WO2024141784A2 - Vaccins et compositions à protection large contre les bètacoronavirus - Google Patents

Vaccins et compositions à protection large contre les bètacoronavirus Download PDF

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WO2024141784A2
WO2024141784A2 PCT/IB2023/000780 IB2023000780W WO2024141784A2 WO 2024141784 A2 WO2024141784 A2 WO 2024141784A2 IB 2023000780 W IB2023000780 W IB 2023000780W WO 2024141784 A2 WO2024141784 A2 WO 2024141784A2
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mol
polypeptide
nucleic acid
rbd
multimer
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WO2024141784A3 (fr
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Tushar Ranjan MOHARANA
Soham Govindarajan SANKARAN
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Popvax Pvt Ltd
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Popvax Pvt Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/53—DNA (RNA) vaccination
    • 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
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/20011—Coronaviridae
    • C12N2770/20022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • 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
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/20011—Coronaviridae
    • C12N2770/20034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • each monomer of the RBD multimer is coupled to the adjacent monomer(s) of the RBD multimer by a linker.
  • each monomer of the fusion peptide multimer is coupled to the adjacent monomer(s) of the fusion peptide multimer by a linker.
  • each monomer of the stem helix multimer is coupled to the adjacent monomer(s) of the stem helix multimer by a linker.
  • a signal peptide is present on the amino-terminus of the polypeptide.
  • the RBD has an amino acid sequence of any one of SEQ ID NOs: 1-3 and 58-65.
  • a polypeptide comprising a receptor binding domain (RBD), a fusion peptide, or a stem helix or a combination thereof.
  • RBD receptor binding domain
  • the fusion peptide, or the stem helix is obtained or derived from a betacoronavirus.
  • the betacoronavirus is a human betacoronavirus.
  • the betacoronavirus is a SARS-CoV-1, a SARS-CoV-2, a MERS-CoV, a HKU1, or an OC43, a bat coronavirus, other betacoronavirus, or a combination thereof.
  • the polypeptide comprises a multimer of the receptor binding domains. In some embodiments, the polypeptide comprises a multimer of the fusion peptide. In some embodiments the polypeptide comprises a multimer of the stem helix. In some embodiments, the polypeptide comprises a multimer of the RBD and a multimer of the fusion peptide. In some embodiments, the polypeptide comprises a multimer of the RBD and a multimer of the stem helix. In some embodiments, the polypeptide comprises a multimer of the fusion peptide 2 FH11238404.3 Attorney Docket No.: PVM-00325 and a multimer of the stem helix. In some embodiments, the fusion peptide is engineered.
  • the polypeptide has an amino acid sequence of any one of SEQ ID NOs: 35-53 and 67.
  • a lipid nanoparticle composition comprising a cationic lipid, a phospholipid, a sterol, a PEG-lipid, and the nucleic acid described herein.
  • the cationic lipid comprises an ionizable lipid.
  • the ionizable lipid is present in an amount from 25 mol percent to 70 mol percent.
  • the phospholipid is present in an amount from 2 mol percent to about 30 mol percent.
  • the sterol is present in an amount from 30 mol percent to about 65 mol percent.
  • provided herein is a method of treating or preventing a disease, 3 FH11238404.3 Attorney Docket No.: PVM-00325 comprising administrating to a subject in need thereof the lipid nanoparticle composition described herein.
  • the nucleic acid described herein in the manufacture of a medicament for the treatment or prevention of a disease in a subject.
  • provided herein is use of a lipid nanoparticle composition described herein in the manufacture of a medicament for the treatment or prevention of a disease in a subject.
  • a method of treating or preventing a disease comprising administrating to a subject in need thereof the polypeptide described herein.
  • the nucleic acid sequence comprises a receptor binding domain (RBD) sequence, a fusion peptide (FP) sequence, or a stem helix (SH) sequence, or a combination thereof, derived or obtained from a betacoronavirus, including codon optimized sequences, fragments, mutants, or variants thereof.
  • the nucleic acid encodes a polypeptide comprising one or more receptor binding domain, one or more fusion peptide, one or more stem helix, or a combination thereof.
  • the nucleic acid sequence comprises multiple repeats or multimers of RBD sequence, fusion peptide sequence, stem helix sequence, or a combination thereof, not necessarily in the same order.
  • the nucleic acid sequence comprises multiple repeats of either RBD sequence, fusion peptide sequence or stem helix sequence, or a combination thereof.
