NZ753689A - Therapeutic nuclease compositions and methods - Google Patents
Therapeutic nuclease compositions and methodsInfo
- Publication number
- NZ753689A NZ753689A NZ753689A NZ75368910A NZ753689A NZ 753689 A NZ753689 A NZ 753689A NZ 753689 A NZ753689 A NZ 753689A NZ 75368910 A NZ75368910 A NZ 75368910A NZ 753689 A NZ753689 A NZ 753689A
- Authority
- NZ
- New Zealand
- Prior art keywords
- domain
- optionally
- polypeptide
- dnase
- linker
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims 5
- 101710163270 Nuclease Proteins 0.000 title abstract 3
- 230000001225 therapeutic effect Effects 0.000 title 1
- 108010053770 Deoxyribonucleases Proteins 0.000 claims abstract 14
- 102000016911 Deoxyribonucleases Human genes 0.000 claims abstract 14
- 102000006382 Ribonucleases Human genes 0.000 claims abstract 12
- 108010083644 Ribonucleases Proteins 0.000 claims abstract 12
- 230000002159 abnormal effect Effects 0.000 claims abstract 2
- 230000028993 immune response Effects 0.000 claims abstract 2
- 108090000765 processed proteins & peptides Proteins 0.000 claims 23
- 229920001184 polypeptide Polymers 0.000 claims 21
- 102000004196 processed proteins & peptides Human genes 0.000 claims 21
- 125000003275 alpha amino acid group Chemical group 0.000 claims 10
- 238000006467 substitution reaction Methods 0.000 claims 7
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims 5
- 230000035772 mutation Effects 0.000 claims 3
- 102000039446 nucleic acids Human genes 0.000 claims 3
- 108020004707 nucleic acids Proteins 0.000 claims 3
- 150000007523 nucleic acids Chemical class 0.000 claims 3
- 108010076504 Protein Sorting Signals Proteins 0.000 claims 2
- 208000021386 Sjogren Syndrome Diseases 0.000 claims 2
- 235000001014 amino acid Nutrition 0.000 claims 2
- 230000001363 autoimmune Effects 0.000 claims 2
- 235000018417 cysteine Nutrition 0.000 claims 2
- 150000001945 cysteines Chemical class 0.000 claims 2
- 239000013604 expression vector Substances 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 238000003259 recombinant expression Methods 0.000 claims 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims 2
- 208000026872 Addison Disease Diseases 0.000 claims 1
- 208000004300 Atrophic Gastritis Diseases 0.000 claims 1
- 206010071155 Autoimmune arthritis Diseases 0.000 claims 1
- 208000023275 Autoimmune disease Diseases 0.000 claims 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 claims 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 claims 1
- 206010008909 Chronic Hepatitis Diseases 0.000 claims 1
- 206010009900 Colitis ulcerative Diseases 0.000 claims 1
- 102000000989 Complement System Proteins Human genes 0.000 claims 1
- 108010069112 Complement System Proteins Proteins 0.000 claims 1
- 206010063075 Cryptogenic cirrhosis Diseases 0.000 claims 1
- 208000036495 Gastritis atrophic Diseases 0.000 claims 1
- 208000024869 Goodpasture syndrome Diseases 0.000 claims 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 claims 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 claims 1
- 101000845618 Homo sapiens Deoxyribonuclease gamma Proteins 0.000 claims 1
- 206010020850 Hyperthyroidism Diseases 0.000 claims 1
- 208000005777 Lupus Nephritis Diseases 0.000 claims 1
- 208000007466 Male Infertility Diseases 0.000 claims 1
- 206010028665 Myxoedema Diseases 0.000 claims 1
- 108020002230 Pancreatic Ribonuclease Proteins 0.000 claims 1
- 102000005891 Pancreatic ribonuclease Human genes 0.000 claims 1
- 206010034277 Pemphigoid Diseases 0.000 claims 1
- 201000011152 Pemphigus Diseases 0.000 claims 1
- 208000031845 Pernicious anaemia Diseases 0.000 claims 1
- 206010057249 Phagocytosis Diseases 0.000 claims 1
- 208000002500 Primary Ovarian Insufficiency Diseases 0.000 claims 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 claims 1
- 206010039710 Scleroderma Diseases 0.000 claims 1
- 206010042742 Sympathetic ophthalmia Diseases 0.000 claims 1
- 201000006704 Ulcerative Colitis Diseases 0.000 claims 1
- 206010046851 Uveitis Diseases 0.000 claims 1
- 150000001413 amino acids Chemical class 0.000 claims 1
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 claims 1
- 208000016644 chronic atrophic gastritis Diseases 0.000 claims 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 claims 1
- 230000004540 complement-dependent cytotoxicity Effects 0.000 claims 1
- 208000018631 connective tissue disease Diseases 0.000 claims 1
- 230000007423 decrease Effects 0.000 claims 1
