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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Immunology (AREA)
  • Diabetes (AREA)
  • Pulmonology (AREA)
  • Genetics & Genomics (AREA)
  • Toxicology (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Rheumatology (AREA)
  • Endocrinology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Transplantation (AREA)
  • Emergency Medicine (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Medicinal Preparation (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
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
US13/145,537 US20110274650A1 (en) 2009-01-21 2010-01-20 Compositions and methods of treating inflammatory and autoimmune diseases
PCT/US2010/021519 WO2010085495A1 (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 (en) 2009-01-21 2010-01-20 Compositions and methods of treating inflammatory and autoimmune diseases

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 (ja)
EP (1) EP2382228B1 (ja)
JP (6) JP5766124B2 (ja)
AU (1) AU2010206840B2 (ja)
CA (1) CA2749539C (ja)
ES (1) ES2825173T3 (ja)
MX (1) MX2011007647A (ja)
WO (1) WO2010085495A1 (ja)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014153063A1 (en) 2013-03-14 2014-09-25 Amgen Inc. AGLYCOSYLATED Fc-CONTAINING POLYPEPTIDES
US20150218260A1 (en) * 2014-02-06 2015-08-06 Hoffman-La Roche Inc. Interleukin-2 fusion proteins and uses thereof
WO2015164815A1 (en) * 2014-04-24 2015-10-29 The Board Of Trustees Of The Leland Stanford Junior University Superagonists, partial agonists and antagonists of interleukin-2
WO2016164937A2 (en) 2015-04-10 2016-10-13 Amgen Inc. Interleukin-2 muteins for the expansion of t-regulatory cells
US10035836B1 (en) 2014-08-11 2018-07-31 Delinia, Inc. Modified IL-2 variants that selectively activate regulatory T cells
US10174091B1 (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) 2020-02-21 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
JP5766124B2 (ja) 2009-01-21 2015-08-19 アムジェン インコーポレイテッド 炎症性疾患および自己免疫疾患の処置の組成物および方法
CU23923B1 (es) * 2010-11-12 2013-07-31 Ct De Inmunología Molecular Polipéptidos derivados de la il-2 con actividad agonista
SI3489255T1 (sl) 2011-02-10 2021-11-30 Roche Glycart Ag Mutantni polipeptidi interlevkina-2
US9669071B2 (en) 2011-03-11 2017-06-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Method for stimulating T lymphocytes with IL-2
EP2683395B1 (en) 2011-03-11 2018-08-01 Assistance Publique - Hôpitaux de Paris Use of low dose il-2 for treating type 1 diabetes
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
RS59789B1 (sr) * 2014-07-21 2020-02-28 Delinia Inc Molekuli koji selektivno aktiviraju regulatorne t ćelije u tretmanima autoimunih bolesti
CA2982362A1 (en) * 2015-04-10 2016-10-13 Amgen Inc. Interleukin-2 muteins for the expansion of t-regulatory cells
CA3019005A1 (en) 2016-05-18 2017-11-23 Cue Biopharma, Inc. T-cell modulatory multimeric polypeptides and methods of use thereof
CA3043630A1 (en) 2016-12-22 2018-06-28 Cue Biopharma, Inc. T-cell modulatory multimeric polypeptides and methods of use thereof
US11851471B2 (en) 2017-01-09 2023-12-26 Cue Biopharma, Inc. T-cell modulatory multimeric polypeptides and methods of use thereof
KR102619015B1 (ko) 2017-03-15 2023-12-28 큐 바이오파마, 인크. 면역 반응을 조절하는 방법
TWI821192B (zh) 2017-07-11 2023-11-11 美商新索思股份有限公司 非天然核苷酸之導入及其方法
KR20200064083A (ko) * 2017-09-07 2020-06-05 큐 바이오파마, 인크. 항원-제시 폴리펩티드 및 이의 사용 방법
MX2020006322A (es) * 2017-12-19 2020-09-18 Xencor Inc Proteinas de fusion il-2 fc modificadas.
US20210060169A1 (en) 2017-12-27 2021-03-04 Kyowa Kirin Co., Ltd. Il-2 variant
WO2019139896A1 (en) 2018-01-09 2019-07-18 Cue Biopharma, Inc. Multimeric t-cell modulatory polypeptides and methods of use thereof
EP3752178A1 (en) 2018-02-16 2020-12-23 Iltoo Pharma Use of interleukin 2 for treating sjögren's syndrome
WO2019173832A2 (en) 2018-03-09 2019-09-12 AskGene Pharma, Inc. Novel cytokine prodrugs
KR20200136453A (ko) 2018-03-28 2020-12-07 브리스톨-마이어스 스큅 컴퍼니 인터루킨-2/인터루킨-2 수용체 알파 융합 단백질 및 사용 방법
