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EP-4735600-A1 - COMPOSITIONS AND METHODS FOR INHIBITING EXPRESSION OF COMPLEMENT FACTOR B (CFB)

EP4735600A1EP 4735600 A1EP4735600 A1EP 4735600A1EP-4735600-A1

Abstract

Compositions and methods useful to reduce expression of CFB gene and for treatment of CFB-associated diseases and conditions are provided. Provided are CFB dsRNA agents, CFB antisense polynucleotide agents, compositions comprising CFB dsRNA agents, and compositions comprising CFB antisense polynucleotide agents that can be used to reduce CFB expression in cells and subjects.

Inventors

  • SHU, DONGXU
  • SHAO, PENGCHENG PATRICK
  • XIA, SHIWEI

Assignees

  • Shanghai Argo Biopharmaceutical Co., Ltd.

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. A double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of CFB, wherein the dsRNA agent including a sense strand and an antisense strand, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO: l and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO: 2, wherein the sense strand and the antisense strand can be partially, substantially, or fully complementary to each other.
  2. The dsRNA agent of claim 1, wherein the dsRNA agent includes a sense strand and an antisense strand, wherein the sense strand comprises at least 15, 16, 17, 18, 19, 20 or 21 contiguous nucleotides that differ by 0, 1, 2, or 3 nucleotides from any one of the nucleotide sequences of nucleotides 483-513, 486-516, 491-521, 483-521, 513-543, 987-1017, 989-1019, 1317-1347, 2237-2267, 2439-2469 of SEQ ID NO: 1, and the antisense strand comprises at least 15, 16, 17, 18, 19, 20 or 21 contiguous nucleotides differing by 0, 1, 2, or 3 nucleotides from the corresponding nucleotide sequence of SEQ ID NO: 2, wherein the sense strand and the antisense strand can be partially, substantially, or fully complementary to each other.
  3. The dsRNA agent of claim 1-2, wherein the sense strand comprises at least 15, 16, 17, 18, 19, 20 or 21 contiguous nucleotides that differ by 0, 1, 2, or 3 nucleotides from any one of the nucleotide sequences of nucleotides 488-508, 491-511, 496-516, 488-516, 518-538, 992-1012, 994-1014, 1322-1342, 2242-2262, 2444-2464 of SEQ ID NO: 1, and the antisense strand comprises at least 15, 16, 17, 18, 19, 20 or 21 contiguous nucleotides differing by 0, 1, 2, or 3 nucleotides from the corresponding nucleotide sequence of SEQ ID NO: 2.
  4. The dsRNA agent of claim 1, wherein said antisense strand comprises a region of complementarity to a CFB RNA transcript RNA transcript which comprises at least 15 contiguous nucleotides differing by no more than 1, 2, or 3 nucleotides from any one of the antisense sequences listed in any one of Tables 1-3.
  5. The dsRNA agent of claim 1, wherein said antisense strand comprises a region of complementarity to a CFB RNA transcript which comprises at least 15 contiguous nucleotides from any one of the antisense sequences listed in any one of Tables 1-3.
  6. The dsRNA agent of claim 1, wherein the double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of CFB, wherein the dsRNA agent comprises a sense strand and an antisense strand, nucleotide positions 2 to 18 in the antisense strand comprising a region of complementarity to a CFB RNA transcript, wherein the region of complementarity comprises at least 15, 16, 17, 18, 19, 20 or 21 contiguous nucleotides that differ by 0, 1, 2, or 3 nucleotides from one of the antisense sequences listed in one of Tables 1-3, and optionally comprising a targeting ligand.
  7. The dsRNA agent of claim 6, wherein the region of complementarity to a CFB RNA transcript comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides that differ by no more than 3 nucleotides from one of the antisense sequences listed in one of Tables 1-3.
  8. The dsRNA agent of any one of claims 1-7, wherein the antisense strand of dsRNA is substantially or fully complementary to any one of a target region of SEQ ID NO: 1, and preferably the dsRNA agent comprises an antisense strand sequence set forth in any one of Tables 1-3.
  9. The dsRNA agent of any one of claims 1-8, wherein the sense strand sequence is at least substantially complementary to or fully complementary to the antisense strand sequence in the dsRNA agent, preferably, wherein the dsRNA agent comprises a sense strand sequence set forth in any one of Tables 1-3.
  10. The dsRNA agent of any one of claims 1-9, wherein the dsRNA agent comprises the sequences set forth as a duplex sequence in any of Tables 1-3.
  11. The dsRNA of any one of claims 1-10, wherein the dsRNA agent comprises at least one modified nucleotide.
  12. The dsRNA agent of any one of claims 1-11, wherein all or substantially all of the nucleotides of the sense strand and/or the antisense strand are modified nucleotides.