  • the RBD sequence, fusion peptide sequence and the stem helix sequence are connected to the other by a linker sequence.
  • the stem helix is an engineered sequence.
  • the fusion peptide is an engineered sequence.
  • the nucleic acid sequence is a DNA or an RNA.
  • the nucleic acid sequence is an mRNA.
  • the RBD sequence encodes an RBD.
  • the fusion peptide sequence encodes a fusion peptide.
  • the polypeptide comprises multiple repeats or multimers of RBD, fusion peptide or stem helix, not necessarily in the same order.
  • the RBD, the fusion peptide, and the stem helix are connected to the other by a linker.
  • the polypeptide has a signal peptide at the N-terminal end of the polypeptide.
  • the fusion peptide is an engineered fusion peptide.
  • the stem helix is an engineered stem helix.
  • provided herein is a nucleic acid sequences described herein, encapsulated in a lipid nanoparticle composition.
  • the lipid nanoparticle composition comprises a cationic lipid, a phospholipid, a sterol, a PEG lipid and the nucleic acid sequence described herein.
  • the nucleic acid is obtained or derived from betacoronaviruses selected from the group comprising embecovirus, sarbecovirus, merbecovirus, nobecovirus and hibecovirus. In some embodiments, the nucleic acid is obtained or derived from a sarbecovirus, and a merbecovirus.
  • the nucleic acid is obtained or derived from a SARS-CoV-1, a SARS-CoV-2, a MERS-CoV, an OC43, a HKU1, a bat coronavirus, other betacoronavirus, or a combination thereof.
  • the polypeptides described herein are expressed recombinantly in an expression system, such as bacterium, yeast, insect, mammalian or other host cells.
  • the polypeptides described herein comprises one or more stabilizers, buffering agents, adjuvants, chelating agents, salts, anti-oxidants, diluents, tonicity modifiers, surfactants, preservatives or a combination thereof.
  • Figure 1 shows a western blot of cell lysate (lane 3) showing expression of polypeptide encoded by the nucleic acid sequence of example 1.
  • Lane 1 and lane 2 are protein ladder and negative control respectively.
  • 5 FH11238404.3 Attorney Docket No.: PVM-00325 DESCRIPTION Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of person skill in the art. Some of the terms are defined briefly here below; the definitions should not be construed in a limiting sense.
  • the singular forms “a”, “an” and “the” as used in the specification also include plural aspects unless the context dictates otherwise.
  • composition or “formulation” has been used interchangeably to mean a lipid nanoparticle composition comprising a nucleic acid sequence, and lipid components such as cationic lipid, phospholipid, sterol, and PEG-lipid.
  • the composition may optionally contain an ionizable polymer.
  • the composition may additionally contains pharmaceutical carriers or excipients, such as but not limited to, buffering agents, stabilizers, tonicity 6 FH11238404.3 Attorney Docket No.: PVM-00325 modifiers, surfactants, chelating agents, salts, anti-oxidants, diluents, and/or preservatives or combinations thereof.
  • the prevention of a condition includes, for example, the reduction of the frequency or severity of one or more symptoms of the medical condition in a population of patients receiving a therapy relative to a control population that did not receive the therapy, e.g., by a statistically and/or clinically significant amount.
  • the prevention of an infection includes reducing the likelihood that a patient receiving a therapy will develop the infection or related symptoms, relative to a patient who does not receive the therapy.
  • molar ratio “mol ratio”, “molar percent”, “mol percent”, “molar %”, or “mol %” have been used interchangeably to mean number of moles of a component expressed as percentage relative to total moles of all lipid components (such as cationic lipid, phospholipid, sterol and PEG-lipid) and, if present, ionizable polymer component(s) present in the lipid nanoparticle compositions described herein.
  • lipid components such as cationic lipid, phospholipid, sterol and PEG-lipid
  • 50 mol % of cationic lipid means, 50 mol % of cationic lipid is present in the lipid nanoparticle composition and other lipids components constitute the remaining 50% such that the total amount of all the lipid components together constitute 100 mol %.
  • 50 mol % of cationic lipid also means, 50 mol % of cationic lipid present in the lipid nanoparticle composition and other 7 FH11238404.3 Attorney Docket No.: PVM-00325 lipids components and ionizable polymer components together constitute the remaining 50 mol % such that the total amount of all the lipid components and ionizable polymer components constitute 100 mol %.
