane receptor subunits: IL-2R ⁇ and IL-2R ⁇ which together activate intracellular signaling events upon IL-2 binding, and CD25 (IL-2R ⁇ ) which serves to present IL-2 to the other 2 receptor subunits.
  • the signals delivered by IL-2R ⁇ include those of the PI3-kinase, Ras-MAP-kinase, and STAT5 pathways.
  • T cells require expression of CD25 to respond to the low concentrations of IL-2 that typically exist in tissues.
  • T cells that express CD25 include both CD4 + FOXP3 + regulatory T cells (T-reg cells)—which are essential for suppressing autoimmune inflammation—and FOXP3 ⁇ T cells that have been activated to express CD25.
  • FOXP3 ⁇ CD25 ⁇ T effector cells (T-eff) may be either CD4 + or CD8 + cells, both of which can be pro-inflammatory and may contribute to autoimmunity, organ graft rejection or graft-versus-host disease.
  • IL-2-stimulated STAT5 signaling is crucial for normal T-reg cell growth and survival and for high FOXP3 expression.
  • IL-2R ⁇ and/or IL-2R ⁇ could be offset by an increased affinity for CD25.
  • Mutational variants of IL-2 have been generated that exhibit up to 170-fold higher affinity for CD25 (US Patent Application Publication No. 2005/0142106; Rao et al., Biochemistry 44, 10696-701 (2005)). These variants were reported to associate for several days with cell surface CD25 and to chronically promote growth of an IL-2-dependent cell line. The authors report that the mutants stimulate persistent T cell growth and, thus, may be useful in methods of viral immunotherapy and in treating cancer or other hyperproliferative disorders.
  • IL-2 Proleukin
  • U.S. Pat. No. 6,955,807 describes IL-2 variants that are said to have reduced toxicity.
  • the patent attributes the toxicity to IL-2-induced stimulation of natural killer (NK) cells, which only express IL-2R ⁇ and IL-2R ⁇ .
  • NK natural killer
  • the IL-2 variants described therein were said to have reduced toxicity because they selectively activate CD25 + T cells over NK cells.
  • the IL-2 variants were said to be useful in therapeutic methods wherein it is beneficial to generally stimulate the immune system, e.g., the treatment of cancer or infectious diseases.
  • immunosuppressive mutational variants of IL-2 that preferentially promote the growth/survival of FOXP3 + regulatory T cells (T-reg cells) over the growth/survival of potentially proinflammatory FOXP3 ⁇ CD25 + T cells.
  • T-reg cells regulatory T cells
  • FOXP3 ⁇ CD25 + T cells By increasing the ratio of T-reg to other T cells and/or by increasing FOXP3 expression in T-reg without activating FOXP3 ⁇ CD25 + T cells, these variants should suppress undesirable inflammation.
  • the unique properties of these IL-2 variants stem from two sets of mutations.
  • One set of mutations results in a reduced affinity for the signaling chains of the IL-2 receptor (IL-2R ⁇ /CD122 and/or IL-2R ⁇ /CD132) and/or a reduced capacity to induce a signaling event from one or both subunits of the IL-2 receptor.
  • the second set of mutations confers higher affinity for CD25 (IL-2R ⁇ ) and may include mutations described by Rao et al. (US Patent Application Publication No. 2005/0142106).
  • certain IL-2 variants induce signaling events that preferentially induce survival, proliferation, activation and/or function of T-reg cells.
  • the IL-2 variant retains the capacity to stimulate, in T-reg cells, STAT5 phosphorylation and/or phosphorylation of one or more of signaling molecules downstream of the IL-2R, e.g., p38, ERK, SYK and LCK.
  • the IL-2 variant retains the capacity to stimulate, in T-reg cells, transcription or protein expression of genes or proteins, such as FOXP3 or IL-10, that are important for T-reg cell survival, proliferation, activation and/or function.
  • the IL-2 variant exhibits a reduced capacity to stimulate endocytosis of IL-2/IL-2R complexes on the surface of CD25 + T cells.
  • the IL-2 variant demonstrates inefficient, reduced, or absence of stimulation of PI3-kinase signaling, such as inefficient, reduced or absent phosphorylation of AKT and/or mTOR (mammalian target of rapamycin).
  • the IL-2 variant retains the ability of wt IL-2 to stimulate STAT5 phosphorylation and/or phosphorylation of one or more of signaling molecules downstream of the IL-2R in T-reg cells, yet demonstrates inefficient, reduced, or absent phosphorylation of STAT5, AKT and/or mTOR or other signaling molecules downstream of the IL-2R in FOXP3 ⁇ CD4 + or CD8 + T cells or NK cells.
  • the IL-2 variant is inefficient or incapable of stimulating survival, growth, activation and/or function of FOXP3 ⁇ CD4 + or CD8 + T cells or NK cells.
  • the methods comprise administering a therapeutically effective amount of one or more immunosuppressive IL-2 variants to a subject.
  • the methods comprising contacting a FOXP3-positive (FOXP3 + ) T cell with an immunosuppressive IL-2 variant.
  • an immunosuppressive IL-2 variant in the preparation of a medicament for the treatment of an inflammatory or autoimmune disorder.
  • compositions of IL-2 variants conjugated to additional protein sequences or other chemical that prolong the stability and/or half-life of the therapeutic in vivo.
  • FIG. 1 Sequences of IL-2 variants. Sequences that vary from germline human IL-2 are not shaded in gray.
  • FIG. 2A-2F An example of flow cytometric data and gating strategy. Representative data is shown in FIG. 1A where 9.5% of CD4 + cells are CD25 + FOXP3 + , 9.9% of CD4 + cells are CD25 + FOXP3 ⁇ and 6.7% of CD8 + cells are CD25 + FOXP3 ⁇ .
  • FOXP3 + CD8 + T cells are typically very infrequent.
  • FIG. 2B Relative number of CD8 + CD25 + FOXP3 ⁇ T cells.
  • FIG. 2C Relative number of CD4 + CD25 + FOXP3 ⁇ T cells.
  • FIG. 2D Relative number of CD4 + CD25 + FOXP3 + T cells.
  • FIG. 2E Ratio of FOXP3 + /FOXP3 ⁇ cells among CD25 + CD4 + T cells.
  • FIG. 2F IL-2-mediated FOXP3 upregulation in FOXP3 + CD4 + T cells.
  • FIG. 3 IL-2 muteins stimulate phospho-STAT5 in T-reg but are inefficient at stimulating signals in other T cells.
  • T cells were stimulated with IL-2 as described in Example 3.
  • Phospho-STAT5 was measured by flow cytometry and phospho-AKT was measured by ELISA (MesoScale Discovery).
  • Abbreviations are as follows: T-reg, FOXP3 + CD4 + T cells; CD4 T-eff, CD4 + CD25 + FOXP3 ⁇ “effector” T cells; CD8 T-eff, CD8 + CD25 + FOXP3 ⁇ “effector” T cells.
  • T-reg cells are essential for maintaining normal immune homeostasis and immune tolerance to self tissues, as well as for suppressing undesirable inflammation. T-reg cells exert their suppressor and regulatory functions through multiple mechanisms which are likely to be regulated by temporal and environmental factors.
  • Current immunosuppressive therapeutics generally target individual proinflammatory pathways and as such often exhibit partial efficacy or are applicable to specific diseases.
  • An alternative immunosuppressive modality might involve the elevation of the numbers and activation state of natural suppressor cells to better enable them to deliver appropriate suppressor molecules/activities at sites of inflammation.
  • Described herein are therapeutic agents that selectively promote T-reg cell proliferation, survival, activation and/or function.
  • selectively promote it is meant the therapeutic agent promotes the activity in T-reg cells but has limited or lacks the ability to promote the activity in non-regulatory T cells.