  13. The dsRNA agent of claim 1-12, wherein the double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of CFB, wherein the dsRNA agent including a sense strand and an antisense strand, wherein the sense strand is complementary to the antisense strand, wherein the antisense strand comprises a region complementary to part of a CFB RNA transcript, wherein each strand is about 15 to about 30 nucleotides in length, wherein the sense strand comprises sequence may be represented by formula (I) : 5′- (N′ L ) n′ N′ L N′ L N′ L N′ L N′ F N′ L N′ F N′ L N′ N1 N′ N2 N′ L N′ L N′ L N′ L N′ L (N′ L ) m′ -3′ (I) wherein: each N′ F represents a 2'-fluoro-modified nucleotide; each N′ N1 and N′ N2 independently represents a modified or unmodified nucleotide; each N′ L independently represents a modified or unmodified nucleotide but not a 2'-fluoro-modified nucleotide, and m′ and n′ are each independently an integer of 0 to 7.
  14. The dsRNA agent of claim 1-12, wherein the double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of CFBis provided, wherein the dsRNA agent including a sense strand and an antisense strand, wherein the sense strand is complementary to the antisense strand, wherein the antisense strand comprises a region complementary to part of a CFB RNA transcript, , wherein each strand is about 18 to about 30 nucleotides in length, wherein the antisense strand comprises sequence may be represented by formula (II) : 3′- (N L ) n N M1 N L N M2 N L N F N L N M3 N M4 N L N L N L N M5 N L N M6 N L N L N F N L -5′ (II) wherein: each N F represents a 2'-fluoro-modified nucleotide; each N M1 , N M2 , N M3 , N M4 , N M5 , and N M6 independently represents a modified or unmodified nucleotide; each N L independently represents a modified or unmodified nucleotide but not a 2'-fluoro-modified nucleotide, and n is an integer of 0 to 7.
  15. The dsRNA agent of claim 1-12, wherein the double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of CFB is provided, wherein the dsRNA agent including a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a dsRNA duplex, wherein said sense strand is complementary to the antisense strand, wherein said antisense strand comprises a region of complementarity to a CFB RNA transcript, wherein the region of complementarity comprises at least 15 contiguous nucleotides, wherein the dsRNA comprises duplex represented by formula (III) : sense: 5′- (N′ L ) n′ N′ L N′ L N′ L N′ L N′ F N′ L N′ F N′ L N′ N1 N′ N2 N′ L N′ L N′ L N′ L N′ L (N′ L ) m′ -3′ antisense: 3′- (N L ) n N M1 N L N M2 N L N F N L N M3 N M4 N L N L N L N M5 N L N M6 N L N L N F N L -5′ (III) wherein: each strand is about 18 to about 30 nucleotides in length; each N F and N′ F independently represents a 2'-fluoro-modified nucleotide; N M1 , N M2 , N M3 , N M4 , N M5 , N′ N1 , and N′ N2 each independently represents a modified or unmodified nucleotide; N′ N1 and N′ N2 include only one 2'-Fluorine modified nucleotides; N M1 , N M2 , N M3 , N M4 , N M5 , and N M6 have only three 2'-fluoro-modified nucleotides; each N L and N′ L independently represents a modified or unmodified nucleotide but not a 2'-fluoro-modified nucleotide, and m′, n′ and n are each independently an integer of 0 to 7.
  16. The dsRNA agent of any one of claims 11-15, wherein the one or more modified nucleotides are independently selected from the group consisting of: a 2’-O-methyl nucleotide, a 2’-Fluoro nucleotide, a 2’-deoxy nucleotide, a 2’3’-seco nucleotide mimic, a locked nucleotide, an unlocked nucleic acid nucleotide (UNA) , a glycol nucleic acid nucleotide (GNA) , a 2’-F-Arabino nucleotide, a 2’-methoyxyethyl nucleotide, an abasic nucleotide, an ribitol, inverted nucleotide, an inverted abasic nucleotide, an isomannide nucleotide, an inverted 2’-Ome nucleotide, an inverted 2’-deoxy nucleotide, a 2’-amino-modified nucleotide, a 2’-alkyl-modified nucleotide, a mopholino nucleotide, a 3’-OMe nucleotide, a nucleotide comprising a 5’-phosphorothioate group, a terminal nucleotide linked to a cholesteryl derivative or dodecanoic acid bisdecylamide group, a 2’-amino-modified nucleotide, a phosphoramidate, or a non-natural base comprising nucleotide.
  17. The dsRNA agent of any one of claims 1-16, comprises an E-vinylphosphonate nucleotide at the 5′ end of the guide strand.
  18. The dsRNA agent of any one of claims 1-17, wherein the dsRNA agent comprises at least one phosphorothioate internucleoside linkage.
  19. The dsRNA agent of any one of claims 1-17 wherein the sense strand comprises at least one phosphorothioate internucleoside linkage.
  20. The dsRNA agent of any one of claims 1-17, wherein the antisense strand comprises at least one phosphorothioate internucleoside linkage.