  • the terms “antibody” and “antibodies” have been used interchangeably herein and means any antibody or antibody fragment (whether produced naturally or recombinantly) which retains antigen binding activity.
  • buffer as used herein means those agents that maintains the pH of a solution in a desired range.
  • cell as used herein means a single cell or a population of cells or plurality of cells.
  • biologically effective amount or “therapeutically effective amount” as used herein means an amount of an agent, for example, a therapeutic, drug, therapeutic agent, prophylactic agent, diagnostic agent, composition, etc., that is sufficient, when administered to a subject suffering from or susceptible to an infection, disease, disorder, and/or condition, to treat, prevent, diagnose, improve symptoms of, and/or delay the onset of the infection, disease, disorder, and/or condition.
  • a therapeutically effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient.
  • treating includes reducing, arresting, or reversing the symptoms, clinical signs, or underlying pathology of a condition to stabilize or improve a subject's condition or to reduce the likelihood that the subject’s condition will worsen as much as if the subject did not receive the treatment.
  • Treatment may be administered to a subject who does not exhibit signs of a disease and/or exhibits only early signs of the disease for the purpose of decreasing the risk of developing pathology associated with the disease.
  • subject refers to a living mammal and may be interchangeably used with the term “patient”.
  • mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including 8 FH11238404.3 Attorney Docket No.: PVM-00325 rodents, such as rats, mice and guinea pigs, and the like. The term does not denote a particular age or gender.
  • Non limiting examples of disease include malignant diseases, autoimmune diseases, inherited diseases, metabolic disorders, or infectious diseases.
  • administration “conjointly” with another compound or composition includes simultaneous administration and/or administration at different times. Conjoint administration also encompasses administration as a co-formulation or administration as separate compositions, including at different dosing frequencies or intervals, and using the same route of administration or different routes of administration.
  • receptor binding domain (RBD) sequence as used herein means a sequence of nucleotides that encodes a receptor binding domain (RBD) of the betacoronavirus.
  • receptor binding domain or “RBD” have been used interchangeably and means either a full length S1 subunit of the spike protein or a fragment thereof of betacoronavirus, including mutant, derivative or variant thereof that retains the ability to interact with the host cell receptors.
  • the receptor binding domain interacts with angiotensin-converting enzyme 2 (ACE2) receptor, dipeptidyl peptidase 4 (DPP4) receptor, 9-O-acetylated sialic acid (9-O-Ac-Sia) receptor or a combination thereof.
  • ACE2 angiotensin-converting enzyme 2
  • DPP4 dipeptidyl peptidase 4
  • 9-O-acetylated sialic acid (9-O-Ac-Sia) receptor or a combination thereof.
  • the RBD also includes any fragments, mutants, derivatives or variants of the RBD.
  • fusion peptide sequence as used herein means a sequence of nucleotides that encodes a fusion peptide of the betacoronavirus. 9 FH11238404.3 Attorney Docket No.: PVM-00325
  • fusion peptide or “FP” have been used interchangeably and means a region spanning amino acids 810 to 909 of the SARS-CoV-2 spike protein (reference polypeptide sequence as described herein), including any other corresponding regions in other betacoronaviruses spike protein (for example, homologous region) that facilitates membrane fusion, and not necessarily starting at the same amino acid position in other betacoronaviruses.
  • the fusion peptide also includes any fragments, mutants, derivatives or variants of the fusion peptide.
  • stem helix sequence or “S2 stem helix sequence” or “SH” have been used interchangeably and means a sequence of nucleotides that encodes a stem helix of the betacoronavirus.
  • linker means a sequence of amino acids that connects RBD and fusion peptide, RBD and stem helix, fusion peptide and stem helix.
  • a linker may provide structural integrity to polypeptide such that the components of the polypeptide remain, as far as possible, in their native or stable conformation.
  • amino acid linker also helps in orientation of a polypeptide such that the domains or epitopes are exposed or displayed for interaction or communication with cells or biomolecules or immune system.
  • signal sequence as used herein means a sequence of nucleotides that encodes a signal peptide.
  • signal peptide as used herein means a sequence of amino acids that transports the polypeptide to specific cell organelles. In some embodiments the signal peptide transports the polypeptide to golgi apparatus or golgi body. The signal peptide is present on the N-terminus of the polypeptide. In some embodiments, the signal peptide is encoded by signal sequence. In some embodiments, the signal peptide is a golgi targeting signal peptide.
