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NZ763982B2 - Compositions and methods for modulating complement factor b expression - Google Patents
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NZ763982B2 - Compositions and methods for modulating complement factor b expression - Google Patents

Compositions and methods for modulating complement factor b expression Download PDF

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Publication number
NZ763982B2
NZ763982B2 NZ763982A NZ76398215A NZ763982B2 NZ 763982 B2 NZ763982 B2 NZ 763982B2 NZ 763982 A NZ763982 A NZ 763982A NZ 76398215 A NZ76398215 A NZ 76398215A NZ 763982 B2 NZ763982 B2 NZ 763982B2
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New Zealand
Prior art keywords
wing segment
compound
sugar
linked nucleosides
modified oligonucleotide
Prior art date
Application number
NZ763982A
Other versions
NZ763982A (en
Inventor
Susan M Freier
Tamar R Grossman
Michael L Mccaleb
Thazha P Prakash
Punit P Seth
Eric E Swayze
Andrew T Watt
Original Assignee
Ionis Pharmaceuticals Inc
Filing date
Publication date
Application filed by Ionis Pharmaceuticals Inc filed Critical Ionis Pharmaceuticals Inc
Publication of NZ763982A publication Critical patent/NZ763982A/en
Publication of NZ763982B2 publication Critical patent/NZ763982B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—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
    • 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
    • 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
    • A61K47/54—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 organic compound
    • A61K47/555—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 organic compound pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells
    • A—HUMAN NECESSITIES
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    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
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    • 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
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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1137—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against enzymes
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/11—Antisense
    • C—CHEMISTRY; METALLURGY
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/315—Phosphorothioates
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/321—2'-O-R Modification
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/33—Chemical structure of the base
    • C12N2310/334—Modified C
    • C12N2310/3341—5-Methylcytosine
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/34—Spatial arrangement of the modifications
    • C12N2310/341—Gapmers, i.e. of the type ===---===
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/34—Spatial arrangement of the modifications
    • C12N2310/346—Spatial arrangement of the modifications having a combination of backbone and sugar modifications
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/35—Nature of the modification
    • C12N2310/351—Conjugate
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/35—Nature of the modification
    • C12N2310/352—Nature of the modification linked to the nucleic acid via a carbon atom
    • C12N2310/3525—MOE, methoxyethoxy
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    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
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    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
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    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/21—Serine endopeptidases (3.4.21)
    • C12Y304/21047—Alternative-complement-pathway C3/C5 convertase (3.4.21.47), i.e. properdin factor B

Abstract

The present embodiments provide methods, compounds, and compositions for treating, preventing, or ameliorating a disease associated with dysregulation of the complement alternative pathway by administering a Complement Factor B (CFB) specific inhibitor to a subject.

Claims (17)