  • assays to screen for agents that selectively promote T-reg cell proliferation, survival, activation and/or function include, but are not limited to, small molecules, peptides, polypeptides, proteins including antibodies, e.g., monoclonal, humanized, human, monovalent, bivalent, and multivalent antibodies.
  • the agent is an IL-2 variant.
  • the IL-2 variant promotes these activities of T-reg cell growth/survival but have a reduced ability, as compared to wild-type IL-2, to promote non-regulatory T-cell (FOXP3 ⁇ CD25 + ) and NK cell proliferation, survival, activation and/or function.
  • such IL-2 variants function through a combination of elevated affinity for the IL-2R subunit IL-2R ⁇ (CD25) and a reduced affinity for the signaling subunits IL-2R ⁇ and/or IL-2R ⁇ .
  • IL-2 and variants thereof have been used in the art as immunostimulatory agents, e.g., in methods of treating cancer or infectious diseases
  • the IL-2 variants described herein are particularly useful as immunosuppressive agents, e.g., in methods of treating inflammatory disorders.
  • IL-2 variants comprise a sequence of amino acids at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to wild-type IL-2.
  • IL-2 variants further include a sequence of amino acids at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to a functional fragment of wild-type IL-2.
  • wild-type IL-2 shall mean the polypeptide having the following amino acid sequence:
  • X is C, S, A or V (SEQ ID NO:1).
  • Variants may contain one or more substitutions, deletions, or insertions within the wild-type IL-2 amino acid sequence.
  • Residues are designated herein by the one letter amino acid code followed by the IL-2 amino acid position, e.g., K35 is the lysine residue at position 35 of SEQ ID NO:1.
  • substitutions are designated herein by the one letter amino acid code followed by the IL-2 amino acid position followed by the substituting one letter amino acid code, e.g., K35A is a substitution of the lysine residue at position 35 of SEQ ID NO:1 with an alanine residue.
  • the invention provides immunosuppressive IL-2 variants that have a higher affinity for IL-2R ⁇ than wild-type IL-2.
  • U.S. Published Patent Application No. 2005/0142106 (incorporated herein by reference in its entirety) describes IL-2 variants that have higher affinity for IL-2R ⁇ than does wild-type IL-2 and methods of making and screening for such variants.
  • Preferred IL-2 variants contain one or more mutations in positions of the IL-2 sequence that either contact IL-2R ⁇ or alter the orientation of other positions contacting IL-2R ⁇ , resulting in higher affinity for IL-2R ⁇ .
  • the mutations may be in or near areas known to be in close proximity to IL-2R ⁇ based on published crystal structures (Xinquan Wang, Mathias Rickert, K. Christopher Garcia. Science 310:1159 2005).
  • IL-2 residues believed to contact IL-2R ⁇ include K35, R38, F42, K43, F44, Y45, E61, E62, K64, P65, E68, V69, L72, and Y107.
  • IL-2 variants having greater affinity for IL-2R ⁇ can include a change in N29, N30, Y31, K35, T37, K48, E68, V69, N71, Q74, S75, or K76.
  • Preferred variants include those having one or more of the following mutations: N29S, N30S, N30D, Y31H, Y31S, K35R, T37A, K48E, V69A, N71R, and Q74P.
  • Immunosuppressive IL-2 variants also include variants that demonstrate altered signaling through certain pathways activated by wild-type IL-2 via the IL-2R and result in preferential proliferation/survival/activation of T-reg.
  • Molecules known to be phosphorylated upon activation of the IL-2R include STAT5, p38, ERK, SYK, LCK, AKT and mTOR.
  • the immunosuppressive IL-2 variant can possess a reduced PI3K signaling ability in FOXP3 ⁇ T cells, which can be measured by a reduction in the phosphorylation of AKT and/or mTOR as compared to wild-type IL-2.
  • Such variants may include mutations in positions that either contact IL-2R ⁇ or IL-2R ⁇ or alter the orientation of other positions contacting IL-2R ⁇ or IL-2R ⁇ .
  • IL-2 residues believed to contact IL-2R ⁇ include L12, Q13, H16, L19, D20, M23, R81, D84, S87, N88, V91, I92, and E95.
  • IL-2 residues believed to contact IL-2R ⁇ include Q11, L18, Q22, E110, N119, T123, Q126, S127, I129, S130, and T133.
  • the IL-2 variant comprises a mutation at E15, H16, Q22, D84, N88, or E95. Examples of such mutations include E15Q, H16N, Q22E, D84N, N88D, and E95Q.
  • the IL-2 variant comprises a combination of mutations.
  • Examples of IL-2 variants having a combination of mutations are provided in FIG. 1 and include haWT (SEQ ID NO:2), haD, (SEQ ID NO:3), haD.1 (SEQ ID NO:4), haD.2 (SEQ ID NO:5), haD.4 (SEQ ID NO:6), haD.5 (SEQ ID NO:7), haD.6 (SEQ ID NO:8), haD.8 (SEQ ID NO:9), and haD.11 (SEQ ID NO:10)d.
  • the IL-2 variant stimulates STAT5 phosphorylation in FOXP3-positive regulatory T cells but has reduced ability to induce STAT5 and AKT phosphorylation in FOXP3-negative T cells as compared to wild-type IL-2.
  • Preferred variants having such properties include haD, haD.1, haD.2, haD.4, haD.5, haD.6, and haD.8.
  • the IL-2 variants may further comprise one or more mutations as compared to the wild-type IL-2 sequence that do not have an effect on the affinity for IL-2R ⁇ or IL-2R ⁇ , provided the IL-2 variant promotes the preferential proliferation, survival, activation or function of FOXP3 + T-reg over that of other T cells that do not express FOXP3.
  • such mutations are conservative mutations.
  • the IL-2 variant may comprise one or more compounds to increase the serum-half-life of the IL-2 variant when administered to a patient.
  • Such half-life extending molecules include water soluble polymers (e.g., polyethylene glycol (PEG)), low- and high-density lipoproteins, antibody Fc (monomer or dimer), transthyretin (TTR), and TGF- ⁇ latency associated peptide (LAP).
  • PEG polyethylene glycol
  • TTR transthyretin
  • LAP TGF- ⁇ latency associated peptide
  • IL-2 variants comprising a combination of serum half-life extending molecules, such as PEGylated TTR (US Pat. Appl. Publ. No. 2003/0195154).
  • the immunosuppressive IL-2 variants can be produced using any suitable method known in the art, including those described in U.S. Pat. No. 6,955,807 for producing immunostimulatory IL-2 variants (incorporated herein by reference). Such methods include constructing a DNA sequence encoding the IL-2 variant and expressing those sequences in a suitably transformed host. This method will produce the recombinant variant of this invention. However, the variants may also be produced by chemical synthesis or a combination of chemical synthesis and recombinant DNA technology. Batch-wise production or perfusion production methods are known in the art. See Freshey, R. I. (ed), “Animal Cell Culture: A Practical Approach,” 2nd ed., 1992, IRL Press.
  • a DNA sequence is constructed by isolating or synthesizing a DNA sequence encoding the wild type IL-2 and then changing one or more codons by site-specific mutagenesis.
  • This technique is well known. See, e.g., Mark et. al., “Site-specific Mutagenesis Of The Human Fibroblast Interferon Gene”, Proc. Natl. Acad. Sci. USA 81, pp. 5662-66 (1984); and U.S. Pat. No. 4,588,585, incorporated herein by reference.
  • Another method of constructing a DNA sequence encoding the IL-2 variant would be chemical synthesis. This for example includes direct synthesis of a peptide by chemical means of the protein sequence encoding for an IL-2 variant exhibiting the properties described herein. This method may incorporate both natural and unnatural amino acids at positions that affect the interactions of IL-2 with the IL2R ⁇ , IL-2R ⁇ , or IL-2R ⁇ . Alternatively, a gene which encodes the desired IL-2 variant may be synthesized by chemical means using an oligonucleotide synthesizer.