  • Betacoronaviruses have been of greater clinical importance as they have been found to cause outbreaks, for example, the 2002-2003 SARS outbreak caused by SARS-CoV-1 or SARS-CoV, the 2012 MERS outbreak caused by Middle East Respiratory Virus, and more recently the 2019-2020 COVID-19 pandemic caused by SARS-CoV-2.
  • the other betacoronaviruses known to infect human beings are HKU1, and OC43.
  • the genome of betacoronaviruses encodes 4 main structural proteins viz spike(S), membrane(M), envelope(E), and nucleocapsid(N) proteins.
  • the spike protein is the immunodominant protein among the major structural proteins.
  • Exemplary fusion peptides includes, but not limited to, the one represented by the following amino acid sequences, including their codon optimized nucleic acid sequences, fragments, mutants, or variants thereof: KPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNG (SEQ ID NO: 4); SFIEDLLFNKVTLADAGFMKQYGECLGDINARDLICAQKFNG (SEQ ID NO: 5); SAIEDLLFDKVTIADPGYMQGY (SEQ ID NO: 6); SFIEDLLFNKVTLADAGFIKQY (SEQ ID NO: 54); KQYGDCLGDIAARDLICAQKFN (SEQ ID NO: 55); KFNGLTVLPPLLTDEMIAQYT (SEQ ID NO: 56); GWTFGAGAALQIPFAMQMAYRFNGI (SEQ ID NO: 57); In some embodiments, the fusion peptide shares at least 70 % identity with the sequences described herein above, including
  • the linker is an amino acid linker.
  • the amino acid linker comprises of about 2-49 amino acids, 2-40 amino acids, 2-40 amino acids, 2-20 amino acids, 2-15 amino acids, or 2-10 amino acids.
  • the amino acid linker may comprise a glycine serine linker, a glycine proline linker, a glycine threonine linker, an alanine serine linker etc.
  • the one or more modified nucleosides is a uridine analog selected from propynyl-uridine, pseudouridine, C5-bromouridine, C5-fluorouridine, C5- 20 FH11238404.3 Attorney Docket No.: PVM-00325 iodouridine, C5-propynyl-uridine, 5-aza-uridine, 2-thio-5-aza-uridine, 2-thio-uridine, 4-thio- pseudouridine, 2-thio-pseudouridine, 5-hydroxy-uridine, 3-methyl-uridine, 5-carboxymethyl- uridine, 1-carboxymethyl-pseudouridine, 1-methyl-3-(3-amino-3- carboxypropyl)pseudouridine, 2-thio-2’-O-methyl-uridine, 5-methoxycarbonylmethyl-2’-O- methyl-uridine, 5-carboxymethylaminomethyl-2’-O-methyl-uridine, 3,2’-
  • IVT reaction includes capping and tailing reactions either co-transcriptionally or separately.
  • a cap analog is added to the in vitro transcription reaction and will be incorporated at the 5’ end of the mRNA during the reaction.
  • Alternative method of capping involves adding the cap post-transcriptionally through an enzymatic reaction.
  • the poly (A) tail can be incorporated into the DNA template sequence, and thus the poly (A) tail will be incorporated into the mRNA by T7 RNA polymerase during the in vitro transcription.
  • Alternative method of tailing involves adding the poly (A) tail post-transcriptionally through an enzymatic reaction.
  • capping and tailing reactions are performed co- transcriptionally i.e., during the IVT reaction.
  • the nucleic acid sequence encodes a polypeptide comprising one or more receptor binding domain, one or more fusion peptide, one or more stem helix, or a combination thereof. In some embodiments, the nucleic acid sequence encodes a polypeptide comprising multimers of RBD, fusion peptide, or stem helix or a combination thereof. In some embodiments, the nucleic acid sequence encodes a polypeptide comprising multimers of RBD. In some embodiments, the nucleic acid sequence encodes a polypeptide comprising multimers of fusion peptide. In some embodiments, the nucleic acid sequence encodes a polypeptide comprising multimers of stem helix.
