WO2024125597A1 - Compositions et procédés pour des maladies infectieuses - Google Patents
Compositions et procédés pour des maladies infectieuses Download PDFInfo
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- WO2024125597A1 WO2024125597A1 PCT/CN2023/138771 CN2023138771W WO2024125597A1 WO 2024125597 A1 WO2024125597 A1 WO 2024125597A1 CN 2023138771 W CN2023138771 W CN 2023138771W WO 2024125597 A1 WO2024125597 A1 WO 2024125597A1
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Definitions
- the present disclosure generally relates to compositions, formulations, methods, and/or uses of nucleic acid vaccines, specifically nucleic acid vaccines (e.g., RNA, mRNA, DNA vaccines) encoding one or more proteins, polypeptides, antigenic peptides, fragments or variants thereof of rabies virus for the prevention, alleviation and/or treatment and/or prevention of rabies and other diseases caused by rabies viral infection, including mitigation of physiologic effects of infection and/or symptoms.
- nucleic acid vaccines e.g., RNA, mRNA, DNA vaccines
- Rabies is a life-threatening zoonotic disease that is caused by infection with viruses of the Lyssavirus genus, which is transmitted via the saliva of an infected animal.
- Rabies virus (RABV) (also known as rabies lyssavirus)
- rabies lyssavirus the prototype virus of the Lyssavirus genus
- Dogs are a common reservoir for rabies viruses, and dog transmitted rabies account for>99%of human cases.
- the virus first infects peripheral motor neurons, and symptoms occur after the virus reaches the central nervous system.
- the disease is almost always invariably fatal following the onset of clinical symptoms occurring unless the subject is treated prior to the onset of symptoms.
- Rabies is considered endemic in more than 100 countries and territories, and poses a threat to more than 3 billion people (WHO epidemiological record) .
- rabies vaccines have been effectively used for disease prevention, the rabies virus is still endemic in many regions of the world and human rabies remains one of the most serious and distressing diseases and an important threat to public health.
- Several inactivated preparations of RABV are available as vaccines to immunize humans and domestic animals.
- live-attenuated and subunit vaccines are available.
- Human rabies vaccines are usually administered intramuscularly or intradermally, and the same vaccines used for pre-exposure prevention (PrEP) can also be given as part of post-exposure prevention (PEP) .
- the rabies virus (RABV) virion is bullet-shaped, with a plasma membrane covered in homotrimers of type 1 transmembrane glycoprotein with peplomers (glycoprotein spikes) .
- the glycoprotein (G protein) has been used as antigen to induce immunity against glycoprotein that provide protection against RABV infection.
- rabies vaccines include the most widely used but highly risk-prone nerve tissue vaccines, or the safer but more costly cell culture and embryonated egg vaccines (CCEEVs) .
- CEEVs cell culture and embryonated egg vaccines
- Risks associated with nerve tissue vaccines include induction of autoimmune central nervous system disease due to their inherent myelin content, the need for multiple injections; and unreliable efficacy (Plotkin SA. Rabies. Clin Infect Dis. 2000; 30: 4-12) .
- avian embryo vaccines and cell culture vaccines that contain inactivated purified virus, and are free from nerve protein are safer and more immunogenic than nerve tissue vaccines, the culture production methods are time-consuming and resource-intensive and the associated cost burden largely restricts the use to the developed world.
- polynucleotides e.g., mRNAs
- the present disclosure provides nucleic acid vaccines, compositions and formulations comprising nucleic acid vaccines, and methods of using same for preventing rabies and other diseases caused by infection of rabies virus (RABV) .
- the nucleic acid vaccines may include polynucleotides which encode at least one structural protein, polypeptide, antigenic peptide, fragment or variant thereof of a rabies virus.
- the rabies viral protein may be the nucleoprotein (N) , the phosphoprotein (P) , the matrix protein (M) , the glycoprotein (G) and/or the polymerase (L) .
- Non-limiting examples of the amino acid sequences of these structural proteins are shown in Table 1 (SEQ ID Nos.: 1-9) .
- the structural protein is the glycoprotein (G) of a rabies virus.
- Non-limiting examples of the amino acid sequences of the glycoproteins (G) are shown in Table 2 (SEQ ID NOs.: 10-27) .
- nucleic acid vaccines for rabies for use in a method of vaccinating a subject for prevention and/treatment of rabies, wherein the nucleic acid vaccine may include at least one polynucleotide encoding at least one structural protein or a fragment thereof of a rabies virus.
- the nucleic acid vaccines described herein may be formulated in one or more lipid nanoparticles (LNPs) .
- LNPs lipid nanoparticles
- compositions and formulations of the nucleic acid vaccines for the treatment and prevention of rabies in human and animals.