- 201000001981 dermatomyositis Diseases 0.000 claims 1
- 206010012601 diabetes mellitus Diseases 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000012636 effector Substances 0.000 claims 1
- 201000002491 encephalomyelitis Diseases 0.000 claims 1
- 208000003816 familial cirrhosis Diseases 0.000 claims 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 claims 1
- 230000002949 hemolytic effect Effects 0.000 claims 1
- 208000006454 hepatitis Diseases 0.000 claims 1
- 239000000710 homodimer Substances 0.000 claims 1
- 102000054371 human DNASE1L3 Human genes 0.000 claims 1
- 230000000366 juvenile effect Effects 0.000 claims 1
- 201000002364 leukopenia Diseases 0.000 claims 1
- 206010025135 lupus erythematosus Diseases 0.000 claims 1
- 201000006417 multiple sclerosis Diseases 0.000 claims 1
- 206010028417 myasthenia gravis Diseases 0.000 claims 1
- 239000002773 nucleotide Substances 0.000 claims 1
- 125000003729 nucleotide group Chemical group 0.000 claims 1
- 230000014207 opsonization Effects 0.000 claims 1
- 201000001976 pemphigus vulgaris Diseases 0.000 claims 1
- 230000008782 phagocytosis Effects 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 208000005987 polymyositis Diseases 0.000 claims 1
- 206010036601 premature menopause Diseases 0.000 claims 1
- 230000009885 systemic effect Effects 0.000 claims 1
- 108010036169 three prime repair exonuclease 1 Proteins 0.000 claims 1
- 206010043778 thyroiditis Diseases 0.000 claims 1
- 208000005057 thyrotoxicosis Diseases 0.000 claims 1
- 230000002265 prevention Effects 0.000 abstract 1
Abstract
Disclosed is a hybrid nuclease molecule comprising an RNase domain, a DNase domain, and a variant Fc domain, wherein both the RNase domain and the DNase domain are operatively coupled to the Fc domain. The hybrid nuclease molecule is useful in the treatment or prevention of a condition associated with an abnormal immune response.
Claims (18)
1. A polypeptide sing an RNase, a DNase, and a variant Fc , wherein the RNase is ively coupled, optionally with a linker, to the variant Fc domain, and n the DNase is operatively coupled, optionally with a linker, to the variant Fc domain, wherein the variant Fc domain is a variant human IgG1 Fc domain comprising an amino acid substitution which decreases binding, compared to wild-type, to an Fc? receptor or a complement protein or both, wherein the polypeptide has a reduced effector function optionally selected from the group consisting of opsonization, phagocytosis, complement dependent cytotoxicity, and antibody-dependent cellular cytotoxicity.
2. The polypeptide of claim 1 wherein: (a) the RNase is a human RNase, such as a human pancreatic RNase 1; and/or (b) the DNase is selected from the group consisting of a Type 1 human DNase, a human DNase 1L3, or human TREX1; and/or (c) the Fc domain comprises a hinge domain, a CH2 domain and a CH3 domain; and/or (d) a leader sequence, such as the human VK3LP peptide, is coupled to the N-terminus of the RNase or the N-terminus of the DNase.
3. The polypeptide of claim 1 or claim 2, wherein: (a) the Fc domain comprises a modified hinge domain sing at least one substitution, ally wherein the modified hinge domain comprises a mutation in one or more of the three hinge nes, such as SCC or SSS; and/or (b) wherein the Fc domain comprises a modified CH2 domain comprising at least one substitution, optionally wherein the substitution is selected from the group consisting S, P331S, N297S or a ation thereof.
4. The polypeptide of claim 1 or claim 2, wherein (a) the RNase comprises an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO:149 optionally without its leader sequence, or ses 100 or more contiguous amino acids from SEQ ID NO: 149; and/or (b) wherein the DNase comprises a human DNase, optionally DNase 1, optionally comprising an amino acid sequence set forth in SEQ ID NO: 139, SEQ ID (27134561_1):AXG NO:143, or SEQ ID NO:142 or comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 139, SEQ ID NO:143, or SEQ ID NO:142; and/or (c) the Fc domain comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, or 98% identical to the amino acid sequence set forth in SEQ ID NO:145, optionally sing a modified hinge domain comprising at least one substitution, optionally wherein the ed hinge domain comprises a on in one or more of the three cysteines, such as SCC or SSS; and/or optionally comprising one or more Fc mutations selected from P238S, P331S, K322S, and N297S.
