NZ761434B2 - Cytokine conjugates for the treatment of autoimmune diseases - Google Patents

Cytokine conjugates for the treatment of autoimmune diseases Download PDF

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Publication number
NZ761434B2
NZ761434B2 NZ761434A NZ76143418A NZ761434B2 NZ 761434 B2 NZ761434 B2 NZ 761434B2 NZ 761434 A NZ761434 A NZ 761434A NZ 76143418 A NZ76143418 A NZ 76143418A NZ 761434 B2 NZ761434 B2 NZ 761434B2
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New Zealand
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polypeptide
modified
fold
seq
amino acid
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NZ761434A
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NZ761434A (en
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Carolina E Caffaro
Marcos Milla
Jerod Ptacin
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Synthorx Inc
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Priority claimed from PCT/US2018/045265 external-priority patent/WO2019028425A1/en
Publication of NZ761434A publication Critical patent/NZ761434A/en
Publication of NZ761434B2 publication Critical patent/NZ761434B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
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    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2013—IL-2
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    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
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    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/643—Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/644—Transferrin, e.g. a lactoferrin or ovotransferrin
    • A—HUMAN NECESSITIES
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    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
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    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • A61K47/6813—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin the drug being a peptidic cytokine, e.g. an interleukin or interferon
    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
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    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • C07K14/7155—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for interleukins [IL]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Disclosed herein are interleukin (IL) conjugates (e.g., IL-2 conjugates) comprising one or more unnatural amino acids for use in the treatment of one or more indications, such as autoimmune disorders. Also described herein are pharmaceutical compositions and kits comprising one or more of the interleukin conjugates (e.g., IL-2 conjugates).

Claims (42)

1. A modified interleukin 2 (IL-2) polypeptide comprising at least one unnatural amino acid covalently attached to a conjugating moiety, wherein the position of the at least one unnatural amino acid is selected from K9, H16, L19, D20, N26, N88, E100, and N119, wherein the residue positions correspond to positions 9, 16, 19, 20, 26, 88, 100, and 119 as set forth in SEQ ID NO: 1; wherein the conjugating moiety is a water-soluble polymer; and wherein the modified IL-2 polypeptide comprises at least 80% sequence identity to SEQ ID NO: 1.
2. The modified IL-2 polypeptide of claim 1, wherein the position of the at least one unnatural amino acid is selected from K9 and H16, wherein the residue positions correspond to positions 9 and 16 as set forth in SEQ ID NO: 1.
3. The modified IL-2 polypeptide of claim 1, wherein the position of the at least one unnatural amino acid is K9, wherein the residue position corresponds to position 9 as set forth in SEQ ID NO: 1.
4. The modified IL-2 polypeptide of claim 1, wherein the position of the at least one unnatural amino acid is H16, wherein the residue position corresponds to position 16 as set forth in SEQ ID NO: 1.
5. The modified IL-2 polypeptide of any one of claims 1-4, wherein the at least one unnatural amino acid: • is a lysine analogue; or • comprises an aromatic side chain.
6. The modified IL-2 polypeptide of any one of claims 1-5, wherein the at least one unnatural amino acid comprises N6-azidoethoxy-L-lysine (AzK), N6-propargylethoxy-L- lysine (PraK), BCN-L-lysine, norbornene lysine, TCO-lysine, methyltetrazine lysine, allyloxycarbonyllysine, p-acetyl-L-phenylalanine, p-azidomethyl-L-phenylalanine (pAMF), p-iodo-L-phenylalanine, m-acetylphenylalanine, p-propargyloxyphenylalanine, p-propargyl-phenylalanine, 3-methyl-phenylalanine, fluorinated phenylalanine, isopropyl-L-phenylalanine, p-azido-L-phenylalanine, p-acyl-L-phenylalanine, p-benzoyl- L-phenylalanine, p-bromophenylalanine, p-amino-L- phenylalanine, O-allyltyrosine, O- methyl-L-tyrosine, Oallyl-L-tyrosine, 4-propyl-L-tyrosine, phosphonotyrosine, L 20643459_1 (GHMatters) P114365.NZ (2-naphthyl)alanine, 2-amino((2-((3-(benzyloxy) oxopropyl)amino)ethyl)selanyl)propanoic acid, or 2-amino(phenylselanyl)propanoic acid.