- nucleic acid vaccines for rabies comprising at least one mRNA, wherein the mRNA comprises a coding region with a nucleic acid sequence that is at least 85%identical, or at least 90%identical, or at least 95%identical to the sequence of a member from the group consisting of SEQ ID NOs.: 29, 31, 33, 35, 37, 39, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88 and 90.
- the mRNA of the nucleic acid vaccines disclosed herein comprises a coding region with a nucleic acid sequence as set forth in SEQ ID NO.: 29.
- the mRNA of the nucleic acid vaccines disclosed herein comprises a coding region with a nucleic acid sequence as set forth in SEQ ID NO.: 31. In some embodiments, the mRNA of the nucleic acid vaccines disclosed herein comprises a coding region with a nucleic acid sequence as set forth in SEQ ID NO.: 33. In some embodiments, the mRNA of the nucleic acid vaccines disclosed herein comprises a coding region with a nucleic acid sequence as set forth in SEQ ID NO.: 35. In some embodiments, the mRNA of the nucleic acid vaccines disclosed herein comprises a coding region with a nucleic acid sequence as set forth in SEQ ID NO.: 37.
- the mRNA of the nucleic acid vaccines disclosed herein comprises a coding region with a nucleic acid sequence as set forth in SEQ ID NO.: 39. In some embodiments, the mRNA of the nucleic acid vaccines disclosed herein comprises a coding region with a nucleic acid sequence as set forth in SEQ ID NO.: 70. In some embodiments, the mRNA of the nucleic acid vaccines disclosed herein comprises a coding region with a nucleic acid sequence as set forth in SEQ ID NO.: 72. In some embodiments, the mRNA of the nucleic acid vaccines disclosed herein comprises a coding region with a nucleic acid sequence as set forth in SEQ ID NO.: 74.
- the mRNA of the nucleic acid vaccines disclosed herein comprises a coding region with a nucleic acid sequence as set forth in SEQ ID NO.: 76. In some embodiments, the mRNA of the nucleic acid vaccines disclosed herein comprises a coding region with a nucleic acid sequence as set forth in SEQ ID NO.: 78. In some embodiments, the mRNA of the nucleic acid vaccines disclosed herein comprises a coding region with a nucleic acid sequence as set forth in SEQ ID NO.: 80. In some embodiments, the mRNA of the nucleic acid vaccines disclosed herein comprises a coding region with a nucleic acid sequence as set forth in SEQ ID NO.: 82.
- the mRNA of the nucleic acid vaccines disclosed herein comprises a coding region with a nucleic acid sequence as set forth in SEQ ID NO.: 84. In some embodiments, the mRNA of the nucleic acid vaccines disclosed herein comprises a coding region with a nucleic acid sequence as set forth in SEQ ID NO.: 86. In some embodiments, the mRNA of the nucleic acid vaccines disclosed herein comprises a coding region with a nucleic acid sequence as set forth in SEQ ID NO.: 88. In some embodiments, the mRNA of the nucleic acid vaccines disclosed herein comprises a coding region with a nucleic acid sequence as set forth in SEQ ID NO.: 90.
- the mRNA of the nucleic acid vaccines disclosed herein comprises a coding region as set forth in SEQ ID NO.: 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, or 90 or at least 85%identical to SEQ ID NO.: 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, or 90.
- These coding regions may include at least one stop codon, at least two stop codons, one stop codon, or two stop codons.
- nucleic acid vaccines for rabies comprising at least one mRNA that comprises a nucleic acid sequence selected from the group consisting of SEQ ID Nos.: 41, 43, 45, 47, 49, 51, 92, 94, 96, 98, 100, and 102.
- the nucleic acid vaccines may be used as pre-exposure prevention (PrEP) . In some embodiments, the nucleic acid vaccines may be used as or as part of post-exposure prevention (PEP) .
- the immune response may be produced by a single administration of the nucleic acid vaccines described herein.
- the immune response may be strengthened by at least one booster administration.
- the immune response may be strengthened by two, three or more booster administrations.
- the immune response may be produced by a booster administration of the nucleic acid vaccines described herein.
- administering the nucleic acid vaccines to a subject comprises administering about 1 ⁇ g to about 100 mg, about 10 ⁇ g to about 10 mg, about 1 ⁇ g to about 500 ⁇ g, about 1 ⁇ g to about 100 ⁇ g, or about 10 ⁇ g to about 100 ⁇ g, of the mRNA of the nucleic acid vaccines to the subject.
- the administering comprises an intramuscular (IM) injection of the nucleic acid vaccine to the subject.
- IM intramuscular
- the nucleic acid vaccines may be administered to a subject in a first dose of the nucleic acid vaccine followed by a second dose of the nucleic acid vaccine after between about 1 and about 5 weeks.