  • Such oligonucleotides are designed based on the amino acid sequence of the desired IL-2 variant, and preferably selecting those codons that are favored in the host cell in which the recombinant variant will be produced.
  • the genetic code is degenerate—that an amino acid may be coded for by more than one codon.
  • Phe (F) is coded for by two codons, TTC or TTT
  • Tyr (Y) is coded for by TAC or TAT
  • his (H) is coded for by CAC or CAT.
  • Trp (W) is coded for by a single codon, TGG. Accordingly, it will be appreciated that for a given DNA sequence encoding a particular IL-2 variant, there will be many DNA degenerate sequences that will code for that IL-2 variant.
  • the DNA sequence encoding the IL-2 variant may or may not also include DNA sequences that encode a signal sequence.
  • Such signal sequence should be one recognized by the cell chosen for expression of the IL-2 variant. It may be prokaryotic, eukaryotic or a combination of the two. It may also be the signal sequence of native IL-2. The inclusion of a signal sequence depends on whether it is desired to secrete the IL-2 variant from the recombinant cells in which it is made. If the chosen cells are prokaryotic, it generally is preferred that the DNA sequence not encode a signal sequence. If the chosen cells are eukaryotic, it generally is preferred that a signal sequence be encoded and most preferably that the wild-type IL-2 signal sequence be used.
  • Standard methods may be applied to synthesize a gene encoding an IL-2 variant.
  • the complete amino acid sequence may be used to construct a back-translated gene.
  • a DNA oligomer containing a nucleotide sequence coding for an IL-2 variant may be synthesized.
  • several small oligonucleotides coding for portions of the desired polypeptide may be synthesized and then ligated.
  • the individual oligonucleotides typically contain 5′ or 3′ overhangs for complementary assembly.
  • the DNA sequences encoding an IL-2 variant will be inserted into an expression vector and operatively linked to an expression control sequence appropriate for expression of the IL-2 variant in the desired transformed host. Proper assembly may be confirmed by nucleotide sequencing, restriction mapping, and expression of a biologically active polypeptide in a suitable host. As is well known in the art, in order to obtain high expression levels of a transfected gene in a host, the gene must be operatively linked to transcriptional and translational expression control sequences that are functional in the chosen expression host. The choice of expression control sequence and expression vector will depend upon the choice of host. A wide variety of expression host/vector combinations may be employed.
  • Any suitable host may be used to produce the IL-2 variant, including bacteria, fungi (including yeasts), plant, insect, mammal, or other appropriate animal cells or cell lines, as well as transgenic animals or plants. More particularly, these hosts may include well known eukaryotic and prokaryotic hosts, such as strains of E. coli, Pseudomonas, Bacillus, Streptomyces , fungi, yeast, insect cells such as Spodoptera frugiperda (Sf9), animal cells such as Chinese hamster ovary (CHO) and mouse cells such as NS/O, African green monkey cells such as COS 1, COS 7, BSC 1, BSC 40, and BNT 10, and human cells, as well as plant cells in tissue culture. For animal cell expression, CHO cells and COS 7 cells in cultures and particularly the CHO cell line CHO (DHFR ⁇ ) or the HKB line are preferred.
  • DHFR ⁇ CHO cell line CHO
  • vectors and expression control sequences will function equally well to express the DNA sequences described herein. Neither will all hosts function equally well with the same expression system. However, one of skill in the art may make a selection among these vectors, expression control sequences and hosts without undue experimentation. For example, in selecting a vector, the host must be considered because the vector must replicate in it. The vectors copy number, the ability to control that copy number, and the expression of any other proteins encoded by the vector, such as antibiotic markers, should also be considered.
  • preferred vectors for use in this invention include those that allow the DNA encoding the IL-2 variants to be amplified in copy number. Such amplifiable vectors are well known in the art.
  • DHFR vectors able to be amplified by DHFR amplification
  • vectors able to be amplified by DHFR amplification see, e.g., Kaufman, U.S. Pat. No. 4,470,461, Kaufman and Sharp, “Construction Of A Modular Dihydrafolate Reductase cDNA Gene: Analysis Of Signals Utilized For Efficient Expression”, Mol. Cell. Biol., 2, pp. 1304-19 (1982)
  • GS glutamine synthetase
  • the IL-2 variants may be glycosylated or unglycosylated depending on the host organism used to produce the variant. If bacteria are chosen as the host, then the IL-2 variant produced will be unglycosylated. Eukaryotic cells, on the other hand, will glycosylate the IL-2 variant, although perhaps not in the same way as native IL-2 is glycosylated.
  • the IL-2 variant produced by the transformed host can be purified according to any suitable method. Various methods are known for purifying IL-2. See, e.g Current Protocols in Protein Science, Vol 2. Eds: John E. Coligan, Ben M. Dunn, Hidde L. Ploehg, David W. Speicher, Paul T. Wingfield, Unit 6.5 (Copyright 1997, John Wiley and Sons, Inc).
  • the biological activity of the IL-2 variants can be assayed by any suitable method known in the art. Such assays include those described in the Examples below.
  • Diseases, disorders, or conditions may be amenable to treatment with or may be prevented by administration of a T-reg-selective IL-2 variant to a subject.
  • diseases, disorders, and conditions include, but are not limited to, inflammation, autoimmune disease, paraneoplastic autroimmune diseases, cartilage inflammation, fibrotic disease and/or bone degradation, arthritis, rheumatoid arthritis, juvenile arthritis, juvenile rheumatoid arthritis, pauciarticular juvenile rheumatoid arthritis, polyarticular juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, juvenile ankylosing spondylitis, juvenile enteropathic arthritis, juvenile reactive arthritis, juvenile Reter's Syndrome, SEA Syndrome (Seronegativity, Enthesopathy, Arthropathy Syndrome), juvenile dermatomyositis, juvenile psoriatic arthritis, juvenile scleroderma, juvenile systemic lupus erythematosus, juvenile vascu
  • treatment encompasses alleviation or prevention of at least one symptom or other aspect of a disorder, or reduction of disease severity, and the like.
  • a T-reg-selective IL-2 variant need not effect a complete cure, or eradicate every symptom or manifestation of a disease, to constitute a viable therapeutic agent.
  • drugs employed as therapeutic agents may reduce the severity of a given disease state, but need not abolish every manifestation of the disease to be regarded as useful therapeutic agents.
  • a prophylactically administered treatment need not be completely effective in preventing the onset of a condition in order to constitute a viable prophylactic agent.