WHAT IS CLAIMED IS:
1. A compound comprising a single stranded modified oligonucleotide and a conjugate group, wherein the modified ucleotide consists of 15 to 30 linked nucleosides having a nucleobase sequence comprising any of the nucleobase sequences of SEQ ID NOs: 440, 198, 228, 237, 444, 448, 450, 453, 455, 549, 598, and wherein the conjugate group comprises: wherein the modified ucleotide has: a gap segment consisting of linked deoxynucleosides; a 5’ wing segment consisting of linked nucleosides; and a 3’ wing segment consisting of linked nucleosides; n the gap segment is positioned between the 5’ wing segment and the 3’ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar and wherein the compound is capable of inhibiting Complement Factor B (CFB) expression.
2. The compound of claim 1, n the single stranded modified oligonucleotide consists of 20 linked nucleosides and has a nucleobase sequence consisting of the sequence recited in SEQ ID NOs: 198, 228, 237, 440, 444, 448, 450, 453, or 455, n the modified oligonucleotide has: a gap segment consisting of ten linked deoxynucleosides; a 5’ wing segment consisting of five linked nucleosides; and a 3’ wing segment consisting of five linked nucleosides; wherein the gap segment is positioned between the 5’ wing segment and the 3’ wing segment, wherein each nucleoside of each wing segment comprises a ethoxyethyl sugar; wherein each ucleoside linkage of the modified ucleotide is a phosphorothioate linkage and wherein each cytosine is a 5-methylcytosine.
3. The compound of claim 1, wherein the single stranded modified oligonucleotide consists of 16 linked nucleosides and has a base ce consisting of the ce recited in SEQ ID NO: 598, wherein the modified oligonucleotide has: a gap t consisting of ten linked deoxynucleosides; a 5’ wing segment consisting of three linked sides; and a 3’ wing segment consisting of three linked nucleosides; wherein the gap segment is positioned between the 5’ wing segment and the 3’ wing t; wherein the 5’ wing segment comprises a 2’-O-methoxyethyl sugar, 2’-O-methoxyethyl sugar, and cEt sugar in the 5’ to 3’ direction; wherein the 3’ wing segment comprises a cEt sugar, cEt sugar, and 2’-O- methoxyethyl sugar in the 5’ to 3’ direction; wherein each internucleoside e of the modified oligonucleotide is a phosphorothioate linkage; and wherein each cytosine is a 5-methylcytosine.
4. The compound of claim 1, wherein the single stranded modified oligonucleotide consists of 16 linked nucleosides and has a nucleobase sequence ting of the sequence recited in SEQ ID NO: 549, wherein the modified oligonucleotide has: a gap segment consisting of ten linked deoxynucleosides; a 5’ wing segment consisting of three linked nucleosides; and a 3’ wing t consisting of three linked nucleosides; wherein the gap segment is positioned between the 5’ wing segment and the 3’ wing segment; wherein each nucleoside of each wing segment comprises a cEt sugar; wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage; and wherein each cytosine is a 5- methylcytosine.
5. The compound of any one of claims 1 - 4, wherein the single stranded modified oligonucleotide is at least 80%, at least 85%, at least 90%, at least 95% or 100% complementary to SEQ ID NO: 1 or 2.
6. The compound of any one of claims 1 - 5, wherein the single stranded modified oligonucleotide comprises at least one modified internucleoside linkage, at least one modified sugar, or at least one ed nucleobase.
7. The compound of claim 6, wherein the internucleoside linkage is a phosphorothioate internucleoside linkage.
8. The nd of any one of claims 1 - 7, wherein the modified sugar is: a) a bicyclic sugar, optionally wherein the bicyclic sugar is selected from the group consisting of: 2)-O-2' (LNA); 2)2-O-2' (ENA); and 4'-CH(CH3)-O-2' (cEt); or b) the modified sugar is 2’-O-methoxyethyl.
9. A pharmaceutical composition comprising the compound of any one of claims 1-8 or a salt thereof and at least one of a pharmaceutically acceptable carrier or diluent.
10. The compound of any one of claims 1 - 8 or the pharmaceutical composition of claim 9 for use in a method of treating a disease associated with dysregulation of the complement alternative pathway.
11. The compound or pharmaceutical composition for use of claim 10, wherein the disease is macular degeneration, age d macular degeneration (AMD), wet AMD, dry AMD or phic Atrophy.
12. The compound or pharmaceutical composition for use of claim 10, wherein the disease is a kidney disease.
13. The compound or pharmaceutical composition for use of claim 12, wherein the kidney e is lupus nephritis, dense deposit disease (DDD), C3 glomerulonephritis , CFHR5 nephropathy, or atypical hemolytic uremic syndrome (aHUS).
14. Use of the compound of any one of claims 1 - 8 or the pharmaceutical composition of claim 7 in the manufacture of a medicament for treating a disease associated with dysregulation of the complement alternative pathway.
15. The use of claim 14, wherein the disease is macular degeneration, age related macular ration (AMD), wet AMD, dry AMD or Geographic Atrophy.
16. The use of claim 14, wherein the disease is a kidney disease.
17. The use of claim 16, n the kidney disease is lupus nephritis, dense deposit disease (DDD), C3 glomerulonephritis (C3GN), CFHR5 nephropathy, or atypical hemolytic uremic syndrome (aHUS).
NZ763982A 2015-05-01 Compositions and methods for modulating complement factor b expression NZ763982B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201461987471P 2014-05-01 2014-05-01
US201462076273P 2014-11-06 2014-11-06
NZ724366A NZ724366B2 (en) 2015-05-01 Compositions and methods for modulating complement factor b expression

Publications (2)

Publication Number Publication Date
NZ763982A NZ763982A (en) 2023-11-24
NZ763982B2 true NZ763982B2 (en) 2024-02-27

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