WO2020007937A1 (en) 2018-07-03 2020-01-09 Iltoo Pharma Use of interleukin-2 for treating systemic sclerosis
EP3836954A1 (en) 2018-08-13 2021-06-23 Iltoo Pharma Combination of interleukin-2 with an interleukin 1 inhibitor, conjugates and therapeutic uses thereof
US20220056094A1 (en) 2018-12-21 2022-02-24 Jiangsu Hengrui Medicine Co., Ltd. Human interleukin-2 variant or derivative thereof
MA54952A (fr) 2019-02-06 2022-05-11 Synthorx Inc Conjugués d'il-2 et méthodes d'utilisation de ceux-ci
WO2020168024A1 (en) 2019-02-15 2020-08-20 Integral Molecular, Inc. Antibodies comprising a common light chain and uses thereof
CR20210471A (es) 2019-02-15 2021-12-08 Integral Molecular Inc Anticuerpos claudina 6 y usos de los mismos
BR112021019178A2 (pt) 2019-03-29 2021-12-07 Centre Nat Rech Scient Variantes de interleucina-2 com atividade biológica modificada
CA3141626A1 (en) 2019-06-12 2020-12-17 AskGene Pharma, Inc. Novel il-15 prodrugs and methods of use thereof
JP2022544236A (ja) 2019-08-13 2022-10-17 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変異タンパク質
WO2021102063A1 (en) 2019-11-20 2021-05-27 Anwita Biosciences, Inc. Cytokine fusion proteins, and their pharmaceutical compositions and therapeutic applications
IL293628A (en) 2019-12-12 2022-08-01 Iltoo Pharma Interleukin 2 chimeric structures
JP2023507115A (ja) 2019-12-17 2023-02-21 アムジエン・インコーポレーテツド 治療における使用のためのデュアルインターロイキン－２／ｔｎｆ受容体アゴニスト
WO2021127495A1 (en) 2019-12-20 2021-06-24 Regeneron Pharmaceuticals, Inc. Novel il2 agonists and methods of use thereof
AU2021206449A1 (en) 2020-01-10 2022-07-21 Bright Peak Therapeutics Ag Modified IL-2 polypeptides and uses thereof
EP4090674A4 (en) 2020-01-14 2024-01-24 Synthekine Inc METHODS AND COMPOSITIONS OF BIASED IL2 MUTEINS
AR121891A1 (es) 2020-04-22 2022-07-20 Merck Sharp & Dohme CONJUGADOS DE INTERLEUCINA 2 HUMANA SESGADOS AL DÍMERO DEL RECEPTOR DE INTERLEUCINA 2 bgᶜ Y CONJUGADOS CON UN POLÍMERO HIDROSOLUBLE NO PEPTÍDICO
EP4143329A2 (en) 2020-04-28 2023-03-08 Anwita Biosciences, Inc. Interleukin-2 polypeptides and fusion proteins thereof, and their pharmaceutical compositions and therapeutic applications
EP4149534A2 (en) 2020-05-12 2023-03-22 Cue Biopharma, Inc. Multimeric t-cell modulatory polypeptides and methods of use thereof
MX2022014082A (es) 2020-06-03 2022-12-07 Ascendis Pharma Oncology Div A/S Secuencias de interleucina (il-2) y usos de las mismas.
EP4182335A2 (en) * 2020-07-14 2023-05-24 Pfizer Inc. Recombinant vaccinia virus
AU2021335032A1 (en) * 2020-08-28 2023-03-09 Ascendis Pharma Oncology Division A/S Glycosylated IL-2 proteins and uses thereof
IL302114A (en) 2020-10-29 2023-06-01 Bristol Myers Squibb Co Fusion proteins for the treatment of diseases
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
MX2023005458A (es) 2020-11-13 2023-05-23 Jiangsu Hengrui Pharmaceuticals Co Ltd Composicion farmaceutica que comprende una variante de la interleucina humana 2 o un derivado de la misma y uso de la misma.
EP4255466A1 (en) * 2020-12-04 2023-10-11 Visterra, Inc. Methods of using interleukin-2 agents
US20230183331A1 (en) * 2021-07-09 2023-06-15 Bright Peak Therapeutics Ag Modified tnf-alpha antibodies and uses thereof
US20230201364A1 (en) 2021-07-09 2023-06-29 Bright Peak Therapeutics Ag Antibody conjugates and manufacture thereof
EP4357357A1 (en) 2021-07-30 2024-04-24 Yunquan Biotechnology (Beijing) Co., Ltd. Human interleukin-2 variant and use thereof
CA3233644A1 (en) 2021-10-06 2023-04-13 David Klatzmann Interleukin 2 chimeric constructs with targeting specificy to inflamed tissues
WO2023133595A2 (en) 2022-01-10 2023-07-13 Sana Biotechnology, Inc. Methods of ex vivo dosing and administration of lipid particles or viral vectors and related systems and uses
WO2023193015A1 (en) 2022-04-01 2023-10-05 Sana Biotechnology, Inc. Cytokine receptor agonist and viral vector combination therapies
WO2024056154A1 (en) 2022-09-12 2024-03-21 INSERM (Institut National de la Santé et de la Recherche Médicale) Interleukin-2 for use in treating autism spectrum disorder