  • One embodiment of the invention is directed to a method comprising administering to a patient A T-reg-selective IL-2 variant in an amount and for a time sufficient to induce a sustained improvement over baseline of an indicator that reflects the severity of the particular disorder.
  • the invention provides pharmaceutical compositions comprising a therapeutically effective amount of one or a plurality of T-reg-selective IL-2 variants of the invention together with a pharmaceutically acceptable diluent, carrier, solubilizer, emulsifier, preservative, and/or adjuvant.
  • the invention provides methods of treating a patient by administering such pharmaceutical composition.
  • patient includes human and animal subjects.
  • acceptable formulation materials preferably are nontoxic to recipients at the dosages and concentrations employed.
  • the pharmaceutical composition may contain formulation materials for modifying, maintaining or preserving, for example, the pH, osmolality, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition.
  • suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine or lysine); antimicrobials; antioxidants (such as ascorbic acid, sodium sulfite or sodium hydrogen-sulfite); buffers (such as borate, bicarbonate, Tris-HCl, citrates, phosphates or other organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediamine tetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (such as glucose, sucrose, mannose or dextrins); proteins (such as serum albumin, gelatin or immunoglobulins); coloring, flavoring and diluting agents; emuls
  • amino acids
  • T-reg-selective IL-2 variant-containing pharmaceutical composition to be employed will depend, for example, upon the therapeutic context and objectives.
  • dosage levels for treatment will vary depending, in part, upon the molecule delivered, the indication for which the T-reg-selective IL-2 variant is being used, the route of administration, and the size (body weight, body surface or organ size) and/or condition (the age and general health) of the patient.
  • the clinician may titer the dosage and modify the route of administration to obtain the optimal therapeutic effect.
  • a typical dosage may range from about 0.1 ⁇ g/kg to up to about 30 mg/kg or more, depending on the factors mentioned above. In specific embodiments, the dosage may range from 0.1 ⁇ g/kg up to about 30 mg/kg, optionally from 1 ⁇ g/kg up to about 30 mg/kg or from 10 ⁇ g/kg up to about 5 mg/kg.
  • Dosing frequency will depend upon the pharmacokinetic parameters of the particular T-reg-selective IL-2 variant in the formulation used.
  • a clinician administers the composition until a dosage is reached that achieves the desired effect.
  • the composition may therefore be administered as a single dose, or as two or more doses (which may or may not contain the same amount of the desired molecule) over time, or as a continuous infusion via an implantation device or catheter. Further refinement of the appropriate dosage is routinely made by those of ordinary skill in the art and is within the ambit of tasks routinely performed by them.
  • the route of administration of the pharmaceutical composition is in accord with known methods, e.g., orally, through injection by intravenous, intraperitoneal, intracerebral (intra-parenchymal), intracerebroventricular, intramuscular, intra-ocular, intraarterial, intraportal, or intralesional routes; by sustained release systems or by implantation devices.
  • the compositions may be administered by bolus injection or continuously by infusion, or by implantation device.
  • T-reg-selective IL-2 variant is administered in combination with other agents useful for treating the condition with which the patient is afflicted.
  • agents include both proteinaceous and non-proteinaceous drugs.
  • dosages may be adjusted accordingly, as is recognized in the pertinent art.
  • “Co-administration” and combination therapy are not limited to simultaneous administration, but also include treatment regimens in which a T-reg-selective IL-2 variant is administered at least once during a course of treatment that involves administering at least one other therapeutic agent to the patient.
  • a T-reg-selective IL-2 variant is administered in combination with an inhibitor of the PI3-K/AKT/mTOR pathway, e.g., rapamycin (rapamune, sirolimus). Inhibitors of this pathway in combination with IL-2 favor T-reg enrichment.
  • an inhibitor of the PI3-K/AKT/mTOR pathway e.g., rapamycin (rapamune, sirolimus).
  • Inhibitors of this pathway in combination with IL-2 favor T-reg enrichment.
  • variant haD, haD.1, haD.2, etc also contained mutations predicted to alter interactions with IL-2R ⁇ and/or IL-2R ⁇ .
  • variant haD.11 was not capable of inducing any signal or altering any cellular phenotype and, as such, served as a control for CD25 binding without IL-2R signaling.
  • All the IL-2 variants contained the C125S mutation for improved manufacturability and terminated with FLAG and HIS-tag sequences (DYKDDDDKGSSHHHHHH) (SEQ ID NO:11)
  • PBMC peripheral blood mononuclear cells
  • CD8 + CD25 + T cells were especially responsive to WT IL-2 and variant haWT, however, all variants that contained mutated IL-2R ⁇ and/or ⁇ contact residues were very inefficient at promoting accumulation of activated CD8 + CD25 + T cells ( FIG. 2B ).
  • FIG. 2C A similar trend was observed for CD4 + CD25 + FOXP3 ⁇ T cells (FIG. 2 C).
  • the growth/survival of FOXP3 + CD4 + T cells was stimulated by several IL-2 variants to a degree similar to that of WT IL-2 ( FIG. 2D ).
  • the ratio of FOXP3 + to FOXP3 ⁇ T cells among CD4 + CD25 + T cells was increased by several IL-2 variants with IL-2R ⁇ -contact residue mutations ( FIG. 2E ). Furthermore, the mutations did not impair IL-2-stimulated FOXP3 upregulation in T-reg ( FIG. 2F ).
  • the IL-2 variants were screened for their ability to stimulate AKT and STAT5 phosphorylation in T cell subsets.
  • Several IL-2 variants were as potent, or nearly as potent, as wt IL-2 at stimulating STAT5 in FOXP3 + T cells 10 min after stimulation.
  • Three hours after washing IL-2 from the media some IL-2 variants (haD, haD.1, haD.2, haD.4, haD.6, and haD.8) continued to stimulate sustained STAT5 signaling at levels higher than that seen with wt IL-2.
  • STAT5 and AKT responses to the haD variants after 10 min stimulation were not nearly as high as those stimulated by wt IL-2 or haWT.
  • T cells Previously activated (with anti-CD3 for 2-3 days) and rested (in fresh culture medium for 2-5 days) T cells were exposed to 1 nM wt or mutant IL-2 for 10 min at 37° C. Cells were then stained (10 min timepoint) or washed and cultured for an additional 3 hrs (3 hr timepoint).
  • a 50 ⁇ l culture was stopped by adding an equal volume of 2 ⁇ lysis buffer and lysates were measured for phospho-AKT with multiplex ELISA plates according to the manufacturer's protocols (MesoScale Discovery, Gaithersburg, Md.).
  • a 50 ⁇ l culture was stopped by adding 1 ml of FOXP3 Fix/Perm Buffer (BioLegend, San Diego, Calif.), incubation at 25° C. for 20 min, and staining for cell surface markers, FOXP3 and phospho-STAT5 according the BioLegend FOXP3 staining protocol.
  • FOXP3 Fix/Perm Buffer BioLegend, San Diego, Calif.
US13/145,537 2009-01-21 2010-01-20 Compositions and methods of treating inflammatory and autoimmune diseases Abandoned US20110274650A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US13/145,537 US20110274650A1 (en) 2009-01-21 2010-01-20 Compositions and methods of treating inflammatory and autoimmune diseases