7. The modified IL-2 polypeptide of any one of claims 1-6 , wherein the water-soluble polymer comprises polyethylene glycol (PEG), poly(propylene glycol) (PPG), copolymers of ethylene glycol and propylene glycol, poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharides), poly(a-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazolines (POZ), poly(N-acryloylmorpholine), or a combination thereof.
8. The modified IL-2 polypeptide of claim 7, wherein the water-soluble polymer comprises
9. The modified IL-2 polypeptide of claims 7 or 8, wherein the PEG has a weight-average molecular weight of from about 5 kDa to about 100 kDa.
10. The modified IL-2 polypeptide of any one of claims 7-9, wherein the PEG has a weight- average molecular weight of about 30 kDa, about 35 kDa, about 40 kDa, about 45 kDa, about 50 kDa, about 55 kDa, about 60 kDa, about 65 kDa, about 70 kDa, or about 75
11. The modified IL-2 polypeptide of any one of claims 7-10, wherein the PEG has a weight- average molecular weight of about 50 kDa.
12. The modified IL-2 polypeptide of any one of claims 1-11, wherein the conjugating moiety is covalently attached to the at least one unnatural amino acid of the modified IL- 2 polypeptide through a linker.
13. The modified IL-2 polypeptide of claim 12, wherein the linker comprises a homobifunctional linker, a heterobifunctional linker, a cleavable or a non-cleavable dipeptide linker, a spacer, or a combination thereof.
14. The modified IL-2 polypeptide of any one of claims 1-13, wherein the modified IL-2 polypeptide comprises an N-terminal deletion.
15. The modified IL-2 polypeptide of any one of claims 1-13, wherein the modified IL-2 polypeptide comprises (i) the sequence of SEQ ID NO: 1 in which the position of the at 20643459_1 (GHMatters) P114365.NZ least one unnatural amino acid is selected from K9, H16, L19, D20, N26, N88, E100, and N119, wherein the residue positions correspond to positions 9, 16, 19, 20, 26, 88, 100, and 119 as set forth in SEQ ID NO: 1, or (ii) the sequence of SEQ ID NO: 1 in which the position of the at least one unnatural amino acid is selected from K9, H16, L19, D20, N26, N88, E100, and N119, wherein the residue positions correspond to positions 9, 16, 19, 20, 26, 88, 100, and 119 as set forth in SEQ ID NO: 1 and having an N-terminal deletion, and wherein the modified IL-2 polypeptide optionally further comprises an additional mutation.
16. The modified IL-2 polypeptide of claim 14 or 15, wherein the N-terminal deletion comprises a deletion of the first 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, or 25 residues from the N-terminus, wherein the residue positions correspond to the positions as set forth in SEQ ID NO: 1.
17. The modified IL-2 polypeptide of any one of claims 1-14 and 16, wherein the modified IL-2 polypeptide comprises about 80%, 85%, or 90%sequence identity to SEQ ID NO: 1.
18. The modified IL-2 polypeptide of any one of claims 1-14 and 16, wherein the modified IL-2 polypeptide comprises about 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 1.
19. The modified IL-2 polypeptide of claim 1, wherein the conjugating moiety comprises PEG, wherein the position of the at least one unnatural amino acid is H16 corresponding to the amino acid position as set forth in SEQ ID NO: 1, and wherein the at least one unnatural amino acid is a lysine analogue.
20. The modified IL-2 polypeptide of any one of claims 1-19, wherein the modified IL-2 polypeptide is capable of expanding CD4+ T regulatory (Treg) cells.
21. The modified IL-2 polypeptide of any one of claims 1-19, wherein the conjugating moiety impairs or blocks the receptor signaling potency of IL-2 with IL-2Rß?, or reduces recruitment of the IL-2R ? subunit to the IL-2/IL-2R ? complex.