Description

COMPOSITIONS AND METHODS FOR INHIBITING EXPRESSION OF COMPLEMENT FACTOR B (CFB) Field of the Invention The invention relates, in part, to compositions and methods that can be used to inhibit a complement factor B (CFB) gene expression. Background Complement was first discovered in the 1890s when it was found to aid or “complement” the killing of bacteria by heat-stable antibodies present in normal serum. The complement system or pathway is part of the innate immune system of host defence against invading pathogens. It mainly consists of more than 30 proteins that are either present as soluble proteins in the blood or are present as membrane-associated proteins. Three main pathways of complement activation have been recognized and are referred to as classical pathway, alternative pathway and lectin pathway. Activation of complement leads to a sequential cascade of enzymatic reactions, known as complement activation pathways resulting in the formation of the potent anaphylatoxins C3a and C5a that elicit a plethora of physiological responses that range from chemoattraction to apoptosis. Initially, complement was thought to play a major role in innate immunity where a robust and rapid response is mounted against invading pathogens. However, recently it is becoming increasingly evident that complement also plays an important role in adaptive immunity involving T and B cells that help in elimination of pathogens, in maintaining immunologic memory preventing pathogenic reinvasion, and is involved in numerous human pathological states. In functional terms, complement activation occurs inherently at a low level (spontaneous cleavage of C3 to yield C3a and C3b) and is reinforced in the presence of microbes via an enzymatic cascade converting inactive forms of enzymes (zymogenes) into their active counterparts. One type of C3 convertases is a complex of C3b and complement factor B (CFB, Factor B) . Once formed, a C3 convertase can convert large amounts of C3 into its cleavage products C3a and C3b within short amount of time. The specific C3 convertase which is a complex of C3b and Factor B has originally been described in the context of the alternative pathway, but may form also in the context of the other two pathways. Within the alternative pathway, Factor B is also a constituent of C5 convertase, acomplex which converts C5, a more downstream component of the pathway, into its active form. Complement Factor B (also known as CFB or “factor B” ) is involved in activation of the alternative pathway. Binding of CFB to C3b (e.g., on a cell surface) renders CFB susceptible to cleavage by Factor D, forming the serine protease C3Bb, which is itself a C3 convertase, leading to an amplification loop for C3 activation. CFB is primarily synthesised in the liver, as well as in low levels at several extrahepatic sites. Several diseases are associated with aberrant acquired or genetic activation of the complement pathway as well as with aberrant or over-expression of CFB. for example, C3 glomerulopathy, systemic lupus erythematosus (SLE) , Lupus Nephritis, IgA nephropathy, diabetic nephropathy, polycystic kidney disease, membranous nephropathy, age-related macular degeneration, atypical hemolytic uremic syndrome, thrombotic microangiopathy, myasthenia gravis, ischemia and reperfusion injury, paroxysmal nocturnal hemoglobinuria, rheumatoid arthritis, immune complex-mediated glomerulonephritis (IC-mediated GN) , post-infectious glomerulonephritis (PIGN) , ischemia/reperfusion injury , antineutrophil cytoplasmic autoantibodies-associated vasculitis (ANCA-AV) , dysbiotic periodontal disease, malarial anaemia and hyperlipidemia. There are currently only few treatments for complement system mediated diseases, disorders and syndromes. The monoclonal humanized antibody Eculizumab is one of them. Although eculizumab has been shown to be effective for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) , atypical hemolytic uremic syndrome (aHUS) , and Myasthenia Gravis, and is currently being evaluated in clinical trials for additional complement component-associated diseases, eculizumab therapy requires weekly high dose infusions followed by biweekly maintenance infusions at a high cost. There is thus a high unmet need for medical treatments of complement mediated or associated diseases. C3 is a pivotal factor in the complement pathway activation. Inhibiting expression of factors such as CFB which are involved in C3 activation therefore presents a promising therapeutic strategy for many complement-mediated diseases. Targeting of CFB expression or activity, e.g., via antisense oligonucleotides, double-stranded siRNAs or small molecule inhibitors targeted to CFB, has been proposed as a potential therapeutic strategy for various complement-mediated conditions. Accordingly, CFB RNAi agents disclosed herein for for treating diseases, disorders, and conditions associated with complement activation by, for example, activation of complement