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 (en) 1986-09-01 1990-01-31 Takeda Chemical Industries, Ltd. Medicament for the treatment or improvement of rheumatoid arthritis or systemic lupus erythematosus
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 (en) 1991-03-27 1996-03-26 Tse-Wen Chang Methods and substances for recruiting therapeutic agents to solid tissues
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
ES2269366T3 (es) 2000-02-11 2007-04-01 Merck Patent Gmbh Mejoramiento de la vida media en circulacion de proteinas de fusion basadas en anticuerpos.
AU2002355955A1 (en) 2001-08-13 2003-03-03 University Of Southern California Interleukin-2 mutants with reduced toxicity
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
WO2005091956A2 (en) 2004-03-05 2005-10-06 Chiron Corporation In vitro test system for predicting patient tolerability of therapeutic agents
AU2006232374B2 (en) * 2005-04-01 2011-08-25 University Of Southern California Preventing rejection of transplanted tissue using regulatory T cells
JP2009527500A (ja) 2006-02-16 2009-07-30 ナセント・バイオロジックス・インコーポレイテッド 免疫機能を改善するための方法および哺乳動物対象における疾患の防止または処置のための方法
JP2009528359A (ja) 2006-02-28 2009-08-06 エラン ファーマシューティカルズ，インコーポレイテッド ナタリズマブを用いて炎症性疾患および自己免疫性疾患を治療する方法
US20090171562A1 (en) 2006-07-06 2009-07-02 Yasuyuki Shimada Navigation System
WO2008003473A2 (en) 2006-07-06 2008-01-10 Merck Patent Gmbh Compositions and methods for enhancing the efficacy of il-2 mediated immune responses
GB0623539D0 (en) 2006-11-24 2007-01-03 Avidex Ltd Polypeptides
JP2010518873A (ja) 2007-02-27 2010-06-03 ジェネンテック， インコーポレイテッド アンタゴニスト抗ｏｘ４０抗体および炎症性疾患および自己免疫性疾患の処置におけるその使用
CA2680792A1 (en) 2007-03-15 2008-09-18 Biogen Idec Ma Inc. Treatment of autoimmune disorders
US8906356B2 (en) 2007-11-05 2014-12-09 Massachusetts Institute Of Technology Mutant interleukin-2 (IL-2) polypeptides
EP2235064B1 (en) 2008-01-07 2015-11-25 Amgen Inc. Method for making antibody fc-heterodimeric molecules using electrostatic steering effects
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 (en) 2008-08-04 2010-02-11 The Trustees Of The University Of Pennsylvania Methods for expanding regulatory t-cells
WO2010021519A2 (en) 2008-08-21 2010-02-25 Industry-Academic Cooperation Foundation, Yonsei University T1-t2 dual modal mri contrast agents
JP5766124B2 (ja) 2009-01-21 2015-08-19 アムジェン インコーポレイテッド 炎症性疾患および自己免疫疾患の処置の組成物および方法
EP2683395B1 (en) 2011-03-11 2018-08-01 Assistance Publique - Hôpitaux de Paris Use of low dose il-2 for treating type 1 diabetes
EP2686345B1 (en) 2011-03-16 2018-04-25 Amgen Inc. Fc variants

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 (en) 2013-03-14 2014-09-25 Amgen Inc. Interleukin-2 muteins for the expansion of t-regulatory cells
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 (en) 2013-03-14 2014-09-25 Amgen Inc. AGLYCOSYLATED Fc-CONTAINING POLYPEPTIDES
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 (en) * 2014-04-24 2015-10-29 The Board Of Trustees Of The Leland Stanford Junior University Superagonists, partial agonists and antagonists of interleukin-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 (en) 2015-04-10 2016-10-13 Amgen Inc. Interleukin-2 muteins for the expansion of t-regulatory cells
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 (en) 2016-05-04 2021-04-21 Amgen Inc. Interleukin-2 muteins for the expansion of t-regulatory cells
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
US10174092B1 (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
US11091527B2 (en) 2017-12-06 2021-08-17 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
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
US10174091B1 (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) 2020-02-21 2024-05-14 Pandion Operations, Inc. Tissue targeted immunotolerance with a CD39 effector

Also Published As

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

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