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US14611109P 2009-01-21 2009-01-21
PCT/US2010/021519 WO2010085495A1 (fr) 2009-01-21 2010-01-20 Compositions et procédés de traitement de maladies inflammatoires et auto-immunes
US13/145,537 US20110274650A1 (en) 2009-01-21 2010-01-20 Compositions and methods of treating inflammatory and autoimmune diseases

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2010/021519 A-371-Of-International WO2010085495A1 (fr) 2009-01-21 2010-01-20 Compositions et procédés de traitement de maladies inflammatoires et auto-immunes

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13/672,417 Continuation US9732134B2 (en) 2009-01-21 2012-11-08 Method of treating graft versus host disease using IL-2 muteins

Publications (1)

Publication Number Publication Date
US20110274650A1 true US20110274650A1 (en) 2011-11-10

Family

ID=42356180

Family Applications (4)

Application Number Title Priority Date Filing Date
US13/145,537 Abandoned US20110274650A1 (en) 2009-01-21 2010-01-20 Compositions and methods of treating inflammatory and autoimmune diseases
US13/672,417 Active US9732134B2 (en) 2009-01-21 2012-11-08 Method of treating graft versus host disease using IL-2 muteins
US15/649,520 Active US11560415B2 (en) 2009-01-21 2017-07-13 Method of promoting regulatory T-cell proliferation
US18/068,970 Pending US20230139534A1 (en) 2009-01-21 2022-12-20 Methods of treating graft versus host disease using il-2 muteins

Family Applications After (3)

Application Number Title Priority Date Filing Date
US13/672,417 Active US9732134B2 (en) 2009-01-21 2012-11-08 Method of treating graft versus host disease using IL-2 muteins
US15/649,520 Active US11560415B2 (en) 2009-01-21 2017-07-13 Method of promoting regulatory T-cell proliferation
US18/068,970 Pending US20230139534A1 (en) 2009-01-21 2022-12-20 Methods of treating graft versus host disease using il-2 muteins

Country Status (8)

Country Link
US (4) US20110274650A1 (fr)
EP (1) EP2382228B1 (fr)
JP (6) JP5766124B2 (fr)
AU (1) AU2010206840B2 (fr)
CA (1) CA2749539C (fr)
ES (1) ES2825173T3 (fr)
MX (1) MX2011007647A (fr)
WO (1) WO2010085495A1 (fr)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014153063A1 (fr) 2013-03-14 2014-09-25 Amgen Inc. Polypeptides contenant fc aglycosylés
US20150218260A1 (en) * 2014-02-06 2015-08-06 Hoffman-La Roche Inc. Interleukin-2 fusion proteins and uses thereof
WO2015164815A1 (fr) * 2014-04-24 2015-10-29 The Board Of Trustees Of The Leland Stanford Junior University Superagonistes, agonistes et antagonistes partiels de l'interleukine-2
WO2016164937A2 (fr) 2015-04-10 2016-10-13 Amgen Inc. Mutéines de l'interleukine-2 pour l'expansion de lymphocytes t régulateurs
US10035836B1 (en) 2014-08-11 2018-07-31 Delinia, Inc. Modified IL-2 variants that selectively activate regulatory T cells
US10174092B1 (en) 2017-12-06 2019-01-08 Pandion Therapeutics, Inc. IL-2 muteins
US10294287B2 (en) 2016-01-20 2019-05-21 Delinia, Inc. Molecules that selectively activate regulatory T cells for the treatment of autoimmune diseases
US10562949B2 (en) 2012-08-10 2020-02-18 Roche Glycart Ag Interleukin-2 fusion proteins and uses thereof
CN111194322A (zh) * 2017-08-03 2020-05-22 辛索克斯公司 用于治疗增生性和感染性疾病的细胞因子缀合物
US10676516B2 (en) 2017-05-24 2020-06-09 Pandion Therapeutics, Inc. Targeted immunotolerance
US10851144B2 (en) 2015-04-10 2020-12-01 Amgen Inc. Interleukin-2 muteins for the expansion of T-regulatory cells
US10946068B2 (en) 2017-12-06 2021-03-16 Pandion Operations, Inc. IL-2 muteins and uses thereof
US10961310B2 (en) 2017-03-15 2021-03-30 Pandion Operations, Inc. Targeted immunotolerance
US11077172B2 (en) 2016-11-08 2021-08-03 Delinia, Inc. IL-2 variants for the treatment of psoriasis
US11542312B2 (en) 2017-06-19 2023-01-03 Medicenna Therapeutics, Inc. IL-2 superagonists in combination with anti-PD-1 antibodies
US11680090B2 (en) 2013-09-24 2023-06-20 Medicenna Therapeutics, Inc. Interleukin-2 fusion proteins and uses thereof
US11739146B2 (en) 2019-05-20 2023-08-29 Pandion Operations, Inc. MAdCAM targeted immunotolerance
US11981715B2 (en) 2021-02-18 2024-05-14 Pandion Operations, Inc. Tissue targeted immunotolerance with a CD39 effector