5. The polypeptide of claim 1, wherein; the ptide comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, or 98% identical to the amino acid sequence set forth in SEQ ID NO:153, optionally without its leader ce; ally wherein the Fc domain comprises a modified hinge domain comprising at least one substitution, optionally wherein the modified hinge domain comprises a mutation in one or more of the three hinge cysteines, such as SCC or SSS; and/or a modified CH2 domain comprising at least one substitution selected from the group consisting of P238S, P331S, N297S or combination thereof.
6. The polypeptide of any preceding claim, wherein: the RNase is operatively coupled to the Fc domain via a linker , optionally wherein the linker domain is a polypeptide linker, such as a gly-ser linker; and/or wherein the RNase is operatively d to the N-terminus of the Fc domain, optionally with a linker; and/or n the RNase is operatively coupled to the inus of the Fc domain, optionally with a linker; and/or wherein the polypeptide comprises a human VK3LP peptide leader sequence coupled to the N-terminus of the RNase.
7. The polypeptide of any preceding claim, wherein: the DNase is operatively coupled to the Fc domain via a second linker domain, optionally wherein the second linker domain is a polypeptide linker, such as an NLG peptide; and/or (27134561_1):AXG wherein the DNase is ively coupled to the N-terminus of the Fc domain, optionally with a linker; and/or wherein the DNase is operatively coupled to the C-terminus of the Fc domain, optionally with a linker; and/or wherein the polypeptide comprises a human VK3LP peptide leader sequence coupled to the N-terminus of the DNase.
8. A composition comprising the polypeptide of any of the preceding claims and a pharmaceutically acceptable carrier.
9. A nucleic acid molecule comprising a nucleotide ce encoding the polypeptide according to any of claims 1 to 7.
10. A recombinant expression vector comprising a nucleic acid molecule ing to claim 9.
11. A host cell transformed with the recombinant expression vector according to claim 10, wherein the host cell is not within a human.
12. A method of making the polypeptide of any of claims 1 to 7, comprising: providing a host cell comprising a nucleic acid ce that encodes the polypeptide; and ining the host cell under conditions in which the polypeptide is expressed, and wherein the host cell is not within a human.
13. A dimeric ptide comprising a polypeptide of any of claims 1-7, optionally a homodimer.
14. A composition sing the dimeric polypeptide of claim 13 and a pharmaceutically acceptable excipient.
15. Use of the polypeptide of any of claims 1 to 7, the composition of claim 8, the dimeric polypeptide of claim 13, or the composition of claim 14, in the manufacture of a medicament for treating or preventing a condition ated with an abnormal immune response; optionally wherein the condition is an autoimmune disease, optionally systemic lupus erythematosus (SLE), or optionally selected from the group consisting of ndependent diabetes mellitus, multiple sclerosis, experimental autoimmune (27134561_1):AXG encephalomyelitis, rheumatoid arthritis, experimental autoimmune arthritis, myasthenia gravis, thy- roiditis, an experimental form of uveoretinitis, Hashimoto’s thyroiditis, y myxoedema, thyrotoxicosis, pernicious anaemia, mune atrophic gastritis, Addison’s disease, premature menopause, male infertility, juvenile es, Good pasture’s syndrome, pemphigus vulgaris, pemphigoid, sympathetic ophthalmia, phacogenic uveitis, autoimmune haemolytic anameia, idiopathic leucopenia, primary biliary cirrhosis, active chronic hepatitis Hbs-ve, cryptogenic cirrhosis, ulcerative colitis, Sjogren’s syndrome, scleroderma, Wegener’s granulomatosis, polymyositis, dermatomyositis, discoid LE, systemic lupus matosus (SLE), and connective tissue disease.
16. The use of claim 15 for treating or ting systemic lupus erythematosus (SLE).
17. The use of claim 15 for treating or preventing lupus nephritis.
18. The use of claim 15 for ng or preventing Sjogren’s syndrome. (27134561_1):AXG
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US25745809P | 2009-11-02 | 2009-11-02 | |
| US37075210P | 2010-08-04 | 2010-08-04 | |
| NZ73537910 | 2010-11-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ753689A true NZ753689A (en) | 2022-10-28 |
Family
ID=84527709
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ753689A NZ753689A (en) | 2009-11-02 | 2010-11-02 | Therapeutic nuclease compositions and methods |
Country Status (1)
| Country | Link |
|---|---|
| NZ (1) | NZ753689A (en) |
-
2010
- 2010-11-02 NZ NZ753689A patent/NZ753689A/en unknown
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| PSEA | Patent sealed | ||
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Free format text: PATENT RENEWED FOR 9 YEARS UNTIL 02 NOV 2023 BY SPRUSON + FERGUSON PTY LTD Effective date: 20230228 |
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| RENW | Renewal (renewal fees accepted) |
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