- the second dose of the nucleic acid vaccine is administered about 4 weeks after the first dose.
- a third dose of the nucleic acid vaccine is administered about 1 to 4 weeks after the second dose.
- the nucleic acid vaccines may be administered to a subject in a first dose of the nucleic acid vaccine followed by a second dose of the nucleic acid vaccine after between within the first 14 days.
- the second dose of the nucleic acid vaccine is administered about 3 days after the first dose.
- the second dose of the nucleic acid vaccine is administered about 5 days after the first dose.
- the second dose of the nucleic acid vaccine is administered about 7 days after the first dose.
- a third dose of the nucleic acid vaccine is administered 14 days after the first dose.
- FIG. 1 is a representative gel image of in vitro translation of Glycoprotein (G) using the mRNA encoding G protein.
- FIG. 2 is representative gel image of in vitro translation of Glycoprotein (G) using the mRNA constructs RAB-001, RAB-002, RAB-003, RAB-004, RAB-005, and RAB-006.
- FIG. 3 displays G protein expression in cells transfected with the mRNA encoding G protein (construct RAB-001 at different concentrations) .
- the non-transfected cells are stained with Hoechst for nucleus and the transfected cells are immuno-labeled with anti-G protein antibodies.
- FIG. 4 displays G protein expression in cells transfected with the mRNA encoding the glycoprotein with signal peptide replaced (construct RAB-002) .
- the non-transfected cells are stained with Hoechst for nucleus and the transfected cells are immuno-labeled with anti-G protein antibodies.
- FIG. 5 displays G protein expression in cells transfected with the mRNA encoding G protein (RAB-003, RAB-004, RAB-005 and RAB-006) .
- the non-transfected cells are stained with Hoechst for nucleus and the transfected cells are immuno-labeled with anti-G protein antibodies.
- FIG. 6 is a representative gel image of in vitro translation of Glycoprotein (G) using the mRNA constructs encoding G protein.
- FIG. 7 is a representative gel image of in vitro translation of Glycoprotein (G) using the mRNA constructs encoding G protein.
- FIG. 8A is a series of charts comparing the mRNA vaccine and the inactivated vaccine total serum IgG on day 14.
- FIG. 8B is a chart comparing the total serum IgG for the mRNA vaccine and the inactivated vaccine.
- FIG. 8C is a chart comparing the neutralizing antibody titer for the mRNA vaccine and the inactivated vaccine.
- FIG. 8D provides the CD4+T Cell immune response detected from Splenocytes on Day 15.
- FIG. 8E provides the CD8+T Cell immune response detected from Splenocytes on Day 15.
- FIG. 8F provides the CD4+T Cell immune response detected from Splenocytes on Day 28.
- FIG. 8G provides the CD8+T Cell immune response detected from Splenocytes on Day 28.
- FIG. 8H provides the T Cell immune response detected by ELISPOT on Day 15 and Day 28.
- FIG. 9A is a chart comparing the total serum IgG for the mRNA vaccine and the inactivated vaccine.
- FIG. 9B is a chart comparing the total serum IgG for the mRNA vaccine and the inactivated vaccine.
- FIG. 9C is a chart comparing the neutralization titers for the mRNA vaccines and the inactivated vaccine.
- FIG. 10 is a chart comparing the total serum IgG for the mRNA vaccine and the inactivated vaccine.
- FIG. 11 is a chart comparing the RNVA titers for the mRNA vaccine and the inactivated vaccine.
- FIG. 12A is a graph demonstrating the survival percentage of vaccinated mice in groups A1 to A7 or injected with PBS in a rabies challenge study.
- FIG. 12B is a graph demonstrating the survival percentage of vaccinated mice in groups B1 to B7 or injected with PBS in a rabies challenge study.
- FIG. 12C is a graph demonstrating the survival percentage of vaccinated mice in groups C1 to C7 or injected with PBS in a rabies challenge study.
- FIG. 13A is a graph illustrating the EC50 value of the mRNA vaccine in Group A (injected on day 0 (D0) ) .
- FIG. 13B is a graph illustrating the EC50 value of the mRNA vaccine for group B (injected on days 0 and 3 (D0/3) ) .
- FIG. 13C is a graph illustrating the EC50 value of the inactivated vaccine.
- nucleic acid vaccines comprising polynucleotides encoding one or more proteins, polypeptides, antigenic peptide, fragments or variants thereof of a rabies virus (RABV) for the prevention, alleviation and/or treatment of rabies and other diseases caused by rabies viral infection.
- the protein may be a structural protein of a rabies virus.
- the structural protein may be the nucleoprotein (N) , the phosphoprotein (P) , the matrix protein (M) , the glycoprotein (G) , and/or the polymerase (L) .
- the antigen protein may be the glycoprotein (G) of a rabies virus, such as the glycoprotein from the Pasteur vaccine strain.
- At least one component of the nucleic acid vaccine is a polynucleotide encoding at least one of the structural proteins or polypeptides, or the fragments or variants of the structural proteins of a rabies virus.
- the polynucleotide may be a RNA polynucleotide such as an mRNA polynucleotide.
- the nucleic acid vaccine includes at least one mRNA polynucleotide encoding at least one of the structural proteins or the fragments or variants of the structural proteins of a rabies virus.
- the polynucleotide may be designed to encode one or more polypeptides of interest from a rabies virus, or fragments, or antigenic peptides, or variants thereof.
- polypeptide of interest of a rabies virus may include, but is not limited to, whole polypeptides, a plurality of polypeptides or fragments of polypeptides or variants of polypeptides, which independently may be encoded by one or more regions or parts or the whole of a polynucleotide from a rabies virus.
- the term “polypeptides of interest” refer to any polypeptide which is selected to be encoded within, or whose function is affected by, the polynucleotides described herein. Any of the peptides or polypeptides described herein may be antigenic (also referred to as immunogenic) .
- polypeptide means a polymer of amino acid residues (natural or unnatural) linked together most often by peptide bonds.
- the term, as used herein, refers to proteins, polypeptides, and peptides of any size, structure, or function, or origin.
- the polypeptides of interest are antigens encoded by the polynucleotides as described herein.
- polypeptide encoded is smaller than about 50 amino acids and the polypeptide is then termed a peptide. If the polypeptide is a peptide, it will be at least about 2, 3, 4, or at least 5 amino acid residues long.
- polypeptides include gene products, naturally occurring polypeptides, synthetic polypeptides, homologs, orthologs, paralogs, fragments and other equivalents, variants, and analogs of the foregoing.
- a polypeptide may be a single molecule or may be a multi-molecular complex such as a dimer, trimer or tetramer. They may also comprise single chain or multichain polypeptides such as antibodies or insulin and may be associated or linked. Most commonly disulfide linkages are found in multichain polypeptides.
- the term polypeptide may also apply to amino acid polymers in which one or more amino acid residues are an artificial chemical analogue of a corresponding naturally occurring amino acid.
- polypeptide variant refers to molecules which differ in their amino acid sequence from a native or reference sequence.
- the amino acid sequence variants may possess substitutions, deletions, and/or insertions at certain positions within the amino acid sequence, as compared to a native or reference sequence.
- variants will possess at least about 50%identity (homology) to a native or reference sequence, and preferably, they will be at least about 80%, or at least about 85%, more preferably at least about 90%, even more preferably at least about 95%identical (homologous) to a native or reference sequence.
- variant mimics are provided.
- the term “variant mimic” is one which contains one or more amino acids which would mimic an activated sequence.
- glutamate may serve as a mimic for phosphoro-threonine and/or phosphoro-serine.
- variant mimics may result in deactivation or in an inactivated product containing the mimic, e.g., phenylalanine may act as an inactivating substitution for tyrosine; or alanine may act as an inactivating substitution for serine.
- “Homology” as it applies to amino acid sequences is defined as the percentage of residues in the candidate amino acid sequence that are identical with the residues in the amino acid sequence of a second sequence after aligning the sequences and introducing gaps, ifnecessary, to achieve the maximum percent homology. Methods and computer programs for the alignment are well known in the art. It is understood that homology depends on a calculation of percent identity but may differ in value due to gap and penalties introduced in the calculation.
- homologs as it applies to polypeptide sequences means the corresponding sequence of other species having substantial identity to a second sequence of a second species.
- Analogs as used herein, is meant to include polypeptide variants which differ by one or more amino acid alterations, e.g., substitutions, additions or deletions of amino acid residues that still maintain one or more of the properties of the parent or starting polypeptide.
- compositions which are polypeptide based including variants and derivatives. These include substitutional, insertional, deletion and covalent variants and derivatives.
- derivative is used synonymously with the term “variant” but generally refers to a molecule that has been modified and/or changed in any way relative to a reference molecule or starting molecule.
- sequence tags or amino acids can be added to the peptide sequences described herein (e.g., at the N-terminal or C-terminal ends) .
- Sequence tags can be used for peptide purification or localization.
- Lysines can be used to increase peptide solubility or to allow for biotinylation.
- amino acid residues located at the carboxy and amino terminal regions of the amino acid sequence of a peptide or protein may optionally be deleted providing for truncated sequences.
- Certain amino acids e.g., C-terminal or N-terminal residues
- substitutional variants when referring to polypeptides are those that have at least one amino acid residue in a native or starting sequence removed and a different amino acid inserted in its place at the same position. The substitutions may be single, where only one amino acid in the molecule has been substituted, or they may be multiple, where two or more amino acids have been substituted in the same molecule.
- conservative amino acid substitution refers to the substitution of an amino acid that is normally present in the sequence with a different amino acid of similar size, charge, or polarity.
- conservative substitutions include the substitution of a non-polar (hydrophobic) residue such as isoleucine, valine and leucine for another non-polar residue.
- conservative substitutions include the substitution of one polar (hydrophilic) residue for another such as between arginine and lysine, between glutamine and asparagine, and between glycine and serine.
- substitution of a basic residue such as lysine, arginine or histidine for another, or the substitution of one acidic residue such as aspartic acid or glutamic acid for another acidic residue are additional examples of conservative substitutions.
- nonconservative substitutions include the substitution of a nonpolar (hydrophobic) amino acid residue such as isoleucine, valine, leucine, alanine, methionine for a polar (hydrophilic) residue such as cysteine, glutamine, glutamic acid or lysine and/or a polar residue for a non-polar residue.
- “Insertional variants” when referring to polypeptides are those with one or more amino acids inserted immediately adjacent to an amino acid at a particular position in a native or starting sequence. “Immediately adjacent” to an amino acid means connected to either the alpha-carboxy or alpha-amino functional group of the amino acid.
- “Deletional variants” when referring to polypeptides are those with one or more amino acids in the native or starting amino acid sequence removed. Ordinarily, deletional variants will have one or more amino acids deleted in a particular region of the molecule.
- Covalent derivatives when referring to polypeptides include modifications of a native or starting protein with an organic proteinaceous or non-proteinaceous derivatizing agent, and/or post-translational modifications. Covalent modifications are traditionally introduced by reacting targeted amino acid residues of the protein with an organic derivatizing agent that is capable of reacting with selected side chains or terminal residues, or by harnessing mechanisms of post-translational modifications that function in selected recombinant host cells. The resultant covalent derivatives are useful in programs directed at identifying residues important for biological activity, for immunoassays, or for the preparation of anti-protein antibodies for immunoaffinity purification of the recombinant glycoprotein. Such modifications are within the ordinary skill in the art and are performed without undue experimentation.
- Features when referring to polypeptides are defined as distinct amino acid sequence-based components of a molecule.
- Features of the polypeptides encoded by the polynucleotides described herein include surface manifestations, local conformational shape, folds, loops, half-loops, domains, half-domains, sites, termini or any combination thereof.
- surface manifestation refers to a polypeptide-based component of a protein appearing on an outermost surface.
- local conformational shape means a polypeptide based structural manifestation of a protein which is located within a definable space of the protein.
- fold refers to the resultant conformation of an amino acid sequence upon energy minimization.
- a fold may occur at the secondary or tertiary level of the folding process.
- secondary level folds include beta sheets and alpha helices.
- tertiary folds include domains and regions formed due to aggregation or separation of energetic forces. Regions formed in this way include hydrophobic and hydrophilic pockets, and the like.
- turn as it relates to polypeptide conformation means a bend which alters the direction of the backbone of a peptide or polypeptide and may involve one, two, three or more amino acid residues.
- loop refers to a structural feature of a polypeptide which may serve to reverse the direction of the backbone of a peptide or polypeptide. Where the loop is found in a polypeptide and only alters the direction of the backbone, it may comprise four or more amino acid residues. Oliva et al. have identified at least 5 classes of protein loops (J. Mol Bio., 266 (4) : 814-830; 1997) . Loops may be open or closed. Closed loops or “cyclic” loops may comprise 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acids between the bridging moieties.
- Such bridging moieties may comprise a cysteine-cysteine bridge (Cys-Cys) typical in polypeptides having disulfide bridges or alternatively bridging moieties may be non-protein based such as the dibromozylyl agents used herein.
- Cys-Cys cysteine-cysteine bridge
- bridging moieties may be non-protein based such as the dibromozylyl agents used herein.
- half-loop refers to a portion of an identified loop having at least halfthe number of amino acid resides as the loop from which it is derived. It is understood that loops may not always contain an even number of amino acid residues. Therefore, in those cases where a loop contains or is identified to comprise an odd number of amino acids, a half-loop of the odd-numbered loop will comprise the whole number portion or next whole number portion of the loop (number of amino acids of the loop/2+/-0.5 amino acids) .
- domain refers to a motif of a polypeptide having one or more identifiable structural or functional characteristics or properties (e.g., binding capacity, serving as a site for protein-protein interactions) .
- sub-domains may be identified within domains or half-domains, these subdomains possessing less than all of the structural or functional properties identified in the domains or half domains from which they were derived. It is also understood that the amino acids that comprise any of the domain types herein need not be contiguous along the backbone of the polypeptide (i.e., nonadjacent amino acids may fold structurally to produce a domain, half-domain or subdomain) .
- site as it pertains to amino acid-based embodiments is used synonymously with “amino acid residue” and “amino acid side chain. ”
- a site represents a position within a peptide or polypeptide that may be modified, manipulated, altered, derivatized or varied within the polypeptide-based molecules described herein.
- terminal refers to an extremity of a peptide or polypeptide. Such extremity is not limited only to the first or final site of the peptide or polypeptide but may include additional amino acids in the terminal regions.
- the polypeptide-based molecules described herein may be characterized as having both an N-terminus (terminated by an amino acid with a free amino group (NH2) ) and a C-terminus (terminated by an amino acid with a free carboxyl group (COOH) ) .
- Proteins described herein are in some cases made up of multiple polypeptide chains brought together by disulfide bonds or by non-covalent forces (multimers, oligomers) . These sorts of proteins will have multiple N-and C-termini.
- the termini of the polypeptides may be modified such that they begin or end, as the case may be, with a non-polypeptide-based moiety such as an organic conjugate.
- any of the features have been identified or defined as a desired component of a polypeptide to be encoded by a polynucleotide described herein, any of several manipulations and/or modifications of these features may be performed by moving, swapping, inverting, deleting, randomizing or duplicating. Furthermore, it is understood that manipulation of features may result in the same outcome as a modification to the molecules described herein. For example, a manipulation which involved deleting a domain would result in the alteration of the length of a molecule just as modification of a nucleic acid to encode less than a full-length molecule would.
- the term “modification” refers to a modification as compared to the canonical set of 20 amino acids.
- the modifications may be various distinct modifications.
- the regions may contain one, two, or more (optionally different) modifications.
- Modifications and manipulations can be accomplished by methods known in the art such as, but not limited to, site directed mutagenesis or a priori incorporation during chemical synthesis.
- the resulting modified molecules may then be tested for activity using in vitro or in vivo assays such as those described herein or any other suitable screening assay known in the art.
- the polypeptides may comprise a consensus sequence which is discovered through rounds of experimentation.
- a “consensus” sequence is a single sequence which represents a collective population of sequences allowing for variability at one or more sites.
- protein fragments, functional protein domains, and homologous proteins are also considered to be within the scope of polypeptides of interest.
- any protein fragment meaning a polypeptide sequence at least one amino acid residue shorter than a reference polypeptide sequence but otherwise identical to a reference protein.
- the protein fragment may contain 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, or greater than 100 amino acids in length.
- any protein that includes a stretch of about 20, about 30, about 40, about 50, or about 100 amino acids, or more, which are about 40%, about 50%, about 60%, about 70%, about 80%, about 85%, about 90%, about 95%, or about 100%identical to any of the sequences described herein can be utilized in accordance with the nucleic acid vaccines described herein.
- a polypeptide to be utilized in accordance with the nucleic acid vaccines described herein includes 2, 3, 4, 5, 6, 7, 8, 9, 10, or more mutations as shown in any of the sequences provided or referenced herein.
- polynucleotides of the present disclosure encode peptides or polypeptides containing substitutions, insertions and/or additions, deletions and covalent modifications with respect to reference sequences, in particular the peptide or polypeptide sequences disclosed herein.
- the polynucleotides may also contain substitutions, insertions and/or additions, deletions and covalent modifications with respect to the polynucleotide reference sequences.
- Reference molecules may share a certain identity with the designed molecules (polypeptides or polynucleotides) .
- identity refers to a relationship between the sequences of two or more peptides, polypeptides or polynucleotides, as determined by comparing the sequences. In the art, identity also means the degree of sequence relatedness between them as determined by the number of matches between strings of two or more amino acid residues or nucleosides. Identity measures the percent of identical matches between the smaller of two or more sequences with gap alignments (if any) addressed by a particular mathematical model or computer program (e.g., “algorithms” ) .
- Identity of related peptides can be readily calculated by known methods. Such methods include, but are not limited to, those described in Computational Molecular Biology, Lesk, A.M., ed., Oxford University Press, N.Y., 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, N.Y., 1993; Computer Analysis of Sequence Data, Part 1, Griffin, A.M., and Griffin, H.G., eds., Humana Press, N.J., 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M. Stockton Press, N.Y, 1991; and Carillo et al., SIAM J. Applied Math. 48: 1073; 1988) .
- the encoded polypeptide variant may have the same or a similar activity as the reference polypeptide.
- the variant may have an altered activity (e.g., increased or decreased) relative to a reference polypeptide.
- variants of a particular polynucleotide or polypeptide described herein will have at least about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%but less than 100%sequence identity to that particular reference polynucleotide or polypeptide as determined by sequence alignment programs and parameters described herein and known to those skilled in the art.
- Such tools for alignment include those of the BLAST suite (Stephen F. Altschul et al., Gapped BLAST and PSLBLAST: a new generation of protein database search programs, Nucleic Acids Res. 1997, 25: 3389-3402. ) Other tools are described herein, specifically in the definition of “Identity. ”
- Rabies disease is a fatal but preventable viral disease. It can spread to people and pets (e.g., dogs) if they are bitten or scratched by a rabid animal. Rabies is responsible for an estimate of tens of thousands global human deaths annually and an estimated 15 million people receive post-exposure prophylaxis annually for exposures. In the United States, rabies is mostly found in wild animals like bats, raccoons, skunks, and foxes. However, in many other countries dogs still carry rabies, and most rabies deaths in people around the world are caused by dog bites. Rabies is caused by rabies viral infection. The rabies viral infections usually begin in muscle tissue following a bite from an infected animal; then the virus crosses neuromuscular junctions to the peripheral and central nervous system, which can cause disease in the brain, ultimately resulting in death.
- Rabies virus (also known as rabies lyssavirus) is a negative-stranded RNA virus of the Rhabdoviridae family.
- the relatively small RNA genome of the virus ( ⁇ 12 kb) encodes for five proteins: nucleoprotein (N) , phosphoprotein (P) , matrix protein (M) , glycoprotein (G) , and polymerase (L) .
- RABV binds to the cell surface receptors, e.g., nicotinic acetylcholine receptor (nAChR) , CD56 and/or TNFRSF16, via its glycoprotein (G) and enters the cell by endocytosis to initiate its life cycle inside the infected cells. Subsequently, the viral membrane fuses with the endosomal membrane to release the viral genome which is transcribed by the polymerase complex. The transcripts are then translated into the viral proteins nucleoprotein (N) , phosphoprotein (P) , matrix protein (M) , glycoprotein (G) , and polymerase (L) . Following replication, viral components including the copied genomic RNA and proteins are assembled forming new RABV virions. The RABV virions are released, starting a new round of infection.
- nAChR nicotinic acetylcholine receptor
- CD56 e.g., CD56 and/or TNFRSF16
- G
- RABV is highly neurotrophic. Rabies virus infects a peripheral nerve first and ascends to the dorsal root ganglion. Once within the spinal cord, the rabies virus spreads rapidly to the brain, resulting in an overwhelming encephalitis that eventually kills the host. Once signs of infection develop there is no effective treatment and, uniquely among infectious diseases, it has a case fatality rate of almost 100%.
- a vaccine regimen can protect against rabies disease both before and shortly after exposure to RABV.
- the development of virus-neutralizing antibodies is critical to preventing infection.
- Rabies nucleic acid vaccine elicited T-cell responses may have the advantage over other types of Rabies vaccine by conferring enhanced protective efficacies. Rabies vaccines are efficient at inducing an anti-rabies antibody response.
- the rabies virus strains may include but are not limited to Pasteur virus, CVS-11, CVS-N2C, Evelyn Rokitniki Abelseth (ERA) , Nishigahara RCEH, SAD B19, PM1503, isolate Human/Algeria/1991, strain Vnukovo-32, China/DRV, China/RMV, Flury, Pitman Moore, Wistar strain and strain silver-haired bat-associated.
- rabies virus isolates may include, but are not limited to, Rabies virus strains according to the NCBI Accession Nos. JQ730682, AF499686, AB569299, AB839170, AB781935, FJ959397, AB362483, EF206720, EF206718, EF206717, EF206715, EF206714, EF206713, EF206712, EF206711, EF206710, EF206709, EF206708, EF206707, EU182346, HM535790, GQ918139, EU877071, EU877070, EU877069, EU182347, M31046, EU877068, EU877067, EF542830, AB839169, JQ647510, KC169986, JX088694, JQ730682, JN609295, JN234411, HQ317918, EF206719,
- the polynucleotides of the nucleic acid vaccine described herein encode more than one fragment, antigenic peptide or variant of a structural protein of a rabies virus, such as the glycoprotein (G) , the nucleoprotein (N) , the phosphoprotein (P) , the matrix protein (M) , and/or the polymerase (L) .
- a structural protein of a rabies virus such as the glycoprotein (G) , the nucleoprotein (N) , the phosphoprotein (P) , the matrix protein (M) , and/or the polymerase (L) .
- the polynucleotides of the nucleic acid vaccine described herein encode a mutated variant of one of the structural proteins, or a fragment of the mutated variant of the structural proteins of a rabies virus.
- the polynucleotides of the nucleic acid vaccine described herein encode a full-length polypeptide of the glycoprotein (G) , or a fragment, or a variant of the glycoprotein of a rabies virus.
- the nucleic acid vaccine described herein may encode one or more proteins, polypeptides, peptides, fragments or variants thereof of the structural proteins of a rabies virus.