Families Citing this family (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110274650A1 (en) 2009-01-21 2011-11-10 Amgen Inc. Compositions and methods of treating inflammatory and autoimmune diseases
CU23923B1 (es) * 2010-11-12 2013-07-31 Ct De Inmunología Molecular Polipéptidos derivados de la il-2 con actividad agonista
AU2012215573B2 (en) * 2011-02-10 2015-11-26 Roche Glycart Ag Mutant interleukin-2 polypeptides
BR112013023151A2 (pt) 2011-03-11 2020-09-15 Assistance Publique - Hôpitaux De Paris interleucina-2 para uso no tratamento de desordem auto-imune, !muno-relacionada ou inflamatória e método para determinar se um regime ou dose de il-2 tem de ser modificado
CN103732241A (zh) 2011-03-11 2014-04-16 公共事业救济局-巴黎医院 低剂量il-2用于治疗自身免疫相关病症或炎性病症的应用
EA201892619A1 (ru) 2011-04-29 2019-04-30 Роше Гликарт Аг Иммуноконъюгаты, содержащие мутантные полипептиды интерлейкина-2
US9481866B2 (en) * 2011-12-16 2016-11-01 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Methods of producing T cell populations enriched for stable regulatory T-cells
DK3172227T3 (da) * 2014-07-21 2019-12-02 Delinia Inc Molekyler der selektivt aktiverer regulatoriske t-celler til behandlingen af autoimmune sygdomme
SG11201708349VA (en) * 2015-04-10 2017-11-29 Amgen Inc Interleukin-2 muteins for the expansion of t-regulatory cells
KR20190019068A (ko) 2016-05-18 2019-02-26 큐 바이오파마, 인크. T-세포 조절 다량체 폴리펩타이드 및 이의 사용 방법
IL303806B1 (en) 2016-12-22 2024-01-01 Cue Biopharma Inc Multimeric polypeptides modulate T cells and methods for their use
WO2018129474A1 (fr) 2017-01-09 2018-07-12 Cue Biopharma, Inc. Polypeptides multimères modulateurs de lymphocytes t et leurs procédés d'utilisation
AU2018234628B2 (en) 2017-03-15 2023-07-20 Cue Biopharma, Inc. Methods for modulating an immune response
EP3652316A4 (fr) 2017-07-11 2021-04-07 Synthorx, Inc. Incorporation de nucléotides non naturels et procédés associés
JP2021500855A (ja) * 2017-09-07 2021-01-14 キュー バイオファーマ， インコーポレイテッド 抗原提示ポリペプチドおよびその使用方法
WO2019125732A1 (fr) * 2017-12-19 2019-06-27 Xencor, Inc. Protéines de fusion il-2 fc modifiées
JP7275049B2 (ja) * 2017-12-27 2023-05-17 協和キリン株式会社 Ｉｌ－２改変体
WO2019139896A1 (fr) 2018-01-09 2019-07-18 Cue Biopharma, Inc. Polypeptides multimères modulateurs de lymphocytes t et leurs procédés d'utilisation
WO2019158764A1 (fr) 2018-02-16 2019-08-22 Iltoo Pharma Utilisation de l'interleukine 2 pour traiter le syndrome de sjögren
WO2019173832A2 (fr) 2018-03-09 2019-09-12 AskGene Pharma, Inc. Nouveaux promédicaments à base de cytokine
MX2020009975A (es) 2018-03-28 2020-10-12 Bristol Myers Squibb Co Proteinas de fusion interleucina-2/receptor alfa de interleucina-2 y metodos de uso.
WO2020007937A1 (fr) 2018-07-03 2020-01-09 Iltoo Pharma Utilisation de l'interleukine-2 pour le traitement de la sclérose systémique
WO2020035482A1 (fr) 2018-08-13 2020-02-20 Iltoo Pharma Combinaison d'interleukine 2 et d'un inhibiteur de l'interleukine 1, conjugués et utilisations thérapeutiques de celle-ci
JP2022513265A (ja) 2018-12-21 2022-02-07 ジエンス ヘンルイ メデイシンカンパニー リミテッド ヒトインターロイキン２の変異体またはその誘導体
WO2020163532A1 (fr) 2019-02-06 2020-08-13 Synthorx, Inc. Conjugués d'il-2 et méthodes d'utilisation de ceux-ci
EP3924389A4 (fr) 2019-02-15 2023-06-14 Integral Molecular, Inc. Anticorps anti-claudine 6 et leurs utilisations
CA3129317A1 (fr) 2019-02-15 2020-08-20 Integral Molecular, Inc. Anticorps comprenant une chaine legere commune et leurs utilisations
WO2020201095A1 (fr) 2019-03-29 2020-10-08 Institut Curie Variants d'interleukine-2 à activité biologique modifiée
KR20220020879A (ko) 2019-06-12 2022-02-21 에스크진 파마, 아이엔씨. 새로운 il-15 프로드럭 및 이를 사용하는 방법
AU2020328038A1 (en) 2019-08-13 2022-03-31 Amgen Inc. Interleukin-2 muteins for the expansion of T-regulatory cells
TW202128961A (zh) 2019-11-20 2021-08-01 美商安維塔生物科學股份有限公司 細胞激素融合蛋白及其醫藥組合物及治療應用
BR112022011414A2 (pt) 2019-12-12 2022-08-30 Iltoo Pharma Construção quimérica, proteína homodimérica, proteína heterodimérica, ácido nucleico, vetor, célula hospedeira, métodos para produzir uma proteína dimérica e para produzir uma proteína heterodimérica
EP4077383A1 (fr) 2019-12-17 2022-10-26 Amgen Inc. Double agoniste de l'interleukine-2/ récepteur du tnf destiné à être utilisé en thérapie
US20210188934A1 (en) 2019-12-20 2021-06-24 Regeneron Pharmaceuticals, Inc. Novel il2 agonists and methods of use thereof
JP2023514010A (ja) 2020-01-10 2023-04-05 ブライト ピーク セラピューティクス エージー 修飾ｉｌ－２ポリペプチドおよびその使用
MX2022008771A (es) 2020-01-14 2022-10-07 Synthekine Inc Metodos y composiciones de muteinas de il2 sesgadas.
EP4139340A1 (fr) 2020-04-22 2023-03-01 Merck Sharp & Dohme LLC Conjugués interleukine-2 humain polarisés pour le dimère bêta gammac de récepteur interleukine-2 et conjugués à un polymère non peptidique soluble dans l'eau
WO2021222150A2 (fr) 2020-04-28 2021-11-04 Anwita Biosciences, Inc. Polypeptides d'interleukine-2 et protéines de fusion de ceux-ci, ainsi que leurs compositions pharmaceutiques et leurs applications thérapeutiques
AU2021272895A1 (en) 2020-05-12 2022-09-22 Cue Biopharma, Inc. Multimeric T-cell modulatory polypeptides and methods of use thereof
CN116133676A (zh) 2020-06-03 2023-05-16 阿森迪斯药物肿瘤股份有限公司 Il-2序列及其用途
JP2023533567A (ja) * 2020-07-14 2023-08-03 ファイザー・インク 組み換えワクシニアウイルス
EP4204439A1 (fr) * 2020-08-28 2023-07-05 Ascendis Pharma Oncology Division A/S Protéines il-2 glycosylées et utilisations correspondantes
AU2021369823A1 (en) 2020-10-29 2023-06-01 Bristol-Myers Squibb Company Fusion proteins for the treatment of disease
CN112279906B (zh) * 2020-10-30 2022-09-20 浙江新码生物医药有限公司 人白细胞介素2-聚乙二醇偶联物及其制备方法与应用
JP2023549191A (ja) 2020-11-13 2023-11-22 江蘇恒瑞医薬股▲ふん▼有限公司 ヒトインターロイキン２の変異体又はその誘導体を含む医薬組成物及びその用途
TW202237171A (zh) * 2020-12-04 2022-10-01 美商威特拉公司 使用介白素-2藥劑之方法
US20230201364A1 (en) 2021-07-09 2023-06-29 Bright Peak Therapeutics Ag Antibody conjugates and manufacture thereof
EP4366779A1 (fr) 2021-07-09 2024-05-15 Bright Peak Therapeutics AG Anticorps anti-tnf modifiés et leurs utilisations
CA3223427A1 (fr) 2021-07-30 2023-02-02 Minghui Dong Variant d'interleukine-2 humaine et son utilisation
WO2023057588A1 (fr) 2021-10-06 2023-04-13 Iltoo Pharma Constructions chimériques d'interleukine 2 ont une spécificité de ciblage vis-à-vis des tissus enflammés
WO2023133595A2 (fr) 2022-01-10 2023-07-13 Sana Biotechnology, Inc. Méthodes de dosage et d'administration ex vivo de particules lipidiques ou de vecteurs viraux ainsi que systèmes et utilisations associés
WO2023193015A1 (fr) 2022-04-01 2023-10-05 Sana Biotechnology, Inc. Polythérapies d'agoniste de récepteur de cytokine et de vecteur viral
WO2024056154A1 (fr) 2022-09-12 2024-03-21 INSERM (Institut National de la Santé et de la Recherche Médicale) Interleukine-2 pour le traitement des troubles du spectre autistique

