WO2024253741A1 - Nanoparticules lipidiques chargées d'arn - Google Patents

Nanoparticules lipidiques chargées d'arn Download PDF

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WO2024253741A1
WO2024253741A1 PCT/US2024/023210 US2024023210W WO2024253741A1 WO 2024253741 A1 WO2024253741 A1 WO 2024253741A1 US 2024023210 W US2024023210 W US 2024023210W WO 2024253741 A1 WO2024253741 A1 WO 2024253741A1
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Darrell Irvine
Byungji KIM
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Massachusetts Institute of Technology
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    • 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
    • C12N15/1138—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 receptors or cell surface proteins
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    • A61K2039/55511—Organic adjuvants
    • A61K2039/55555—Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
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    • A61K2039/575—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 humoral response
    • A—HUMAN NECESSITIES
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]
    • C—CHEMISTRY; METALLURGY
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/323—Chemical structure of the sugar modified ring structure
    • C12N2310/3231—Chemical structure of the sugar modified ring structure having an additional ring, e.g. LNA, ENA
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    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • MBHB 23-0811-WO MIT 24973H RNA-Loaded Lipid Nanoparticles Federal Funding Statement This invention was made with government support under EB025854, CA265706, and AI144462 awarded by the National Institutes of Health. The government has certain rights in the invention. Sequence Listing Statement A computer readable form of the Sequence Listing is filed with this application by electronic submission and is incorporated into this application by reference in its entirety. The Sequence Listing is contained in the file created on March 13, 2024 having the file name “23- 0811-WO.xml” and is 122,127 bytes in size. Background RNA vaccines have emerged as a breakthrough technology in the COVID-19 pandemic.
  • repRNA self-replicating RNA
  • nsP non- structural protein
  • the segment also allows the repRNA construct to be recognized as a viral infection via activation of toll-like receptor-7 (TLR7)-induced response.
  • TLR7 toll-like receptor-7
  • compositions comprising: (a) a lipid nanoparticle (LNP); (b) a self-replicating RNA encoding a gene of interest loaded within the LNP; and (c) an inhibitory nucleic acid targeting IFN- ⁇ / ⁇ receptor 1(Ifnar1) gene loaded within the LNP.
  • the inhibitory nucleic acid comprises a short interfering RNA (siRNA).
  • the inhibitory nucleic acid targets a region of the Ifnar1 gene comprising the nucleotide sequence selected from SEQ ID NO:1-4, 83, and 89.
  • the inhibitory nucleic acid targets a region of the Ifnar1 gene comprising the nucleotide sequence selected from SEQ ID NO:1-24 and 83-95.
  • the inhibitory nucleic acid comprises a double stranded siRNA sequence comprising the nucleotide sequence of a pair of sequences selected from the following pairs: (a) sense (5'-->3'): GUU GAU CCG UUU AUU CCA UU (SEQ ID NO:25) and anti-sense (5'-->3'): AAU GGA AUA AAC GGA UCA AC (SEQ ID NO:26) (IFNAR1.1 mouse minimal sequence); (b) sense (5'-->3'): GUA GAA GUA AAG CAC GCG CC (SEQ ID NO:27) and anti-sense (5'-->3'): GGC GCG UGC UUU ACU UCU AC (SEQ ID NO:28) (IFNAR1.2 mouse minimal sequence); (c) sense (5'-->3'):
  • the 5’ end of the sequences are phosphorylated.
  • the nucleic acids comprise a two nucleotide single stranded overhang at the 3’ terminus.
  • the two nucleotide single stranded overhang at the 3’ terminus comprises dTdT.
  • the inhibitory nucleic acid comprises a double stranded siRNA sequence comprising the nucleotide sequence of a pair of sequences selected from the following pairs: (a) sense (5'-->3'): GUU GAU CCG UUU AUU CCA UUC dTdT (SEQ ID NO: 72) and anti-sense (5'-->3'): GAA UGG AAU AAA CGG AUC AAC dTdT (SEQ ID NO:73) (IFNAR1.1 mouse 21 nt sequence with overhang); (b) sense (5'-->3'): GUA GAA GUA AAG CAC GCG CCU dTdT (SEQ ID NO:74) and anti-sense (5'-->3'): AGG CGC GUG CUU UAC UUC UAC dTdT (SEQ ID NO:75); (IFNAR1.2 mouse 21 nt sequence with overhang); (c) sense (5'-->3'): CAA AGC UCA G
  • the 5’ end of the siRNA is phosphorylated, and the 3’ end is hydroxylated.
  • the siRNA comprises one or more locked nucleic acids (LNA).
  • the gene of interest encodes an antigen, including but not limited to an immunogenic portion of a viral, bacterial, parasitic, protozoan, fungal, or tumor antigen.
  • the antigen comprises a human immunodeficiency virus (HIV) or a severe acute respiratory syndrome (SARS) antigen.
  • HIV human immunodeficiency virus
  • SARS severe acute respiratory syndrome
  • the LNP comprises an ionizable lipid, a helper lipid, cholesterol, and a polymer-conjugated lipid.
  • the helper lipid comprises phosphocholines, phosphoethanolamines, or combinations thereof.
  • the polymer-conjugated lipid comprises polyethylene glycol or polysarcosine conjugated to phosphoethanolamines, 1,2-dimyristoyl-rac-glycero, or other amphiphilic molecules.
  • the amine-to-phosphate (N:P) ratio in the LNP loaded with RNA ranges from about 1:1 to about 20:1. In another embodiment, the lipid-to-RNA volume ratio in the LNP may range from about 1:1 to about 1:20.
  • the LNP comprises (a) N1,N3,N5-tris(3-(didodecylamino)propyl)benzene-1,3,5-tricarboxamide (TT3), (b) (6Z,9Z,28Z,31Z)-Heptatriaconta-6,9,28,31-tetraen-19-yl 4- (dimethylamino) butanoate (DLin-MC3-DMA), (c) 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), (d) cholesterol, and (e) 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG- PEG2k);
  • the disclosure provides vaccines comprising a composition of the disclosure where the gene of interest encodes an antigen.
  • the disclosure also provides methods for generating an immune response against an antigen, comprising administering to a subject an amount effective to generate an immune response in the subject of the composition or vaccine of any embodiment herein where the gene of interest encodes an antigen.
  • the methods comprise of treating an infection or limiting development of an infection in a subject in need thereof comprising administering to the subject the composition or vaccine of any embodiment herein where the gene of interest encodes an antigen in an effective amount to induce an immune response against the antigen.
  • the antigen comprises an HIV antigen, and the subject is at risk of, or has, an HIV infection.
  • the antigen comprises a SARS-CoV-2 antigen, and the subject is at risk of, or has, an SARS-CoV-2 infection.
  • the subject may be any mammalian subject, including but not limited to a human subject.
  • Description of the Figures Figure 1. Self-replicating RNA (repRNA) and the type I interferon (IFN) pathway recognition of repRNA vaccines.
  • repRNA Self-replicating RNA
  • IFN type I interferon pathway recognition of repRNA vaccines.
  • ISGs Interferon-stimulated response element
  • ISGs inhibit replication inhibition and modulate immune response to viral infections. It may also suppress repRNA replication from lipid nanoparticle (LNP) vaccines (1).
  • LNP lipid nanoparticle
  • MYD88 triggering by endocytosed LNP vaccines may promote adjuvant responses, including early differentiation of follicular helper T (Tfh) cells (2).
  • Tfh follicular helper T
  • LNP-repRNA refers to LNPs loaded with repRNA encoding for either the HIV immunogen or a reporter protein
  • LNP-repRNA/siRNA refers to LNPs that load a combination of the repRNA and siRNA against Ifnar1 (two candidate siRNA sequences are tested, labeled as siIFNAR1.1.
  • LNP-repRNA + LNP-siRNA refers to a cocktail mixture of LNPs loaded with only the repRNA and LNPs loaded with only the siIFNAR1.2;
  • (b-c) Groups balb/c mice (n 3 animals/group averaged across a total of 6 legs/group) were injected i.m. in both the left and right gastrocnemius muscles with 1 ⁇ g replicon RNA in LNPs.
  • C2C12 mouse myoblasts were treated with PBS, LNPs loaded with repRNA encoding for GFP (repGFP), LNPs that co-load repGFP and siRNA against Ifnar1 (repGFP/siIFNAR1.1 and repGFP/siIFNAR1.2), LNPs that co-load repGFP and siRNA encoding scrambled of the sequence against Ifnar1 (repGFP/siScramble), or a mixture of LNPs loaded with only the repRNA and LNPs loaded with only the siIFNAR1.2.
  • repGFP repRNA encoding for GFP
  • repGFP/siIFNAR1.1 and repGFP/siIFNAR1.2 LNPs that co-load repGFP and siRNA encoding scrambled of the sequence against Ifnar1
  • repGFP/siScramble LNPs that co-load repGFP and siRNA encoding scrambled of the sequence against Ifnar
  • qRT-PCR Quantitative real-time polymerase chain reaction
  • Serum antibody responses were quantified by ELISA assay conducted on mouse sera collected from 0 to 112 days post-vaccination (f). **, p ⁇ 0.01; ***, p ⁇ 0.001; ****, p ⁇ 0.0001 by two-way ANOVA with Tukey’s post test.
  • Percentage of antigen-specific IgG out of total IgG secreted by bone-marrow plasma cells (h) and antigen-specific T cell (splenocyte) activity (i- j) were quantified by ELISpot: (i) a representative image of the ELISpot wells for each group; and (j) counted number of spots per 106 cells in response to overlapping peptides for the HIV immunogen.
  • compositions comprising: (a) a lipid nanoparticle (LNP); (b) a self-replicating RNA (repRNA) encoding a gene of interest loaded within the LNP; and (c) an inhibitory nucleic acid targeting IFN- ⁇ / ⁇ receptor 1(Ifnar1) gene loaded within the LNP.
  • LNP lipid nanoparticle
  • repRNA self-replicating RNA
  • compositions of the invention ⁇ silence IFN- ⁇ / ⁇ receptor 1 (Ifnar1) to suppress type 1 interferon response upon administration of the compositions, permitting higher levels and more prolonged expression of repRNAs, which could be effective for promoting humoral immunity to vaccine immunogens.
  • Replicon RNA repRNA
  • RepRNA vaccine encodes not only antigen genes but also the genes necessary for RNA replication.
  • RepRNA is self-replicative and can play the role of an adjuvant by itself, which elicits robust immunity.
  • the mouse and human Ifnar1 gene sequences are provided in Table 1 below.
  • the inhibitory nucleic acid may be any inhibitory nucleic acid that can serve to inhibit Ifnar1 expression, including but not limited to antisense nucleic acids and a short interfering RNA (siRNA).
  • the inhibitory nucleic acid targets a region of the Ifnar1 gene comprising the nucleotide sequence selected from SEQ ID NO:1-4.
  • gttgatccgt ttattccatt (SEQ ID NO:1) (IFNAR1.1 minimal sequence, mouse); gtagaagtaa agcacgcgcc (SEQ ID NO:2) (IFNAR1.2 minimal sequence, mouse); gtgctccaaa acagtctgga (SEQ ID NO:3) (IFNAR1.1 minimal sequence, human); tcatagatga caactttatc (SEQ ID NO:4) (IFNAR1.2 minimal sequence, human); tcatagatga caactttatc (SEQ ID NO:83) (IFNAR1.3 minimal sequence, human); and tgttcattca tcccgagaac (SEQ ID NO:89 (IFNAR1.4 minimal sequence, human).
  • the nucleic acid sequence of SEQ ID NO:1 is in exon 3 in the mouse Ifnar1 gene.
  • the nucleic acid sequence of SEQ ID NO:2 is in exon 11 or 12 in the mouse Ifnar1 gene.
  • the nucleic acid sequence of SEQ ID NO:3 is in exon3 or 4 in the human Ifnar1 gene.
  • the nucleic acid sequence of SEQ ID NO:4 is in exon 8 in the human Ifnar1 gene.
  • the nucleic acid sequence of SEQ ID NO:83 is in exon 2 in the human Ifnar1 gene.
  • the nucleic acid sequence of SEQ ID NO:89 is in exon 11 in the human Ifnar1 gene.
  • the inhibitory nucleic acid targets a region of the Ifnar1 gene comprising the nucleotide sequence selected from SEQ ID NO:1-24 and 83-95.
  • IFNAR1.1 (mouse) Exon 3 RefSeq: NM_010508.2
  • IFNAR1.2 (mouse) Exon 11 RefSeq: NM_010508.2
  • IFNAR1.1 (human) Exon 3 or 4 RefSeq: NP_000620.2; XP_005261021.1; XP_011527854.1- IFNAR1.2 (human) Exon 8 RefSeq: NP_000620.2; XP_005261021.1 ⁇
  • IFNAR1.3 (human) Exon 2 RefSeq: NM_000629.2, XM_005260964.2, XM_011529552.1 8 IFNAR1.4 (human) Exon 11 RefSeq: NM_000629.2; XM_00526096
  • siRNA is a class of double-stranded RNA at first non-coding RNA molecules, typically 20-25 base pairs in length, similar to miRNA, and operating within the RNA interference (RNAi) pathway. It interferes with the expression of specific genes with complementary nucleotide sequences by degrading mRNA after transcription, preventing translation.
  • siRNAs have a well-defined structure that is a short (usually 20 to 25-bp) double- stranded RNA (dsRNA), and may have phosphorylated 5' ends and hydroxylated 3' ends with two overhanging nucleotides.
  • the inhibitory nucleic acid comprises a double stranded siRNA sequence comprising the nucleotide sequence of a pair of sequences selected from the following pairs: (a) sense (5'-->3'): GUU GAU CCG UUU AUU CCA UU (SEQ ID NO:25) and anti-sense (5'-->3'): AAU GGA AUA AAC GGA UCA AC (SEQ ID NO:26) (IFNAR1.1 mouse minimal sequence); (b) sense (5'-->3'): GUA GAA GUA AAG CAC GCG CC (SEQ ID NO:27) and anti-sense (5'-->3'): GGC GCG UGC UUU ACU UCU AC (SEQ ID NO:28) (IFNAR1.2 mouse minimal sequence); (c) sense (5'-->3'): CAA AGC UCA GAU UGG UCC UC (SEQ ID NO:29) and anti-sense (5'-->3'): anti-sense (5
  • the inhibitory nucleic acid comprises a double stranded siRNA sequence comprising the nucleotide sequence of a pair of sequences selected from the following pairs: (a) sense (5'-->3'): GUU GAU CCG UUU AUU CCA UU (SEQ ID NO:25) and anti-sense (5'-->3'): AAU GGA AUA AAC GGA UCA AC (SEQ ID NO:26) (IFNAR1.1 mouse minimal sequence); (b) sense (5'-->3'): GUA GAA GUA AAG CAC GCG CC (SEQ ID NO:27) and anti-sense (5'-->3'): GGC GCG UGC UUU ACU UCU AC (SEQ ID NO:28) (IFNAR1.2 mouse minimal sequence); (c) sense (5'-->3'): CAA AGC UCA GAU UGG UCC UC (SEQ ID NO:29) and anti-sense (5'-->3'): anti-sense
  • the 5’ end of the sequences are phosphorylated.
  • the nucleic acids comprise a two nucleotide single stranded overhang at the 3’ terminus.
  • the two nucleotide single stranded overhang at the 3’ terminus comprises dTdT.
  • the two nucleotide single stranded overhang at the 3’ terminus may comprise UU, or may be complementary to the target mRNA.
  • the inhibitory nucleic acid comprises a double stranded siRNA sequence comprising the nucleotide sequence of a pair of sequences selected from the following pairs: (a) sense (5'-->3'): GUU GAU CCG UUU AUU CCA UUC dTdT (SEQ ID NO: 72) and anti-sense (5'-->3'): GAA UGG AAU AAA CGG AUC AAC dTdT (SEQ ID NO:73) (IFNAR1.1 mouse 21 nt sequence with overhang); (b) sense (5'-->3'): GUA GAA GUA AAG CAC GCG CCU dTdT (SEQ ID NO:74) and anti-sense (5'-->3'): AGG CGC GUG CUU UAC UUC UAC dTdT (SEQ ID NO:75); (IFNAR1.2 mouse 21 nt sequence with overhang); (c) sense (5'-->3'): CAA AGC UCA G
  • the 5’ end of the siRNA strands may be phosphorylated. In other embodiments, the 5’ end of the siRNA strands are not phosphorylated. In another embodiment, the 3’ end of the siRNA strands are hydroxylated; in other embodiments they are not hydroxylated. In one embodiment, the 5’ end of the siRNA strands are phosphorylated and the 3’ end of the siRNA strands are hydroxylated.
  • the siRNAs may comprise chemically modified residues to enhance stability or other beneficial characteristics.
  • Modifications may include, for example, end modifications, e.g., 5 ⁇ -end modifications (phosphorylation, conjugation, inverted linkages) or 3 ⁇ -end modifications (conjugation, DNA nucleotides, inverted linkages, etc.); sugar modifications (e.g., at the 2 ⁇ -position or 4 ⁇ -position) or replacement of the sugar; and/or backbone modifications, including modification or replacement of the phosphodiester linkages.
  • the siRNA may be modified to comprise one or more locked nucleic acids (LNA).
  • LNA locked nucleic acids
  • a locked nucleic acid is a nucleotide having a modified ribose moiety in which the ribose moiety comprises an extra bridge connecting the 2 ⁇ and 4 ⁇ carbons.
  • the repRNA may encode any gene of interest, including but not limited to a gene encoding a therapeutic protein, antigen, immunogen, reporter protein, cytokine, etc.
  • the gene of interest encodes an antigen.
  • the antigen may be any antigen suitable for an intended purpose.
  • the antigen comprises an immunogenic portion of a viral, bacterial, parasitic, protozoan, fungal, or tumor antigen.
  • viruses comprising suitable antigens include, but are not limited to, e.g., respiratory syncytial virus (RSV), hepatitis B virus (HBV), hepatitis C virus (HCV), Dengue virus, herpes simplex virus (HSV; e.g., HSV-I, HSV-II), molluscum contagiosum virus, vaccinia virus, variola virus, lentivirus, human immunodeficiency virus (HIV), human papilloma virus (HPV), cytomegalovirus (CMV), varicella zoster virus (VZV), rhinovirus, enterovirus, adenovirus, coronavirus (e.g., SARS), influenza virus (flu), para-influenza virus, mumps virus, measles virus, papovavirus, hepadnavirus, flavivirus, retrovirus, arenavirus (e.g., Lymphocytic Choriomeningitis Virus, Junin virus,
  • the antigen can be CMV glycoprotein gH, or gL; Parvovirus; HIV glycoprotein gp120 or gp140, HIV p55 gag, pol; or RSV-F antigen.
  • the antigen is a viral antigen.
  • the viral antigen is an HIV antigen comprising gp120 or gp140.
  • engineered HIV antigen is an engineered variant of gp120 (engineered Outer Domain, eOD).
  • the engineered HIV antigen is an engineered variant of gp140 (SOSIP).
  • the antigen is from a parasite.
  • the antigen is derived from a species from within the Plasmodium genus, such as P. falciparum, P. vivax, P. malariae or P. ovale.
  • the immunogenic composition may be used for preparation of a vaccine for immunizing against malaria.
  • the antigen is from a bacterial pathogen.
  • Exemplary bacterial pathogens include, e.g., Neisseria spp, including N. gonorrhea and N. meningitides; Streptococcus spp, including S. pneumoniae, S. pyogenes, S. agalactiae, S. mutans; Haemophilus spp, including H. influenzae type B, non typeable H. influenzae, H. ducreyi; Moraxella spp, including M. catarrhalis, also known as Branhamella catarrhalis; Bordetella spp, including B. pertussis, B. parapertussis and B. bronchiseptica; Mycobacterium spp., including M.
  • Neisseria spp including N. gonorrhea and N. meningitides
  • Streptococcus spp including S. pneumoniae, S. pyogenes, S. agalactiae, S. mutans
  • tuberculosis M. bovis, M. leprae, M. avium, M. paratuberculosis, M. smegmatis; Legionella spp, including L. pneumophila; Escherichia spp, including enterotoxic E. coli, enterohemorragic E. coli, enteropathogenic E. coli; Vibrio spp, including V. cholera, Shigella spp, including S. sonnei, S. dysenteriae, S. flexnerii; Yersinia spp, including Y. enterocolitica, Y. pestis, Y. pseudotuberculosis, Campylobacter spp, including C. jejuni and C.
  • Salmonella spp including S. typhi, S. paratyphi, S. choleraesuis, S. enteritidis; Listeria spp., including L. monocytogenes; Helicobacter spp, including H pylori; Pseudomonas spp, including P. aeruginosa, Staphylococcus spp., including S. aureus, S. epidermidis; Enterococcus spp., including E. faecalis, E. faecium; Clostridium spp., including C. tetani, C. botulinum, C. difficile; Bacillus spp., including B.
  • Corynebacterium spp. including C. diphtheriae; Borrelia spp., including B. burgdorferi, B. garinii, B. afzelii, B. andersonii, B. hermsii; Ehrlichia spp., including E. equi and the agent of the Human Granulocytic Ehrlichiosis; Rickettsia spp, including R. rickettsii; Chlamydia spp., including C. trachomatis, C. neumoniae, C. psittaci; Leptsira spp., including L.
  • the antigen is from a fungal pathogen.
  • fungal pathogens include, e.g., Aspergillus fumigatus, A. flavus, A. niger, A. terreus, A. nidulans, Coccidioides immitis, Coccidioides posadasii, Cryptococcus neoformans, Histoplasma capsulatum, Candida albicans, and Pneumocystis jirovecii.
  • the antigen is from a protozoan pathogen.
  • Exemplary protozoan pathogens include, e.g., Toxoplasma gondii and Strongyloides stercoralis.
  • the antigen is from a multicellular parasitic pathogen.
  • Exemplary multicellular parasitic pathogens include, e.g., trematodes (flukes), cestodes (tapeworms), nematodes (roundworms), and arthropods.
  • the antigen is derived from a tumor antigen selected from: (a) cancer-testis antigens such as NY-ESO-1, SSX2, SCP1 as well as RAGE, BAGE, GAGE and MAGE family polypeptides, for example, GAGE-1, GAGE-2, MAGE-1, MAGE-2, MAGE- 3, MAGE-4, MAGE-5, MAGE-6, and MAGE-12 (which can be used, for example, to address melanoma, lung, head and neck, NSCLC, breast, gastrointestinal, and bladder tumors; (b) mutated antigens, for example, p53 (associated with various solid tumors, e.g., colorectal, lung, head and neck cancer), p21/Ras (associated with, e.g., melanoma, pancreatic cancer and colorectal cancer), CDK4 (associated with, e.g., melanoma), MUM1 (associated with, e.g., melanoma),
  • tumor immunogens include, but are not limited to, p15, Hom/Mel-40, H-Ras, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Epstein Barr virus antigens, EBNA, human papillomavirus (HPV) antigens, including E6 and E7, hepatitis B and C virus antigens, human T-cell lymphotropic virus antigens, TSP-180, p185erbB2, p180erbB-3, c-met, mn- 23H1, TAG-72-4, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras, p16, TAGE, PSCA, CT7, 43-9F, 5T4, 791 Tgp72, beta-HCG, BCA225, BTAA, CA 125, CA 15-3 (CA 27.29 ⁇ BCAA), CA 195, CA 242, CA-50, CAM43, CD68 ⁇ KP1,
  • the antigen comprises a human immunodeficiency virus (HIV) or a severe acute respiratory syndrome (SARS) antigen.
  • the compositions may comprise any lipid nanoparticle (LNP).
  • the LNP comprises an ionizable lipid, a helper lipid, cholesterol, and a polymer-conjugated lipid.
  • helper lipid may comprise, for example phosphocholines, phosphoethanolamines, or combinations thereof.
  • the polymer- conjugated lipid may comprise, for example, polyethylene glycol or polysarcosine conjugated to phosphoethanolamines, 1,2-dimyristoyl-rac-glycero, or other amphiphilic or lipid-like molecules.
  • the amine-to-phosphate (N:P) ratio in the LNP loaded with RNA may range from about 1:1 to about 20:1.
  • the lipid-to-RNA volume ratio in the LNP may range from about 1:1 to about 1:20 (i.e., the ratio between the volume of lipids (all components mixed at predetermined molar ratio) in ethanol, and the volume of the RNA (repRNA + siRNA) in water or acidic buffer).
  • the LNP comprises (a) N1,N3,N5-tris(3-(didodecylamino)propyl)benzene-1,3,5-tricarboxamide (TT3), (b) (6Z,9Z,28Z,31Z)-Heptatriaconta-6,9,28,31-tetraen-19-yl 4- (dimethylamino) butanoate (DLin-MC3-DMA), (c) 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), (d) cholesterol, and (e) 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG- PEG2k); In one exemplary embodiment, the molar ratio of LNP components is about 10 (TT3):25 (DLin-MC3-DMA):20 (DOPE):40 (cholesterol):5(DMG-PEG2k).
  • compositions may comprise any other components as appropriate for an intended purpose.
  • the composition may further comprise an adjuvant.
  • adjuvant refers to any substance that acts to augment and/or direct antigen-specific immune responses when used in combination with specific antigens. When combined with a vaccine antigen, adjuvant increases the immune response to the vaccine antigen as compared to the response induced by the vaccine antigen alone. Adjuvants help drive immunological mechanisms and shape the output immune response to vaccine antigens.
  • Exemplary antigens that might be used with the compositions of the disclosure may comprise aluminum salts (“alum”; aluminum hydroxide, aluminum phosphate), “Adjuvant System 04” (AS04), trehalose-6,6’-dimycolate (TDM), muramyl dipeptide (MDP), pluronic block copolymers, alum solution, aluminum hydroxide, ADJUMER® (polyphosphazene); aluminum phosphate gel; glucans from algae; algammulin; aluminum hydroxide gel (alum); highly protein-adsorbing aluminum hydroxide gel; low viscosity aluminum hydroxide gel; AF or SPT (emulsion of squalane (5%), Tween 80 (0.2%), Pluronic L121 (1.25%), phosphate-buffered saline, pH 7.4); AVRIDINETM (propanediamine); BAY R1005TM ((N-(2-deoxy-2-L-leucylamino-b-D-glucopy
  • MPLTM (3-Q-desacyl-4 ⁇ -monophosphoryl lipid A); MTP-PE and MTP-PE liposomes ((N-acetyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(1,2- dipalmitoyl-sn-glycero-3-(hydroxyphosphoryloxy))-ethylamide, monosodium salt); MURAMETIDETM (Nac-Mur-L-Ala-D-GCn-OCH3); MURAPALMITINETM and D- MURAPALMITINETM (Nac-Mur-L-Thr-D-isoCln-sn-g
  • the gene of interest encodes an antigen
  • the compositions may comprise vaccines.
  • the disclosure provides pharmaceutical compositions comprising the composition or vaccine of any embodiment herein and a pharmaceutically acceptable carrier.
  • the disclosure further comprises methods for generating an immune response against an antigen, comprising administering to a subject an amount effective to generate an immune response in the subject of the composition or vaccine of any embodiment herein, wherein the gene of interest encodes an antigen.
  • the disclosure also provides methods of treating an infection or limiting development of an infection comprising administering to a subject in need thereof the composition or vaccine of any embodiment herein in an effective amount to induce an immune response against the antigen.
  • the antigen comprises an HIV antigen, and the subject is at risk of, or has, an HIV infection.
  • the antigen comprises a SARS-CoV-2 antigen
  • the subject is at risk of, or has, an SARS-CoV-2 infection.
  • limiting development includes, but is not limited to accomplishing one or more of the following: (a) generating an immune response (antibody and/or cell-based) HIV or SARS- CoV-2 in the subject; (b) generating neutralizing antibodies against HIV or SARS- CoV-2 in the subject (b) limiting build-up of HIV or SARS- CoV-2 titer in the subject after exposure to HIV or SARS- CoV-2; and/or (c) limiting or preventing development of HIV or SARS- CoV-2 symptoms after infection.
  • Exemplary symptoms of HIV infection include, but are not limited to, fever, fatigue, swollen lymph nodes, diarrhea, weight loss, oral yeast infection, shingles, and/or pneumonia.
  • Exemplary symptoms of SARS-CoV-2 infection include, but are not limited to, fever, fatigue, cough, shortness of breath, chest pressure and/or pain, loss or diminution of the sense of smell, loss or diminution of the sense of taste, and respiratory issues including but not limited to pneumonia, bronchitis, severe acute respiratory syndrome (SARS), and upper and lower respiratory tract infections.
  • “treat” or “treating” includes, but is not limited to accomplishing one or more of the following: (a) reducing HIV titer in the subject; (b) limiting any increase of HIV titer in the subject; (c) reducing the severity of HIV symptoms; (d) limiting or preventing development of HIV symptoms after infection; (e) inhibiting worsening of HIV symptoms; (f) limiting or preventing recurrence of HIV symptoms in subjects that were previously symptomatic for HIV infection; and/or (e) improving survival.
  • acceptable formulation materials preferably are nontoxic to recipients at the dosages and concentrations employed.
  • the formulation material(s) are for s.c. and/or I.V. administration.
  • the pharmaceutical composition can contain formulation materials for modifying, maintaining or preserving, for example, the pH, osmolality, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition.
  • suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine or lysine); antimicrobials; antioxidants (such as ascorbic acid, sodium sulfite or sodium hydrogen- sulfite); buffers (such as borate, bicarbonate, Tris-HCl, citrates, phosphates or other organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediamine tetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin or hydroxypropyl-beta- cyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (such as glucose, mannose or dextrins); proteins (such as serum albumin, gelatin or immunoglobulins); coloring, flavoring and diluting agents; emulsifying amino acids (such
  • the formulation comprises PBS; 20 mM NaOAC, pH 5.2, 50 mM NaCl; and/or 10 mM NAOAC, pH 5.2, 9% Sucrose.
  • the optimal pharmaceutical composition will be determined by one skilled in the art depending upon, for example, the intended route of administration, delivery format and desired dosage. See, for example, Remington's Pharmaceutical Sciences, supra. In some embodiments, such compositions may influence the physical state, stability, rate of in vivo release and rate of in vivo clearance of the immunogenic composition.
  • the subject may be any mammalian subject that may benefit from the methods of the disclosure, including but not limited to humans, dogs, cats, horses, cattle, chickens, goats, etc.
  • Table 1 Examples RNA vaccines have emerged as a breakthrough technology in the COVID-19 pandemic.
  • An advancement on this technology uses self-replicating RNA (repRNA) in lieu of mRNAs.
  • repRNA self-replicating RNA
  • repRNA has the potential for much more prolonged expression, which could be effective for promoting humoral immunity to vaccine immunogens.
  • repRNA self-replicating RNA
  • IFN type 1 interferon
  • This recognition machinery is particularly important to study for repRNAs, because the repRNA is inherently based on the alphaviral RNA, in which the non-structural protein (nsP) segments of the back-bone enable replication of the gene of interest (Fig.1a).
  • the segment also allows the repRNA construct to be recognized as a viral infection via activation of toll-like receptor-7 (TLR7)-induced response.
  • TLR7 toll-like receptor-7
  • This innate immune recognition may hinder the response by inhibiting RNA replication and translation, or by overstimulating innate immunity (Fig.1b).
  • LNP-formulated repRNA vaccines Three lipid nanoparticle (LNP)-formulated repRNA vaccines are compared (Fig.2a): (1) a baseline LNP that loaded repRNA encoding for the antigen or a reporter; (2) an LNP that co-loads repRNA encoding for the antigen or a reporter and an siRNA against Ifnar1; and (3) a cocktail mix of LNPs, one loading repRNA encoding either an antigen or reporter, and the other loading the siRNA against Ifnar1.
  • a cocktail mix of LNPs one loading repRNA encoding either an antigen or reporter, and the other loading the siRNA against Ifnar1.
  • Lipid nanoparticles were synthesized using a microfluidic system mixing an organic phase of lipids in ethanol with aqueous phase repRNA in water to induce self- assembly of LNPs encapsulating the replicon (LNP-RNA).
  • LNPs were prepared using a 2:1 ratio of ionizable lipid amine groups to repRNA phosphates (equivalent to a 2.9:1 ionizable lipid:RNA mass ratio). The resulting particles were dialyzed into pH 7.4 phosphate-buffered saline (PBS).
  • PBS pH 7.4 phosphate-buffered saline
  • Our LNP formulation is composed of N 1 ,N 3 ,N 5 -tris(3- (didodecylamino)propyl)benzene-1,3,5-tricarboxamide (TT3), (6Z,9Z,28Z,31Z)- Heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino) butanoate (DLin-MC3-DMA), 1,2- dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), Cholesterol, and 1,2-dimyristoyl-rac- glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG2k) at a molar ratio of 10:25:20:40:5.
  • Fig.4a-c show the RNA expression levels in the muscle, where we found that LNPs loaded with only the repGFP triggered a strong Ifnar1 expression within 24h of injection, which rapidly decreased over the following week (Fig. 4a). Conversely, LNPs that were loaded with both repGFP and siINFAR1.1 or siIFNAR1.2, as well as the mixture co-treatment group, effectively silenced Ifnar1 expression for three days following injection, before a sudden recovery at day 7.
  • MCP-1 monocyte chemotactic protein-1
  • IP-10 interleukin-6
  • RANTES Regulated on Activation, Normal T-Cell Expressed and Secreted
  • siRNA co-delivery amplified trimer-binding GC B cells compared to all of the control groups (Fig.5c and e).
  • the siIFNAR1 co-loaded groups generated significantly more antigen-specific B cells that displayed higher mean fluorescence intensity to both antigen tetramers (Fig.5d and e), indicating that these B cells may have higher binding affinity.
  • ELISPOT analysis of trimer- specific and total IgG-producing cells was carried out on bone marrow plasma cells 6 weeks post vaccination; we compared the ratio between total IgG and HIV immunogen-specific IgG that was produced by the harvested bone-marrow plasma cells at week 6 post-vaccination. This analysis revealed a trend toward increased antigen-specific plasma cell responses elicited by co-delivery of siIFNAR1 with repRNA in the same LNPs (Fig.5h).
  • IFN- ⁇ -producing antigen-specific T cell responses in the spleen were also induced significantly more strongly by vaccines that were co-loaded with repAg and siIFNAR1 compared to the baseline repAg vaccine or with a scramble siRNA or the co-treatment group (Fig.5i and j).

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Abstract

L'invention concerne des compositions qui comprennent une nanoparticule lipidique (LNP); un ARN auto-répliquant codant pour un gène d'intérêt chargé à l'intérieur de la LNP; et un acide nucléique inhibiteur, tel qu'un petit ARN interférent (ARNsi) ciblant un gène de récepteur I de l'IFN-α/p (Ifharl) chargé dans le LNP temporel, et l'utilisation des compositions pour générer une réponse immunitaire.
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WO2016005704A1 (fr) 2014-07-09 2016-01-14 Mecachrome France Culasse, element et semelle de moteur a piston
US20160185825A1 (en) 2011-10-12 2016-06-30 University Of Washington, Center For Commercialization Engineered outer domain (eod) of hiv gp120 and mutants thereof
WO2022266415A1 (fr) * 2021-06-18 2022-12-22 Ionis Pharmaceuticals, Inc. Composés et méthodes pour réduire l'expression d'ifnar1

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US20160185825A1 (en) 2011-10-12 2016-06-30 University Of Washington, Center For Commercialization Engineered outer domain (eod) of hiv gp120 and mutants thereof
WO2016005704A1 (fr) 2014-07-09 2016-01-14 Mecachrome France Culasse, element et semelle de moteur a piston
WO2022266415A1 (fr) * 2021-06-18 2022-12-22 Ionis Pharmaceuticals, Inc. Composés et méthodes pour réduire l'expression d'ifnar1

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