22. The modified IL-2 polypeptide of any one of claims 1-19, wherein CD4+ Treg cell proliferation induced by the modified IL-2 polypeptide is equivalent to or greater than that of a wild-type IL-2 polypeptide. 20643459_1 (GHMatters) P114365.NZ
23. The modified IL-2 polypeptide of any one of claims 1-19, wherein the modified IL-2 polypeptide induces proliferation of the CD4+ Treg cells to a population that is sufficient to modulate a disease course in an animal model.
24. The modified IL-2 polypeptide of any one of claims 1-19, wherein the modified IL-2 polypeptide exhibits a first receptor signaling potency to IL-2Rß? and a second receptor signaling potency to IL-2Raß?, wherein the first receptor signaling potency is at least 2- fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 50- fold, 100-fold, 500-fold, or 1000-fold lower than the second receptor signaling potency.
25. The modified IL-2 polypeptide of claim 24, wherein the first receptor signaling potency of the modified IL-2 polypeptide is lower than a receptor signaling potency of a wild- type IL-2 polypeptide to IL-2Rß?.
26. The modified IL-2 polypeptide of claim 24, wherein the second receptor signaling potency of the modified IL-2 polypeptide is lower than a receptor signaling potency of a wild-type IL-2 polypeptide to IL-2Raß?.
27. The modified IL-2 polypeptide of any one of claims 1-19, wherein the modified IL-2 polypeptide provides an increase in a recruitment of an IL-2Ra subunit to the IL-2 polypeptide leading to activation of interleukin 2 aß? receptor (IL-2Raß?), wherein the increase in recruitment is compared to a recruitment of an IL-2Ra subunit by a wild-type IL-2 polypeptide.
28. The modified IL-2 polypeptide of any one of claims 1-19, wherein the modified IL-2 polypeptide provides a decrease in a recruitment of an IL-2R ? subunit to the IL-2/IL-2R ? complex, wherein the reduced recruitment is compared to a recruitment of an IL-2Rß subunit and/or IL-2R ? subunit by a wild-type IL-2 polypeptide.
29. A pharmaceutical composition comprising the modified IL-2 polypeptide of any one of claims 1-28, and a pharmaceutically acceptable excipient.
30. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition is formulated for systemic delivery.
31. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition is formulated for parenteral administration. 20643459_1 (GHMatters) P114365.NZ
32. Use of the modified IL-2 polypeptide of any one of claims 1-28 or the pharmaceutical composition of any one of claims 29-31 in the manufacture of a medicament for treating an autoimmune disease or disorder in a subject in need thereof.
33. The use of claim 32, wherein the autoimmune disease or disorder comprises alopecia areata, autoimmune hemolytic anemia, autoimmune hepatitis, dermatomyositis, type 1 diabetes, juvenile idiopathic arthritis, glomerulonephritis, Graves’ disease, Guillain-Barré syndrome, idiopathic thrombocytopenic purpura, myasthenia gravis, multiple sclerosis, pemphigus/pemphigoid, pernicious anemia, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma, Sjögren’s syndrome, systemic lupus erythematosus, thyroiditis, uveitis, vitiligo, or Wegener’s granulomatosis.
34. The use of claims 32 or 33, wherein an additional therapeutic agent is to be administered.
35. The use of claim 34, wherein the medicament and the additional therapeutic agent are to be administered simultaneously.
36. The use of claim 33, wherein the medicament and the additional therapeutic agent are to be administered sequentially.
37. The use of claim 36, wherein the medicament is to be administered prior to the additional therapeutic agent.
38. The use of claim 36, wherein the medicament is to be administered after the additional therapeutic agent.
39. An in vitro or ex vivo method of expanding a CD4+ regulatory T (Treg) cell population, comprising: contacting a cell population comprising Treg cells with the modified IL-2 polypeptide of any one of claims 1-28 or the pharmaceutical composition of any one of claims 29-31 for a time sufficient to induce formation of a complex with an IL-2Raß?, thereby stimulating the expansion of the Treg cells of the population.
40. The method of claim 39, wherein the method is an in vitro method.
41. The method of claim 39, wherein the method is an ex vivo method.
42. The method of any one of claims 39-41, wherein the cell population is from a human subject. 20643459_1 (GHMatters) P114365.NZ
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