Family Cites Families (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4470461A (en) 1982-09-30 1984-09-11 Phillips Petroleum Company Organic nitro compounds as cosurfactants in enhanced oil recovery processes
US4588585A (en) 1982-10-19 1986-05-13 Cetus Corporation Human recombinant cysteine depleted interferon-β muteins
US4518584A (en) 1983-04-15 1985-05-21 Cetus Corporation Human recombinant interleukin-2 muteins
GB8601597D0 (en) 1986-01-23 1986-02-26 Wilson R H Nucleotide sequences
EP0262802A3 (fr) 1986-09-01 1990-01-31 Takeda Chemical Industries, Ltd. Médicament pour le traitement de l'arthrite rhumatoide ou du lupus érythémateux systémique
GB8809129D0 (en) 1988-04-18 1988-05-18 Celltech Ltd Recombinant dna methods vectors and host cells
US5466447A (en) 1988-06-29 1995-11-14 Amgen Inc. Method for treating psoriasis
JPH03500415A (ja) 1988-07-05 1991-01-31 アムジエン・インコーポレーテツド インターロイキン２類似体
CA2062582C (fr) 1991-03-27 1996-03-26 Tse-Wen Chang Methodes et substances pour recruter des agents therapeutiques a des tissus solides
US5229109A (en) 1992-04-14 1993-07-20 Board Of Regents, The University Of Texas System Low toxicity interleukin-2 analogues for use in immunotherapy
US6955807B1 (en) 1998-05-15 2005-10-18 Bayer Pharmaceuticals Corporation IL-2 selective agonists and antagonists
DZ2788A1 (fr) 1998-05-15 2003-12-01 Bayer Ag Agonistes et antagonistes selectifs à IL-2.
US6737056B1 (en) 1999-01-15 2004-05-18 Genentech, Inc. Polypeptide variants with altered effector function
US6348192B1 (en) 1999-05-11 2002-02-19 Bayer Corporation Interleukin-2 mutein expressed from mammalian cells
MXPA02007733A (es) 2000-02-11 2004-09-10 Merck Patent Gmbh Mejoramiento de la vida media circulante de proteinas de fusion basadas en anticuerpos.
JP2005507870A (ja) 2001-08-13 2005-03-24 ユニバーシティ・オブ・サザン・カリフォルニア 低毒性のインターロイキン−２突然変異体
RU2312677C9 (ru) 2001-12-04 2008-03-27 Мерк Патент Гмбх Иммуноцитокины с модулированной селективностью
US20030191056A1 (en) 2002-04-04 2003-10-09 Kenneth Walker Use of transthyretin peptide/protein fusions to increase the serum half-life of pharmacologically active peptides/proteins
AR043504A1 (es) 2003-03-17 2005-08-03 Novartis Ag Composiciones farmaceuticas que comprenden rapamicina para el tratamiento de enfermedades inflamatorias
US7569215B2 (en) * 2003-07-18 2009-08-04 Massachusetts Institute Of Technology Mutant interleukin-2 (IL-2) polypeptides
JP2007527242A (ja) 2004-03-05 2007-09-27 カイロン コーポレーション 治療剤の患者耐容性を予測するためのインビトロ試験システム
AU2006232374B2 (en) * 2005-04-01 2011-08-25 University Of Southern California Preventing rejection of transplanted tissue using regulatory T cells
CA2642532A1 (fr) 2006-02-16 2007-08-23 Nascent Biologics, Inc. Procedes d'amelioration de la fonction immunitaire et procedes de prevention et de traitement de maladie chez un sujet mammalien
EP2676967B1 (fr) 2006-02-28 2019-08-14 Biogen MA Inc. Procédés de traitement de maladies inflammatoires et auto-immunes avec du natalizumab
JP2009542592A (ja) 2006-07-06 2009-12-03 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｉｌ−２媒介性免疫応答の有効性を高める組成物および方法
DE112007001471T5 (de) 2006-07-06 2009-04-30 Mitsubishi Electric Corp. Navigationssystem
GB0623539D0 (en) 2006-11-24 2007-01-03 Avidex Ltd Polypeptides
CA2679399A1 (fr) 2007-02-27 2008-09-04 Genetech, Inc. Anticorps antagoniste d'ox40, et leur utilisation dans le traitement de maladies inflammatoires et auto-immunes
CN101951940A (zh) 2007-03-15 2011-01-19 比奥根艾迪克Ma公司 自身免疫病的治疗
WO2009061853A2 (fr) 2007-11-05 2009-05-14 Massachusetts Institute Of Technology Polypeptides d'interleukine-2 (il-2) mutants
EP2235064B1 (fr) 2008-01-07 2015-11-25 Amgen Inc. Méthode de fabrication de molécules hétérodimères fc d'anticorps utilisant les effets de conduite électrostatique
DE102008023820A1 (de) 2008-05-08 2009-11-12 Aicuris Gmbh & Co. Kg Mittel zur Behandlung und/oder Prophylaxe einer Autoimmunerkrankung und zur Bildung von Regulatorischen T-Zellen
WO2010017220A1 (fr) 2008-08-04 2010-02-11 The Trustees Of The University Of Pennsylvania Procédés d’expansion des lymphocytes t régulateurs
US20110200534A1 (en) 2008-08-21 2011-08-18 Industry-Academic Cooperation Foundation, Yonsei U T1-T2 Dual Modal MRI Contrast Agents
US20110274650A1 (en) * 2009-01-21 2011-11-10 Amgen Inc. Compositions and methods of treating inflammatory and autoimmune diseases
CN103732241A (zh) 2011-03-11 2014-04-16 公共事业救济局-巴黎医院 低剂量il-2用于治疗自身免疫相关病症或炎性病症的应用
CA2830254C (fr) 2011-03-16 2019-09-10 Amgen Inc. Variants de fc

Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10562949B2 (en) 2012-08-10 2020-02-18 Roche Glycart Ag Interleukin-2 fusion proteins and uses thereof
US11365232B2 (en) 2012-08-10 2022-06-21 Roche Glycart Ag Interleukin-2 fusion proteins and uses thereof
WO2014153111A2 (fr) 2013-03-14 2014-09-25 Amgen Inc. Mutéines d'interleukine 2 pour la propagation de lymphocytes t régulateurs
JP2016518823A (ja) * 2013-03-14 2016-06-30 アムジエン・インコーポレーテツド 制御性ｔ細胞の増殖のためのインターロイキン−２ムテイン
JP2021040630A (ja) * 2013-03-14 2021-03-18 アムジエン・インコーポレーテツド 制御性ｔ細胞の増殖のためのインターロイキン−２ムテイン
WO2014153063A1 (fr) 2013-03-14 2014-09-25 Amgen Inc. Polypeptides contenant fc aglycosylés
JP7227951B2 (ja) 2013-03-14 2023-02-22 アムジエン・インコーポレーテツド 制御性ｔ細胞の増殖のためのインターロイキン－２ムテイン
JP2019058182A (ja) * 2013-03-14 2019-04-18 アムジエン・インコーポレーテツド 制御性ｔ細胞の増殖のためのインターロイキン−２ムテイン
US11680090B2 (en) 2013-09-24 2023-06-20 Medicenna Therapeutics, Inc. Interleukin-2 fusion proteins and uses thereof
US20150218260A1 (en) * 2014-02-06 2015-08-06 Hoffman-La Roche Inc. Interleukin-2 fusion proteins and uses thereof
US11098099B2 (en) * 2014-02-06 2021-08-24 Hoffmann-La Roche Inc. Interleukin-2 fusion proteins and uses thereof
CN106659757A (zh) * 2014-04-24 2017-05-10 利兰斯坦福初级大学董事会 白介素2的超级激动剂、部分激动剂和拮抗剂
US10654905B2 (en) 2014-04-24 2020-05-19 The Board Of Trustees Of The Leland Stanford Junior University Method of treating graft versus host disease with an interleukin-2 mutein
WO2015164815A1 (fr) * 2014-04-24 2015-10-29 The Board Of Trustees Of The Leland Stanford Junior University Superagonistes, agonistes et antagonistes partiels de l'interleukine-2
US11384131B2 (en) 2014-04-24 2022-07-12 The Board Of Trustees Of The Leland Stanford Junior University Superagonists, partial agonists and antagonists of interleukin-2
US10035836B1 (en) 2014-08-11 2018-07-31 Delinia, Inc. Modified IL-2 variants that selectively activate regulatory T cells
WO2016164937A2 (fr) 2015-04-10 2016-10-13 Amgen Inc. Mutéines de l'interleukine-2 pour l'expansion de lymphocytes t régulateurs
US10851144B2 (en) 2015-04-10 2020-12-01 Amgen Inc. Interleukin-2 muteins for the expansion of T-regulatory cells
US11976103B2 (en) 2015-04-10 2024-05-07 Amgen Inc. Interleukin-2 muteins for the expansion of T-regulatory cells
US10774126B2 (en) 2016-01-20 2020-09-15 Delinia, Inc. Molecules that selectively activate regulatory T cells for the treatment of autoimmune diseases
US10875901B2 (en) 2016-01-20 2020-12-29 Delinia, Inc. Molecules that selectively activate regulatory T cells for the treatment of autoimmune diseases
US10766938B2 (en) 2016-01-20 2020-09-08 Delinia, Inc. Nucleic acid encoding human IL-2 variant
US10294287B2 (en) 2016-01-20 2019-05-21 Delinia, Inc. Molecules that selectively activate regulatory T cells for the treatment of autoimmune diseases
US11535657B2 (en) 2016-01-20 2022-12-27 Delinia, Inc. Molecules that selectively activate regulatory T cells for the treatment of autoimmune diseases
EP3808764A1 (fr) 2016-05-04 2021-04-21 Amgen Inc. Mutéines de l'interleukine-2 pour l'expansion de lymphocytes t régulateurs
US11077172B2 (en) 2016-11-08 2021-08-03 Delinia, Inc. IL-2 variants for the treatment of psoriasis
US10961310B2 (en) 2017-03-15 2021-03-30 Pandion Operations, Inc. Targeted immunotolerance
US11466068B2 (en) 2017-05-24 2022-10-11 Pandion Operations, Inc. Targeted immunotolerance
US10676516B2 (en) 2017-05-24 2020-06-09 Pandion Therapeutics, Inc. Targeted immunotolerance
US11542312B2 (en) 2017-06-19 2023-01-03 Medicenna Therapeutics, Inc. IL-2 superagonists in combination with anti-PD-1 antibodies
CN111194322A (zh) * 2017-08-03 2020-05-22 辛索克斯公司 用于治疗增生性和感染性疾病的细胞因子缀合物
US10174091B1 (en) 2017-12-06 2019-01-08 Pandion Therapeutics, Inc. IL-2 muteins
US10946068B2 (en) 2017-12-06 2021-03-16 Pandion Operations, Inc. IL-2 muteins and uses thereof
US11091526B2 (en) 2017-12-06 2021-08-17 Pandion Operations, Inc. IL-2 muteins and uses thereof
US11091527B2 (en) 2017-12-06 2021-08-17 Pandion Operations, Inc. IL-2 muteins and uses thereof
US11779632B2 (en) 2017-12-06 2023-10-10 Pandion Operation, Inc. IL-2 muteins and uses thereof
US11945852B2 (en) 2017-12-06 2024-04-02 Pandion Operations, Inc. IL-2 muteins and uses thereof
US11965008B2 (en) 2017-12-06 2024-04-23 Pandion Operations, Inc. IL-2 muteins and uses thereof
US10174092B1 (en) 2017-12-06 2019-01-08 Pandion Therapeutics, Inc. IL-2 muteins
US11739146B2 (en) 2019-05-20 2023-08-29 Pandion Operations, Inc. MAdCAM targeted immunotolerance
US11981715B2 (en) 2021-02-18 2024-05-14 Pandion Operations, Inc. Tissue targeted immunotolerance with a CD39 effector

Also Published As

Publication number Publication date
CA2749539A1 (fr) 2010-07-29
EP2382228A4 (fr) 2013-01-09
JP2012515778A (ja) 2012-07-12
WO2010085495A1 (fr) 2010-07-29
AU2010206840A1 (en) 2011-07-21
JP2021185191A (ja) 2021-12-09
EP2382228A1 (fr) 2011-11-02
JP2016138140A (ja) 2016-08-04
US11560415B2 (en) 2023-01-24
JP2014133756A (ja) 2014-07-24
US9732134B2 (en) 2017-08-15
JP2020023550A (ja) 2020-02-13
CA2749539C (fr) 2022-07-19
ES2825173T3 (es) 2021-05-14
AU2010206840B2 (en) 2015-02-05
US20230139534A1 (en) 2023-05-04
US20170313753A1 (en) 2017-11-02
MX2011007647A (es) 2011-09-01
US20130195795A1 (en) 2013-08-01
EP2382228B1 (fr) 2020-08-26
JP2018087244A (ja) 2018-06-07
JP5766124B2 (ja) 2015-08-19

Similar Documents

Publication Publication Date Title
US20230139534A1 (en) Methods of treating graft versus host disease using il-2 muteins
JP7272663B2 (ja) インターロイキン－２／インターロイキン－２受容体アルファ融合タンパク質および使用方法
KR100607609B1 (ko) Ｉｌ-2 선택성 작용제 및 길항제
JP4502580B2 (ja) 敗血症の治療または予防のためのｉｌ−１８阻害剤の使用
US6955807B1 (en) IL-2 selective agonists and antagonists
Gillespie et al. Interleukin-18: perspectives on the newest interleukin
KR19980702238A (ko) 인터루킨-15의 길항제
KR20230060514A (ko) 인터루킨-2 뮤테인 및 이의 용도
US20020150555A1 (en) Osteoclastgenic inhibitory agent
US20070190024A1 (en) Il-11 muteins
EA009604B1 (ru) ПРИМЕНЕНИЕ МУТАНТНОГО ПОЛИПЕПТИДА β-ЦЕПИ РЕЦЕПТОРА ИНТЕРФЕРОНА ТИПА I ДЛЯ ПРИГОТОВЛЕНИЯ ЛЕКАРСТВЕННОГО СРЕДСТВА, МОДУЛИРУЮЩЕГО ЭФФЕКТЫ ИНТЕРФЕРОНА-β, И ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ, СОДЕРЖАЩАЯ УКАЗАННЫЙ ПОЛИПЕПТИД
AU2002309887B2 (en) Use of IL-18 inhibitors for the treatment or prevention of sepsis
AU2002309887A1 (en) Use of IL-18 inhibitors for the treatment or prevention of sepsis

Legal Events

Date Code Title Description
AS Assignment

Owner name: AMGEN INC., CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:GAVIN, MARC A.;LI, LI;REEL/FRAME:026636/0109

Effective date: 20110720

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION