WO2026037221A1 - Réactif d'arni ciblant le complément c3 et son utilisation - Google Patents

Réactif d'arni ciblant le complément c3 et son utilisation

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Publication number
WO2026037221A1
WO2026037221A1 PCT/CN2025/113754 CN2025113754W WO2026037221A1 WO 2026037221 A1 WO2026037221 A1 WO 2026037221A1 CN 2025113754 W CN2025113754 W CN 2025113754W WO 2026037221 A1 WO2026037221 A1 WO 2026037221A1
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pat
nucleotides
seq
rnai reagent
nucleotide
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蒋伟文
郁东
兰涛
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Synerk Biopharmaceuticals Ltd
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Synerk Biopharmaceuticals Ltd
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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
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • 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
    • C—CHEMISTRY; METALLURGY
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    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/10—Cells modified by introduction of foreign genetic material

Definitions

  • This invention belongs to the field of biomedicine, specifically relating to RNAi reagents targeting C3 complement and their uses.
  • the complement system is a human immune defense system composed of more than 30 proteins (Janeway, CA Jr et al., 2001). There are three main complement activation pathways: the classical pathway, the alternative pathway, and the lectin pathway (Abbas AK et al., 2010). Complement activation leads to a series of chain reactions involving enzymatic reactions, forming anaphylatoxins C3a and C5a, which further trigger downstream physiological responses.
  • the classical pathway is activated by the binding of C1 to classical pathway activators (primarily antigen-antibody complexes containing IgM, IgG1, IgG2, or IgG3).
  • classical pathway activators primarily antigen-antibody complexes containing IgM, IgG1, IgG2, or IgG3.
  • the reaction sequence of the classical complement activation pathway is: C1, 4, 2, 3, 5, 6, 7, 8, 9. This biochemical pathway creates a pore in the cell membrane, causing the target cell to swell and rupture due to the inability to maintain osmotic pressure.
  • the activation of the alternative pathway depends on the spontaneous hydrolysis of C3 into C3a and C3b, and the combination of C3b with B, D and P factors to enter a reaction similar to the classical pathway.
  • Mannose-binding lectins can recognize mannose and fructose residues on the surface of pathogens, and then bind to the pathogen surface and carry out a reaction similar to the activation of the classical pathway.
  • Abnormal complement activation can lead to a series of pathological changes in many diseases, such as paroxysmal nocturnal hemoglobinuria (PNH), generalized myasthenia gravis (GMG), rheumatoid arthritis (RA), and neuromyelitis optica (NMO).
  • PNH paroxysmal nocturnal hemoglobinuria
  • GCG generalized myasthenia gravis
  • RA rheumatoid arthritis
  • NMO neuromyelitis optica
  • Complement Component 3 plays a crucial role in the entire complement system. Both the classical and alternative activation pathways rely on C3 activation (Lambris 2001). C3 is also the most abundant complement in human blood, primarily produced in the liver (de Bruijn MH and Fey GH, 1985). Currently, only one monoclonal antibody, Pegacetacoplan, is effective against C3 complement; it is expensive and requires frequent injections.
  • RNA interference refers to the highly conserved phenomenon of efficient and specific degradation of homologous mRNA induced by double-stranded small interfering RNA (siRNA) during evolution. RNAi drugs also have the advantage of longer duration of action compared to antibody drugs. Therefore, the research and development of siRNAs targeting C3 complement is of great significance.
  • the first object of the present invention is to provide an RNAi reagent comprising: an antisense strand containing at least 15 consecutive nucleotides, wherein the at least 15 consecutive nucleotides differ by no more than 3 nucleotides from any at least 15 consecutive nucleotides in any of the sequences shown in SEQ ID NO: 54-106; and a sense strand containing a nucleotide sequence that is at least partially complementary to the antisense strand.
  • the present invention also provides an isolated cell containing the aforementioned RNAi reagent.
  • the present invention also provides a pharmaceutical composition comprising the aforementioned RNAi reagent.
  • a second objective of the present invention is to provide a method for inhibiting the expression of C3 complement in cells, the method comprising: contacting the cells with the RNAi reagent or the pharmaceutical composition thereof to inhibit the expression of C3 complement in the cells.
  • the present invention also provides the use of the RNAi reagent or the pharmaceutical composition described herein in the treatment and/or prevention of diseases related to C3 complement.
  • the present invention also provides the use of the RNAi reagent or the pharmaceutical composition described herein in the preparation of medicaments for the treatment and/or prevention of diseases related to C3 complement.
  • RNAi reagent of the present invention can effectively inhibit the expression of C3 complement in cells, and therefore can be used to treat diseases related to C3 complement.
  • Figure 1 shows the efficacy of different siRNAs in human C3 transgenic mice in Example 3 of this invention.
  • Figure 2 shows the long-term inhibitory effect of PAT-0038T in human C3 transgenic mice in Example 5 of the present invention.
  • the technical solution of "A, and/or, B, and/or, C, and/or, D” includes any one of A, B, C, and D (that is, a technical solution that is connected by "logical OR”), as well as any and all combinations of A, B, C, and D, that is, combinations of any two or three of A, B, C, and D, and also combinations of all four of A, B, C, and D (that is, a technical solution that is connected by "logical AND").
  • the numerical range represented by endpoints includes all numerical values and fractions contained within that range, as well as the endpoints mentioned.
  • This invention relates to concentration values, which include fluctuations within a certain range. For example, fluctuations are allowed within a corresponding precision range. For instance, 2% can fluctuate within ⁇ 0.1%. For larger values or values that do not require overly precise control, even greater fluctuations are permitted. For example, 80% can fluctuate within ranges of ⁇ 1%, ⁇ 2%, ⁇ 5%, etc.
  • the technical features described in an open-ended manner include both closed-ended technical solutions composed of the listed features and open-ended technical solutions that include the listed features.
  • RNAi reagent also known as “RNAi trigger” means a composition containing RNA or RNA-like (e.g., chemically modified RNA) oligonucleotide molecules capable of degrading or inhibiting (e.g., under appropriate conditions, degrading or inhibiting) the translation of messenger RNA (mRNA) transcripts of target mRNA in a sequence-specific manner.
  • RNAi reagents may function via RNA interference mechanisms (i.e., by interaction with RNA interference pathways in mammalian cells, such as RNA-induced silencing complexes or RISC) or via any alternative mechanism or pathway.
  • RNAi reagents function primarily through RNA interference mechanisms as used herein, the disclosed RNAi reagents are not bound to or limited by any particular pathway or mechanism of action.
  • the RNAi reagents disclosed herein consist of a sense strand and an antisense strand, and include, but are not limited to, short (or small) interfering RNA (siRNA), double-stranded RNA (dsRNA), microRNA (miRNA), short hairpin RNA (shRNA), and dicer substrates.
  • the antisense strand of the RNAi reagent described herein is at least partially complementary to the target mRNA (i.e., C3 complement mRNA).
  • the RNAi reagent may include one or more modified nucleotides and/or one or more non-phosphodiester bonds.
  • the antisense strand contains at least 15 consecutive nucleotides, and the at least n consecutive nucleotides differ from any at least 15 consecutive nucleotides in a reference sequence (e.g., the sequence shown in SEQ ID No. X or the nucleotide sequence of positions 1-21 of the shown sequence) by no more than 3 nucleotides
  • the alignment involved includes alignment with at least 15 consecutive nucleotides starting at any position (e.g., positions 1, 2, 3, ..., 7, or 8) in the reference sequence.
  • the antisense strand contains 21 consecutive nucleotides, wherein the sequence of positions 1-15 differs from the sequence of positions 2-16 of the reference sequence in one, two, or three places, and the nucleotides 16-20 in the antisense strand (positive strand) are all identical or all different from the sequence of positions 17-21 of the reference sequence; such sequences are also within the scope of this invention.
  • the antisense strand contains 21 consecutive nucleotides, wherein the sequence of nucleotides 1 to 15 is identical to the sequence of nucleotides 1 to 15 of the reference sequence, and nucleotides 16 to 21 of the antisense strand (positive strand) are either identical or different from the sequence of nucleotides 16 to 21 of the reference sequence; such sequences are also within the scope of this invention.
  • completely complementary means that in a hybridization pair of nucleobase or nucleotide sequences, all (100%) bases in the adjacent sequence of the first oligonucleotide hybridize with the same number of bases in the adjacent sequence of the second oligonucleotide.
  • the adjacent sequence may comprise all or part of the first or second nucleotide sequence.
  • substantially complementary means that in a hybridization pair of nucleobase or nucleotide sequence molecules, at least 70% but not all of the bases in the adjacent sequence of the first oligonucleotide hybridizes with the same number of bases in the adjacent sequence of the second oligonucleotide.
  • the adjacent sequence may comprise all or part of the first or second nucleotide sequence.
  • the term "at least partially complementary” means that in a hybridization pair of nucleobase or nucleotide sequence molecules, the first oligonucleotide and the second oligonucleotide are partially complementary, substantially complementary, or completely complementary.
  • treatment refers to a method or procedure taken to provide relief or reduction of the number, severity, and/or frequency of one or more disease symptoms in a subject.
  • the treatment may include prevention, management, preventative treatment, and/or suppression or reduction of the number, severity, and/or frequency of one or more disease symptoms in a subject.
  • the present invention first provides an RNAi reagent comprising: an antisense strand containing at least 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleotides, wherein the at least 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleotides differ from any at least 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleotides in any of the sequences shown in SEQ ID NO: 54-106 by no more than 0, 1, 2, or 3 nucleotides; and a sense strand comprising a nucleotide sequence that is at least partially complementary (e.g., partially complementary, substantially complementary, or completely complementary) to the antisense strand.
  • the positive strand has 15 to 30 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30) nucleotides (bases).
  • RNAi reagents such as siRNA
  • siRNA-20 siRNA-21 with the positive strand sequence SEQ ID NO: 21 and the negative strand sequence SEQ ID NO: 74, siRNA-22 with the positive strand sequence SEQ ID NO: 22 and the negative strand sequence SEQ ID NO: 75, siRNA-23 with the positive strand sequence SEQ ID NO: 23 and the negative strand sequence SEQ ID NO: 76, siRNA-24 with the positive strand sequence SEQ ID NO: 24 and the negative strand sequence SEQ ID NO: 77, siRNA-25 with the positive strand sequence SEQ ID NO: 25 and the negative strand sequence SEQ ID NO: 78, siRNA-26 with the positive strand sequence SEQ ID NO: 26 and the negative strand sequence SEQ ID NO: 79, and siRNA-26 with the positive strand sequence SEQ ID NO: 27 and the negative strand sequence SEQ ID NO: 74, are all siRNA-20.
  • siRNA-27 with SEQ ID NO: 80 siRNA-28 with SEQ ID NO: 28 and antisense sequence with SEQ ID NO: 81
  • siRNA-29 with SEQ ID NO: 29 and antisense sequence with SEQ ID NO: 82 siRNA-30 with SEQ ID NO: 30 and antisense sequence with SEQ ID NO: 83
  • siRNA-31 with SEQ ID NO: 31 and antisense sequence with SEQ ID NO: 84 siRNA-32 with SEQ ID NO: 32 and antisense sequence with SEQ ID NO: 85
  • siRNA-33 with SEQ ID NO: 33 and antisense sequence with SEQ ID NO: 86 siRNA-33 with SEQ ID NO: 86.
  • siRNA-47 with Q ID NO: 100 siRNA-48 with the sense strand sequence SEQ ID NO: 48 and the antisense strand sequence SEQ ID NO: 101
  • siRNA-51 with the sense strand sequence SEQ ID NO: 51 and the antisense strand sequence SEQ ID NO: 104 siRNA-52 with the sense strand sequence SEQ ID NO: 52 and the antisense strand sequence SEQ ID NO: 105
  • the RNAi reagent is siRNA-1 with a sense strand sequence of SEQ ID NO: 1 and an antisense strand sequence of SEQ ID NO: 54, siRNA-2 with a sense strand sequence of SEQ ID NO: 2 and an antisense strand sequence of SEQ ID NO: 55, siRNA-3 with a sense strand sequence of SEQ ID NO: 3 and an antisense strand sequence of SEQ ID NO: 56, siRNA-4 with a sense strand sequence of SEQ ID NO: 4 and an antisense strand sequence of SEQ ID NO: 57, siRNA-5 with a sense strand sequence of SEQ ID NO: 55 and an antisense strand sequence of SEQ ID NO: 58, siRNA-6 with a sense strand sequence of SEQ ID NO: 6 and an antisense strand sequence of SEQ ID NO: 59, and siRNA-6 with a sense strand sequence of SEQ ID NO: 7 and an antisense strand sequence of SEQ ID NO: 59.
  • siRNA-47 with EQ ID NO: 100 siRNA-48 with the sense strand sequence SEQ ID NO: 48 and the antisense strand sequence SEQ ID NO: 101
  • the antisense strand contains a nucleotide sequence differing from any of the sequences shown in SEQ ID NO: 54, 55, 57, 59, 62, 63, 67–69, 76, 80–82, 88–95, 98, 99, 101, 105 by 0, 1, or 2 nucleotides, and the sense strand contains a nucleotide sequence at least partially complementary to the antisense strand (e.g., partially complementary, substantially complementary, or fully complementary).
  • the sense strand contains a nucleotide sequence differing from any of the sequences shown in SEQ ID NO: 1, 2, 4, 6, 9, 10, 14–16, 23, 27–29, 35–42, 45, 46, 48, 52 by 0, 1, or 2 nucleotides.
  • SEQ ID NO: 1 2, 4, 6, 9, 10, 14–16, 23, 27–29, 35–42, 45, 46, 48, 52 by 0, 1, or 2 nucleotides.
  • the sense strand contains a nucleotide sequence that differs from the sequence shown in SEQ ID NO: 9 by 0, 1, or 2 nucleotides
  • the antisense strand contains a nucleotide sequence that differs from the sequence shown in SEQ ID NO: 62 by 0, 1, or 2 nucleotides.
  • the sense strand contains a nucleotide sequence that differs from the sequence shown in SEQ ID NO: 10 by 0, 1, or 2 nucleotides
  • the antisense strand contains a nucleotide sequence that differs from the sequence shown in SEQ ID NO: 63 by 0, 1, or 2 nucleotides.
  • the sense strand contains a nucleotide sequence that differs from the sequence shown in SEQ ID NO: 38 by 0, 1, or 2 nucleotides
  • the antisense strand contains a nucleotide sequence that differs from the sequence shown in SEQ ID NO: 91 by 0, 1, or 2 nucleotides.
  • the inhibitory effect of the RNAi reagent is further enhanced when the above sequences are present.
  • the inhibitory effect is particularly optimal when the sense strand sequence is as shown in SEQ ID NO: 38 and the antisense strand sequence is as shown in SEQ ID NO: 91.
  • All nucleotide groups in the above RNAi reagents may be unmodified or contain at least one modified nucleotide group, and the modification may be on nucleotides at any position.
  • the justice chain and the antisense chain may be partially complementary, substantially complementary, or completely complementary to each other.
  • sequence identity of the sense or antisense strand in the RNAi reagent when the sequence identity of the sense or antisense strand in the RNAi reagent is less than 100% or differs by more than one nucleotide from the corresponding sequence mentioned in this invention, it still has an inhibitory effect on C3 complement that is similar to (e.g., still has an efficacy equivalent to 80-120%, 85-115%, or 90-110% of the corresponding sequence) or equivalent to (e.g., still has an efficacy equivalent to 95-105% of the corresponding sequence).
  • the two bases at the 3' end of the antisense strand can be replaced with UU, AA, CU, UC, AG, CC, GG, or UG, or any combination of two nucleic acids.
  • Such nucleic acid sequences are also within the scope of protection of this invention.
  • the RNAi reagent has an inhibitory efficiency of not less than 50% against C3 complement (e.g., 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%).
  • the present invention also provides target gene sites for nucleic acids as described above.
  • the target gene sites are marked as any item in column 1 of Table 1.
  • Column 1 indicates the position of the first base of the target gene in the human C3 complement mRNA sequence, and so on; the numbers in columns 3 and 5 represent sequence numbers, for example, "1" represents SEQ ID NO: 1.
  • the reference sequence for the target gene is the coding sequence of human C3 complement mRNA, NM_000064.4.
  • the positive strand of the RNAi reagent has at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%) sequence identity with the isochronous sequences at positions 200-400, 400-600, 600-900, 1200-1400, 1300-1500, 2500-2600, 2800-3000, 3700-3900, or 4000-4700 of NM_000064.4.
  • the RNAi reagent targets any position within the region of nucleotides 200-400, 400-600, 600-900, 1200-1400, 1300-1500, 2500-2600, 2800-3000, 3700-3900, or 4000-4700 in NM_000064.4.
  • the RNAi reagent targets any position within the region of nucleotides 200-300, 400-500, 650-750, 700-850, 1250-1350, 1350-1450, 2500-2600, 2800-2950, 3750-3850, 4100-4300, 4400-4550, or 4550-4650 in NM_000064.4.
  • the RNAi reagent targets any position within the region of nucleotides 760-810 in NM_000064.4.
  • the RNAi reagent targets any position within the region of nucleotides 4110-4160 in NM_000064.4.
  • the RNAi reagent targets any position within the region of nucleotides 4590-4640 in NM_000064.4.
  • the RNAi reagent contains nucleotide groups as basic structural units, the nucleotide groups containing phosphate groups, ribose groups and bases, and preferably, the RNAi reagent contains at least one modified nucleotide group.
  • RNAi reagents containing modified groups have an inhibition efficiency of not less than 50% against C3 complement (e.g., 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%).
  • the modified nucleotide group is a nucleotide group whose phosphate group and/or ribose group are modified.
  • the modified site may be at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in the sense strand and/or antisense strand.
  • modification of the phosphate group refers to modifying the oxygen in the phosphate group, including phosphate thioate modification and boranophosphate modification.
  • the oxygen in the phosphate group is replaced by sulfur, borane, amino, alkyl, or alkoxy groups, as shown in the following formulas. These modifications can stabilize the structure of nucleic acids and maintain high specificity and high affinity of base pairing.
  • BASE represents a base A, U, C, G, or T.
  • X can be oxygen (O) or sulfur (S).
  • R can be the same or different in the above structures, such as: hydrogen (H), fluorine (F), methoxy (OME) or methoxyethyl (MOE), hydroxyl, allyl, ethylamino, propargyl, amino, cyanoethyl, acetyl, etc.
  • R’ and R” can each independently be hydrogen (H), methyl (CH3), ethyl (CH2CH3), propyl (CH2CH2CH3), isopropyl (CH(CH3)2), allyl, propargyl, acyloxybenzyl, acyloxyethyl.
  • modification of the ribose group refers to the modification of the 2′-hydroxyl group (2′-OH) in the ribose group.
  • substituents such as methoxy or fluorine at the 2′-hydroxyl position of the ribose group makes the nucleic acid less susceptible to cleavage by ribonucleases, thereby increasing the stability of the nucleic acid and giving it stronger resistance to nuclease hydrolysis.
  • Modification of the 2′-hydroxyl group in the pentose of nucleotides includes 2′-fluoromodification (e.g., 2′-arabino-fluoro modification), 2′-methoxymodification (2′-OME), 2′-methoxyethylmodification (2′-MOE), 2′-2,4-dinitrophenol modification (2′-DNP modification), 2′,4′-constrained ethylmodification, 2′-aminomodification (2′-Amino modification), 2′-deoxymodification (2′-Deoxy modification), BNA, acyclic nucleic acid modification, misaligned nucleic acid modification, L-type nucleic acid modification, etc.
  • 2′-fluoromodification e.g., 2′-arabino-fluoro modification
  • 2′-OME 2′-methoxyethylmodification
  • 2′-MOE 2′-2,4-dinitrophenol modification
  • 2′-DNP modification 2′,
  • BNA inner-ring bridging nucleotide refers to a restricted or inaccessible nucleotide.
  • BNAs can contain bridging structures with "fixed" C 3'-endoglycosylation rings, including five-, six-, or seven-membered rings. This bridge is typically incorporated into the 2', 4' positions of the ribosome to provide 2',4'-BNA nucleotides, such as locked-ethyl (LNA), ring-locked-ethyl (ENA), and ethyl-locked nucleic acid (cET BNA).
  • LNA locked-ethyl
  • ENA ring-locked-ethyl
  • cET BNA ethyl-locked nucleic acid
  • Acyclic nucleic acids are nucleotides formed by opening the sugar ring of the nucleotide, such as unlocked nucleic acid (UNA) and glycerol nucleic acid (GNA).
  • UNA unlocked nucleic acid
  • GAA glycerol nucleic acid
  • Misalignment refers to the replacement of the 3',5'-phosphate bond with a 2',5'-phosphate bond.
  • L-type nucleic acid modification refers to the replacement of a naturally occurring D-type nucleic acid with its mirror-image L-type nucleic acid.
  • BASE represents the bases A, U, C, G, or T.
  • R can be the same or different in the above structures, for example: hydrogen (H), fluorine (F), methoxy (OME) or methoxyethyl (MOE), hydroxyl, allyl, ethylamino, propargyl, cyanoethyl, acetyl, etc.
  • the nucleotide group containing a uracil or cytosine base in the sense strand of the RNAi reagent is a nucleotide group whose riboside group has been modified; that is, the 2'-OH of the riboside group in the uracil or cytosine base-containing nucleotide group in the sense strand of the RNAi reagent is replaced by a methoxy or fluorine group.
  • the 3' ends of both the sense and antisense strands of the RNAi reagent may be linked with dTdT; or, the 3' end of the antisense strand of the RNAi reagent may be linked with AA or UU or any combination of two nucleic acids (which may be, but is not limited to, CC, GG, or UG), giving the sequence a specific inducing factor for mRNA degradation.
  • the RNAi reagent with the above modifications exhibits superior in vivo inhibitory effects, and the above modifications can further reduce the immunogenicity of the RNAi reagent of the present invention in vivo.
  • the RNAi reagent of the present invention may further include a modification of the 5' end of the antisense strand by linking a monophosphate nucleoside.
  • the 5'-monophosphate at the terminal of the siRNA strand is important for RISC recognition. Phosphorylation of the 5'-hydroxyl group plays a role in the efficient loading of siRNA onto Ago2 within the cell.
  • the 5'-terminal monophosphate in the siRNA strand interacts with Argonaute-2 (Ago2) via an H-bond, thereby ensuring accurate target localization and precise cleavage of the mRNA.
  • RNAi reagent of the present invention trans-vinyl phosphate (VP) is preferred, but other monophosphate nucleoside derivatives may also be included.
  • VP trans-vinyl phosphate
  • BASE represents the base A, U, C, G, or T.
  • R can be the same or different in the above structures, such as: hydrogen (H), fluorine (F), methoxy (OME) or methoxyethyl (MOE), hydroxyl, allyl, ethylamino, propargyl, cyanoethyl, amino, acetyl, etc.
  • At least one nucleotide in the RNAi reagent is a modified nucleotide or includes a modified interphase bond.
  • the modified inter-linked bonds are preferably one or more selected from phosphate thioester nucleotide inter-linked bonds and methylphosphonate nucleotide inter-linked bonds. In some embodiments, the modified inter-linked bonds are further preferably one or more selected from phosphate thioester monoester nucleotide inter-linked bonds and phosphate thioester diester nucleotide inter-linked bonds.
  • the antisense chain comprises 5’-nNfnNfnNfnnnnnnnNfnNfnnnnnnnnnnnnnnnn-3’. Compared to other modification methods, the above-described antisense chain modification scheme exhibits significantly better inhibition of C3 complement.
  • the positive strand has at least one (preferably two, three, or four) nucleotides at positions 7, 9, 10, and 11 counting from the 5' end that are 2'-fluoronucleotides, and the remaining nucleotides are 2'-O-methylnucleotides.
  • the last 2 to 4 (e.g., 2, 3, or 4) nucleotides at the 5' end and/or 3' end of the antisense strand contain thiophosphate nucleotide bonds
  • the last 2 to 4 (e.g., 2, 3, or 4) nucleotides at the 5' end and/or 3' end of the sense strand contain thiophosphate nucleotide bonds.
  • the last three nucleotides at the 5' and 3' ends of the antisense strand contain a phosphate thioester nucleotide bond, and the last three nucleotides at the 5' end of the sense strand contain a phosphate thioester nucleotide bond.
  • the antisense strand contains a nucleotide sequence that differs from any of the antisense strands shown in Table 2 or Table 3 by 0, 1, or 2 nucleotides.
  • the positive strand contains a nucleotide sequence that differs from any of the positive strands shown in Table 2 or Table 3 by 0, 1, or 2 nucleotides.
  • the RNAi reagent contains a double strand as shown in either Table 2 or Table 3.
  • the RNAi reagent contains a compound selected from PAT-0001, PAT-0002, PAT-0004, PAT-0006, PAT-0009, PAT-0009.1, PAT-0009.2, PAT-0010, PAT-0010.1, PAT-0010.2, PAT-0014, PAT-0015, PAT-0016, PAT-0023, PAT-0027, PAT-0028, PA.
  • the double-stranded RNAi reagents containing any of the above double-stranded RNAi compounds exhibit excellent inhibitory effects on C3 complement in cell experiments.
  • T-0029 PAT-0035, PAT-0036, PAT-0037, PAT-0038, PAT-0038.1, PAT-0038.2, PAT-0038.3, PAT-0038.4, PAT-0038.5, PAT-0039, PAT-0040, PAT-0041, PAT-0042, PAT-0045, PAT-0046, PAT-0048, and PAT-0052.
  • the RNAi reagent contains a double strand selected from any one of PAT-0009, PAT-0010, and PAT-0038. RNAi reagents containing the aforementioned double strands achieve excellent inhibitory effects on C3 complement both in vivo and in vitro.
  • the RNAi reagent contains the double strand described in PAT-0038. RNAi reagents containing the aforementioned double strand achieve optimal inhibitory effects on C3 complement both in vivo and in vitro.
  • the nucleotide represented by the lowercase letter indicates that the nucleotide is a 2'-O-methyl nucleotide; f indicates that the nucleotide adjacent to it on the left is a 2'-fluoro nucleotide; s indicates that the two adjacent nucleotides on the left and right are connected by a phosphate diester nucleotide bond.
  • RNAi reagent according to the present invention can be obtained by conventional methods in the art, such as solid-phase synthesis and liquid-phase synthesis. Solid-phase synthesis is available through commercially available custom services and is therefore commercially available.
  • the modified nucleotide groups can be introduced using nucleotide monomers with corresponding modifications.
  • the present invention can further construct shRNA expression plasmids with the same or similar functions as the above RNAi reagents.
  • the method for constructing the expression plasmid is known to those skilled in the art and will not be described in detail here.
  • the RNAi reagent further comprises at least one ligand that is attached to one or more of the 5' end of the antisense strand, the 3' end of the antisense strand, the 5' end of the sense strand, and the 3' end of the sense strand.
  • the sense and antisense strands of this invention exhibit superior inhibitory effects when applied to different targeted drug delivery systems.
  • the efficacy advantages of the naked and modified sequences in this invention do not depend on the choice of target vector.
  • this invention also optimizes the targeted drug delivery system, resulting in the following technical solution.
  • the ligand is attached to the 5' or 3' end of the positive strand of the nucleic acid. In some embodiments, the ligand is attached to the 5' end of the positive strand of the nucleic acid. In some embodiments, the ligand is attached to the 3' end of the positive strand of the nucleic acid.
  • the ligand is attached to the 5' or 3' end of the antisense strand of the nucleic acid. In some embodiments, the ligand is attached to the 5' end of the antisense strand of the nucleic acid. In some embodiments, the ligand is attached to the 3' end of the antisense strand of the nucleic acid.
  • the ligand is attached to the 3' end of the positive strand of the nucleic acid.
  • the ligand is a GalNAc derivative; more preferably, the ligand is one or more GalNAc derivatives linked by a single-chain, double-chain, or triple-chain branched ligand.
  • the RNAi reagent comprises a compound with the structure shown in Formula I:
  • Nu represents a nucleic acid composed of the sense strand and the antisense strand.
  • This targeted drug delivery system utilizes the structural characteristics on its left side to improve the cell penetration ability of nucleic acid drugs (Nu), enhance their stability within cells, and has a simple preparation process and strong practicality.
  • the present invention also provides an isolated cell containing the aforementioned RNAi reagent.
  • the cells can be used for purposes such as gene function research, disease model research, or drug screening.
  • the cells do not develop into an animal individual.
  • the cells may be microbial cells or animal cells, but the animal cells are not animal embryonic stem cells or cells at various stages of formation and development (e.g., germ cells, fertilized egg cells, etc.).
  • the present invention also provides a pharmaceutical composition comprising the aforementioned RNAi reagent.
  • the pharmaceutical composition can be prepared using conventional methods from the RNAi reagent and the pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be an injection solution.
  • the injection solution can be used for subcutaneous, intramuscular, or intravenous injection.
  • the content of pharmaceutically acceptable carrier can be 1-100,000 parts by weight relative to 1 part by weight of the RNAi reagent (e.g., 1 part by weight, 5 parts by weight, 10 parts by weight, 50 parts by weight, 100 parts by weight, 500 parts by weight, 1,000 parts by weight, 5,000 parts by weight, 10,000 parts by weight, 50,000 parts by weight, 100,000 parts by weight, or any value between any two of the above).
  • the pharmaceutically acceptable carrier may be any of the carriers conventionally used in the art, for example, it may include at least one of a pH buffer, a protective agent, and an osmotic pressure regulator.
  • the pH buffer may be a tris(hydroxymethyl)aminomethane hydrochloride buffer with a pH of 7.5-8.5 and/or a phosphate buffer with a pH of 5.5-8.5, preferably a phosphate buffer with a pH of 5.5-8.5.
  • the protective agent may be at least one of inositol, sorbitol, and sucrose.
  • the content of the protective agent may be 0.01-30% by weight (e.g., 0.01% by weight, 0.05% by weight, 0.1% by weight, 0.5% by weight, 1% by weight, 5% by weight, 10% by weight, 15% by weight, 20% by weight, 25% by weight, 30% by weight, or any value between any two of the above).
  • the osmotic pressure regulator may be sodium chloride and/or potassium chloride.
  • the content of the osmotic pressure regulator is such that the osmotic pressure of the pharmaceutical composition is 200-700 milliohms/kg.
  • the content of the osmotic pressure regulator can be determined by those skilled in the art based on the desired osmotic pressure.
  • the pharmaceutically acceptable carrier is a liposome.
  • the liposome can be any type of liposome capable of encapsulating nucleic acids, and its diameter can be 25-1000 nm, including but not limited to cholesterol and its analogues or derivatives.
  • the dosage of the pharmaceutical composition described in this invention can be a conventional dosage in the art, which can be determined based on various parameters, particularly the age, weight, and sex of the subject. For example, for female mice aged 3-4 months and weighing 25-30g, the dosage of the pharmaceutical composition can be 0.01-100 mg/kg body weight, preferably 1-10 mg/kg body weight, based on the amount of the RNAi reagent in the pharmaceutical composition.
  • the present invention also provides a method for inhibiting the expression of C3 complement in cells, the method comprising: contacting the cells with the RNAi reagent or the pharmaceutical composition to inhibit the expression of C3 complement in the cells.
  • the cells are in a subject, for example, a human subject, such as a subject with C3 complement-related disease, or a subject who needs to prevent the risk of C3 complement-related disease.
  • the cells are located in vitro.
  • the method is based on research purposes or is used to construct animal models.
  • contacting the cells with the nucleic acid inhibits C3 complement expression by at least 50%, 60%, 70%, 80%, 90%, or 95% (e.g., compared to C3 complement expression levels prior to the cells' first contact with the nucleic acid; e.g., before administering a first dose of the nucleic acid to the subject).
  • inhibiting C3 complement expression reduces C3 complement protein levels in the subject's serum sample by at least 50%, 60%, 70%, 80%, 90%, or 95%, e.g., compared to C3 complement expression levels prior to the cells' first contact with the nucleic acid.
  • the present invention also provides the use of the RNAi reagent or the pharmaceutical composition described herein in the treatment and/or prevention of diseases related to C3 complement.
  • the present invention also provides the use of the RNAi reagent or the pharmaceutical composition described herein in the preparation of medicaments for the treatment and/or prevention of diseases related to C3 complement.
  • the disease is: (i) a disease associated with enhanced or elevated C3 complement; or (ii) a disease that would benefit from reduced C3 complement expression.
  • the disease is selected from one or more of the following: paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, hereditary angioedema (HAE), multiple sclerosis, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjogren's syndrome, membranoproliferative glomerulonephritis (MPGN), IgA nephropathy (IgAN), primary membranous nephropathy (primary MN), C3 glomerulonephropathy (C3G), acute tubular necrosis (ATN), focal segmental glomerulosclerosis (FSGS), diabetic nephropathy (DN), neuromyelitis optica (NMO), age-related macular degeneration (AMD), Guillain-Barré syndrome, multifocal motor neuropathy, and generalized
  • PNH
  • the subject can be a mammal, including primates (such as humans, non-human primates such as monkeys and chimpanzees), non-primates (such as cattle, pigs, horses, goats, rabbits, sheep, hamsters, guinea pigs, cats, dogs, rats, or mice), or birds.
  • primates such as humans, non-human primates such as monkeys and chimpanzees
  • non-primates such as cattle, pigs, horses, goats, rabbits, sheep, hamsters, guinea pigs, cats, dogs, rats, or mice
  • the subject is preferably a primate, and more preferably a human.
  • the medication can be administered via multiple routes, depending on whether local or systemic treatment is required. Dosage can be referenced as described above and will not be repeated here.
  • administration can be local (e.g., percutaneous patch), pulmonary, such as by inhalation or blowing of powder or spray, including via nebulizer; intratracheal, nasal, epidermal, and percutaneous, oral or parenteral.
  • Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; subcutaneous, such as via a transplant device; or intracranial, such as via intraparenchymal, intrathecal or intracardiac administration.
  • the RNAi reagent or the pharmaceutical composition is administered to the subject via subcutaneous, intravenous, and/or intramuscular administration.
  • the measurement parameters involving raw material components may have slight deviations within the weighing accuracy range unless otherwise specified. Temperature and time parameters are subject to acceptable deviations due to instrument testing accuracy or operational precision.
  • RNAiMAX 1.5 ⁇ L/well
  • siRNA small interfering nucleic acid
  • RNA was extracted from cell culture supernatant, wash with PBS, aspirate again, add 50 ⁇ L of prepared lysis buffer (as recommended by the Cells-to-CT kit (ThermoFisher Scientific, Cat#4391851c)), mix well, incubate for 10 min, and then add 2.5 ⁇ L of stop solution to terminate the reaction for 2 min.
  • RT-PCR was performed according to the recommendations of the High Capacity cDNA Reverse Transcription Kits (Thermo Fisher, catalog number: 4368814), with each reaction containing 10 ⁇ L of lysed liquid. Gene expression was quantified using real-time fluorescence PCR.
  • the TaqMan probe for human C3 was Hs00163811_m1, and the probe for the internal control gene (human HPRT1) was Hs02800695_m1 (Thermo Fisher Scientific, Waltham, MA, USA). PCR conditions were 95°C for 20 seconds per cycle, followed by 40 cycles of 95°C for 1 second and 60°C for 20 seconds.
  • the real-time fluorescence PCR system used was the QuantStudio TM 6 Pro real-time fluorescence quantitative PCR system (Thermo Fisher).
  • C3 gene expression was calculated as 2 ⁇ - ⁇ Ct, with human HPRT1 gene expression used as an internal control. C3 gene expression levels were expressed as a percentage relative to the control group (RNAiMAX only). Results are shown in Table 4 below.
  • Example 1 The siRNA obtained in Example 1 was further diluted and validated in Hep3B cells as described above. The inhibitory effect of siRNA on C3 gene expression was expressed as a percentage relative to the control group containing only RNAiMAX. The results are shown in Table 5 below.
  • the 3' end of the positive strand of the siRNA selected in Example 2 was coupled with Tri-GalNAc (the structure of which is shown in Formula I), and subcutaneously injected into human C3 transgenic mice (Shanghai Southern Model Biotechnology Co., Ltd.). Blood samples were collected on day 14, and the plasma level of human C3 protein was measured using an ELISA kit (Abcam, ab108823). PBS was used as a control group in this experiment. The results are shown in Figure 1.
  • cell culture medium DMEM, 10% fetal bovine serum, 1% penicillin + streptomycin solution
  • Hep3B Procell, Cat#CL-0102
  • RNAiMAX 1.5 ⁇ L/well
  • siRNA small interfering nucleic acids
  • RNA was aspirated, washed with PBS, and then 50 ⁇ L of prepared lysis buffer (as recommended by the Cells-to-CT kit (Thermo Fisher Scientific, Cat#4391851c)) was added and mixed. After standing for 10 min, 2.5 ⁇ L of stop solution was added to terminate the reaction for 2 min.
  • RT-PCR was performed according to the recommendations of the High Capacity cDNA Reverse Transcription Kits (Thermo Fisher, catalog number: 4368814), with each reaction containing 10 ⁇ L of lysed liquid. Gene expression was quantified using real-time fluorescence PCR.
  • the TaqMan probe for human C3 was Hs00163811_m1, and the probe for the internal control gene (human HPRT1) was Hs02800695_m1 (Thermo Fisher Scientific, Waltham, MA, USA). PCR conditions were 95°C for 20 seconds per cycle, followed by 40 cycles of 95°C for 1 second and 60°C for 20 seconds.
  • the real-time PCR instrument used was the QuantStudio TM 6 Pro real-time quantitative PCR system (Thermo Fisher).
  • C3 gene expression was calculated as 2 ⁇ - ⁇ Ct, with human HPRT1 gene expression used as an internal control.
  • C3 gene expression levels were expressed as a percentage relative to the control group (RNAiMAX only), and the IC50 value was calculated using Prism GraphPad. The results are shown in Table 8.

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Abstract

L'invention concerne un réactif d'ARNi ciblant le complément C3 et son utilisation. Le réactif d'ARNi peut inhiber efficacement l'expression du complément C3 dans les cellules, et peut ainsi être utilisé pour traiter des maladies liées au complément C3.
PCT/CN2025/113754 2024-08-16 2025-08-11 Réactif d'arni ciblant le complément c3 et son utilisation Pending WO2026037221A1 (fr)

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