  • polypeptides includes, but not limited to, the ones represented by the following amino acid sequences, including their codon optimized nucleic acid sequences, fragments, mutants or variants thereof: SP_RBD-FP-SH MPSSVSWGILLLAGLCCLVPVSLAEDPQGDAARVQPTESIVRFPNITNLCPFGEVFN ATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSF VIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLF RKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLS FELLHAPATVCGPKKSTNLVKNKCVNFGGSGGKPSKRSFIEDLLFNKVTLADAGFI KQYGDCLGDIAARDLICAQKFNGGGSGGLQPELD
  • the RBD is linked to the FP via a linker.
  • the FP is linked to the SH via a linker.
  • the SH is linked to the RBD via a linker.
  • the RBD is linked to the FP via a linker.
  • the FP is linked to the SH via a linker.
  • the RBD is linked to the FP via a linker.
  • the FP is linked to the SH via a linker.
  • the SH is linked to the SH via a linker.
  • the SH is linked to the SH via a linker.
  • SP_RBD-FP-FP-FP-SH 27 FH11238404.3 Attorney Docket No.: PVM-00325 MPSSVSWGILLLAGLCCLVPVSLAEDPQGDAARVQPTESIVRFPNITNLCPFGEVFN ATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSF VIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLF RKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLS FELLHAPATVCGPKKSTNLVKNKCVNFGGSGGKPSKRSFIEDLLFNKVTL
  • the RBD is linked to the FP via a linker.
  • the FP is linked to the FP via a linker.
  • the FP is linked to the FP via a linker.
  • the FP is linked to the SH via a linker.
  • the RBD is linked to the FP via a linker.
  • the FP is linked SH via a linker.
  • the SH is linked to the SH via a linker.
  • the SH is linked to SH via a linker.
  • SP_RBD-FP-FP-FP-SH MDAMKRGLCCVLLLCGAVFVSPSRVQPTESIVRFPNITNLCPFGEVFNATRFASVY AWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVR QIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPF ERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPA TVCGPKKSTNLVKNKCVNFGGSGGKPSKRSFIEDLLFNKVTLADAGFIKQYGDCL GDIAARDLICAQKFNGGGSGGKPSKRSFIEDLLFNK
  • the RBD is linked to the FP via a linker.
  • the FP is linked to the FP via a linker.
  • the FP is linked to the FP via a linker.
  • the FP is linked to the SH via a linker.
  • the RBD is linked to the FP via a linker.
  • the FP is linked to the FP via a linker.
  • the FP is linked to the FP via a linker.
  • the FP is linked to the SH via a linker.
  • the SH is linked to the SH via a linker.
  • the purified polypeptides may be formulated with suitable excipients, such as but not limited to, buffering agents, stabilizers, adjuvants, tonicity modifiers, surfactants, chelating agents, salts, anti-oxidants, diluents, preservatives, or a combination thereof.
  • suitable excipients such as but not limited to, buffering agents, stabilizers, adjuvants, tonicity modifiers, surfactants, chelating agents, salts, anti-oxidants, diluents, preservatives, or a combination thereof.
  • Lipid nanoparticles (LNP) composition The nucleic acid sequences as described herein may be encapsulated in a lipid nanoparticle composition.
  • Exemplary cationic lipid for use in the lipid nanoparticle compositions include, but are not limited to, N,N-dioleyl-N,N-dimethylammonium chloride (DODAC); N-(2,3- dioleyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA); N,N-distearyl-N,N- dimethylammonium bromide(DDAB); N-(2,3dioleoyloxy)propyl)-N,N,N- trimethylammonium chloride (DOTAP); 3-(N—(N',N'-dimethylaminoethane)- carbamoyl)cholesterol (DC-Chol), N-(l-(2,3-dioleoyloxy)propyl)N-2- (sperminecarboxamido)ethyl)-N,N-dimethylammoniumtrifluoracetate (DOSPA), dioctadecylami
  • Phospholipids includes a lipid containing a hydrophilic head with a phosphate group and a hydrophobic tail composed of fatty acid chains attached to a glycerol or sphingosine backbone.
  • Exemplary phospholipids for use in the lipid nanoparticle compositions include, but are not limited to, 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn- glycero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2- dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3- phosphocholine (DSPC), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), 1-palmitoyl- 2-oleoyl-
  • PEG-lipid is selected from mPEG-Dimyristoyl glycerol (mPEG-DMG), mPEG-N,N-Ditetradecylacetamide (mPEG-DTA or ALC0159), mPEG- 40 FH11238404.3 Attorney Docket No.: PVM-00325 Cholesterol (mPEG-CLS), mPEG-DSPE, mPEG-DMPE, mPEG-DPPE, mPEG-DLPE, mPEG-DOPE, mPEG-DPPC, mPEG-DSPC, 1,2-Distearoyl-sn-Glycero-3- Phosphoethanolamine with conjugated methoxyl poly(ethylene glycol) (mPEG-DSPE), 1,2- dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG 2000) or mixtures thereof.
  • mPEG-DSPE mPEG-Dim
  • the lipid nanoparticle composition additionally may contain an ionizable polymer.
  • Ionizable polymer means a compound formed from a plurality of repeating units called monomers. Polymers are produced through a process called polymerization wherein two or more monomers are linked through chemical bonds to form the polymer. In some embodiments, the polymer is branched or unbranched. In some embodiments, the polymer may be homopolymer, i.e., consisting of same type of repeat units or monomers, or heteropolymer, i.e., consisting of more than one type of repeat units or monomers. The terms heteropolymer and copolymer have been used interchangeably herein.
  • the lipid nanoparticle compositions comprise an ionizable polymer.
  • the ionizable polymer may be selected from chitosan, chitosan derivatives, cellulose derivatives, poly-L-lysine (PLL), poly-L-glutamic acid, protamine, polyethyleneimine, their derivatives, or a combination thereof.
  • the ionizable polymer is positively charged at acidic pH i.e., pH 1.0 to 6.9 and is neutral around physiological pH (pH 7.0 to 7.5).
  • the molecular weight of chitosan or its derivatives is from about 25 kDa to 375 Kda, from about 30 kDa to about 350 kDa, from about from about 35 kDa to about 325 kDa, from about 40 kDa to about 300 kDa, from about 40 kDa to about 250 kDa, from about 40 kDa to about 225 kDa, from about 40 kDa to about 220 kDa, from about 40 kDa to about 210 kDa, or from about 40 kDa to about 200 kDa or any range therein.
  • the proportion of chitosan or its derivatives or a combination thereof present in the lipid nanoparticle compositions is from about 1 mol % to about 25 mol %, preferably about 1 mol % to 20 mol %, most preferably about 1 mol % to about 15 mol %.
  • lipid nanoparticle composition 45 FH11238404.3 Attorney Docket No.: PVM-00325 comprising an ionizable polymer, a cationic lipid, a phospholipid, a sterol, a PEG-lipid and the nucleic acid sequence as described herein.
  • the disclosure relates to use of a lipid nanoparticle composition comprising a cationic lipid, a phospholipid, a sterol, a PEG-lipid, and the nucleic acid sequence as described herein in the manufacture of a medicament for the treatment or prevention of a disease in a subject.
  • the biologically effective amount of nucleic acid sequence is from about 0.1 ⁇ g to 1000 ⁇ g, 0.1 ⁇ g to 950 ⁇ g, 0.1 ⁇ g to 900 ⁇ g, 0.1 ⁇ g to 850 ⁇ g, 0.1 ⁇ g to 800 ⁇ g, 0.1 ⁇ g to 750 ⁇ g, 0.1 ⁇ g to 700 ⁇ g, 0.1 ⁇ g to 650, 0.1 ⁇ g to 600, 0.1 ⁇ g to 550, 0.1 ⁇ g to 500 ⁇ g or any range therein.
  • the biologically effective amount of nucleic acid sequence is 0.1 ⁇ g, 0.2 ⁇ g, 0.3 ⁇ g, 0.4 ⁇ g, 0.5 ⁇ g, 0.6 ⁇ g, 0.7, ⁇ g, 0.8 ⁇ g, 0.9 ⁇ g, 1 ⁇ g, 2 ⁇ g, 3 ⁇ g, 4 ⁇ g, 5 ⁇ g, 6 ⁇ g, 7 ⁇ g, 8 ⁇ g, 9 ⁇ g, 10 ⁇ g, 15 ⁇ g, 20 ⁇ g, 25 ⁇ g, 30 ⁇ g, 35 ⁇ g, 40 ⁇ g, 45 ⁇ g, 50 ⁇ g, 55 ⁇ g, 60 ⁇ g, 65 ⁇ g, 70 ⁇ g, 75 ⁇ g, 80 ⁇ g, 85 ⁇ g, 90 ⁇ g, 100 ⁇ g, 110 ⁇ g, 120 ⁇ g, 130 ⁇ g, 140 ⁇ g, 150 ⁇ g, 160 ⁇ g, 170 ⁇ g, 180 ⁇ g, 190 ⁇ g, 200
  • nucleic acid according to any of the preceding paragraphs, wherein a linker connects the RBD with the fusion peptide or vice versa. 13. The nucleic acid according to any of the preceding paragraphs, wherein a linker connects the fusion peptide with stem helix or vice versa. 14. The nucleic acid according to any of the preceding paragraphs, wherein a linker connects the stem helix with the RBD or vice versa. 47 FH11238404.3 Attorney Docket No.: PVM-00325 15. The nucleic acid according to any of the preceding paragraphs, wherein each monomer of the RBD multimer is coupled to the adjacent monomer(s) of the RBD multimer by a linker. 16.
  • each monomer of the fusion peptide multimer is coupled to the adjacent monomer(s) of the fusion peptide multimer by a linker.
  • each monomer of the stem helix multimer is coupled to the adjacent monomer(s) of the stem helix multimer by a linker.
  • a signal peptide is present on the amino-terminus of the polypeptide. 19.
  • RBD receptor binding domain
  • the betacoronavirus is a human betacoronavirus.
  • 43. The lipid nanoparticle composition according to any one of paragraphs 37-42, additionally comprising an ionizable polymer. 44.
  • 46. A method of treating or preventing a disease comprising administrating to a subject in need thereof the nucleic acid according to any one of paragraphs 1 to 18.
  • 47. A method of treating of preventing a disease, comprising administrating to a subject in need thereof the lipid nanoparticle composition according to any one of paragraphs 37 to 45.
  • CRL3216 CRL3216, ATCC
  • CRL3216 ATCC
  • Gibco DMEM medium high glucose, pyruvate (Catalogue no. 11995065, ThermoFisher Scientific) supplemented with 10% fetal bovine serum and 100 units/mL penicillin-streptomycin, and cultured to achieve 70-80% confluency.
  • Transfection mix containing nucleic acid sequence of example 1 (mRNA, 0.5-1 ug of example 1) and LipofectamineTM 2000 (2.5 uL) in 100 uL serum free medium was incubated for 15 min at room temperature and added to the cells and left for incubation for 24 and 48 hours.
  • Spent media was collected by aspiration, and cells were collected with ice-cold 1x PBS (1 mL) with hard pipetting. The cells were centrifuged at 4000 g for 5 min at 4 °C. Excess PBS was aspirated. The cells were suspended gently in 100 ⁇ L of 1x NETN lysis buffer (100 mM NaCl, 20 mM Tris-Cl (pH 8.0), 0.5 mM EDTA, 0.5 % (v/v) Nonidet P-40 (NP-40)) with inhibitors and kept on ice for 20 min. The lysate was centrifuged at 16,000 g for 20 min at 4 °C. The supernatant was aspirated into microtubes.
  • 1x NETN lysis buffer 100 mM NaCl, 20 mM Tris-Cl (pH 8.0), 0.5 mM EDTA, 0.5 % (v/v) Nonidet P-40 (NP-40)
  • the primary antibody SARS-CoV-2 spike RBD polyclonal antibody (Catalogue no. E-AB-V-1006 Elab Sciences), diluted at a 1:200 ratio along with a secondary-HRP ready to use anti-rabbit antibody and chemiluminescent substrate (both components of Detection Module compatible with Jess, Catalogue no. DM-001, ProteinSimple, Bio-Techne), were dispensed into assigned wells within a provided microplate by the manufacturer. This plate was then inserted into the Jess 53 FH11238404.3 Attorney Docket No.: PVM-00325 instrument where samples were drawn into individual capillaries located on a 25-capillary cassette (12-230 kDa Separation Module Catalogue no.

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Abstract

La présente invention concerne de manière générale des acides nucléiques codant pour un polypeptide. Le polypeptide comprend un domaine de liaison de récepteur (RBD), un peptide de fusion ou une hélice à tige, ou une combinaison de ceux-ci. Le RBD, le peptide de fusion ou l'hélice à tige sont obtenus ou dérivés d'un bêtacoronavirus.
PCT/IB2023/000780 2022-12-29 2023-12-28 Vaccins et compositions à protection large contre les bètacoronavirus Ceased WO2024141784A2 (fr)

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