- the nucleic acid vaccine described herein encode at least one protein, polypeptide, antigenic peptide, fragment or variant derived from the glycoprotein (G) , the nucleoprotein (N) , the phosphoprotein (P) , the matrix protein (M) , and/or the RNA polymerase (L) of Rabies virus strain Pasteur vaccins (PV) (the Pasteur vaccine strain) .
- the nucleic acid vaccine described herein may encode at least one structural protein with at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%or 100%of any of the sequences in Table 1 or fragments of any of the sequences in Table 1 or variants of any of the sequences in Table 1.
- the coding sequences of mRNA vaccines described herein may be based on the coding sequence of the glycoprotein (G) from Rabies virus strain Pasteur vaccins (PV) (SEQ ID NO.: 1) .
- the nucleic acid vaccine described herein may encode the glycoprotein with at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%or 100%of the sequence of the glycoprotein (G) of the Pasteur vaccine strain, i.e., SEQ ID NO.: 1 in Table 1.
- the nucleic acid vaccine may be an mRNA vaccine that, when translated, produces one or more proteins, peptides, fragments or variants thereof of the structural proteins of rabies virus.
- the polynucleotides of the mRNA vaccine are mRNA polynucleotides encoding one or more proteins, polypeptides, peptides, fragments or variants thereof of the structural proteins of a rabies virus.
- the coding sequences of mRNA vaccines described herein may be based on the coding sequence of the glycoprotein (G) from other Rabies virus strains.
- Non-limiting examples of the sequence of the glycoprotein (G) of the structural proteins of Rabies virus are provided in Table 2.
- the nucleic acid vaccine described herein may encode the glycoprotein with at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%or 100%of the sequence of the glycoprotein of Table 2.
- the coding sequences of mRNA vaccines described herein may be based on the coding sequence of the glycoprotein (G) from rabies virus stains according to the NCBI Accession Nos., but not limited to, JQ730682, AF499686, AB569299, AB839170, AB781935, FJ959397, AB362483, EF206720, EF206718, EF206717, EF206715, EF206714, EF206713, EF206712, EF206711, EF206710, EF206709, EF206708, EF206707, EU182346, HM535790, GQ918139, EU877071, EU877070, EU877069, EU182347, M
- the nucleic acid vaccines described herein comprise an mRNA polynucleotide encoding proteins, polypeptides, antigenic peptides, fragments or variants of the structural proteins of the Pasteur vaccine stain such as, but not limited to, those in Table 1 and/or Table 2.
- Non-limiting examples of a RNA sequence encoding proteins, antigenic peptides, fragments or variants of the structural proteins of Rabies virus are provided in Table 3.
- the mRNA polynucleotide encoding the glycoprotein of rabies virus comprises the coding sequence of SEQ ID NO.: 29, 31, 33, 35, 37, 39, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88 or 90, or a variant thereof.
- the nucleic acid vaccines may comprise a region encoding any of the sequences listed in Tables 1-2 or a fragment or antigenic peptide or variant thereof.
- the nucleic acid vaccines may comprise hybrid or chimeric regions, or mimics or variants.
- the nucleic acid vaccines may comprise any of the polynucleotide sequences listed in Table 3-4. In Table 3-4, WT means “wild-type. ”
- any of the sequences referred to in Tables 1-4 or variants thereof may also be used in a memory booster vaccine described herein. In some embodiments, any of the sequences referred to in Tables 1-4 or variants thereof may also be used in a booster vaccine shortly after the infection of a rabies virus.
- the nucleic acid vaccine described herein encodes a protein or fragment or variant thereof that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%identical to a protein provided by an amino acid sequence in Table 1.
- the nucleic acid vaccine described herein encodes a protein or fragment or variant thereof that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%identical to a glycoprotein provided by an amino acid sequence in Table 2.
- the terms “identical” or percent “identity” in the context of two or more polypeptide sequences refer to two or more sequences that are the same. The percent identity between polypeptide sequences may be performed using algorithms known in the art, such as BLAST and CLUSTAL.
- sequence of the structural protein of a rabies virus or fragment or antigenic peptide or variant thereof may be obtained from any source.
- sequence of the structural protein of a rabies virus or fragment or antigenic peptide or variant thereof is from a strain that is capable of or at risk of infecting human subjects and/or animal subjects.
- polynucleotide sequence of the structural protein of a rabies virus (RABV) or fragment or antigenic peptide or variant thereof may be modified or optimized (such as codon optimized) for expression in a particular cell or host organism.
- the nucleic acid vaccine described herein may be a multivalent vaccine.
- the multivalent vaccine may include polynucleotides that encodes at least two different proteins, polypeptides, peptides, fragments or variants thereof of a rabies virus (RABV) .
- RABV rabies virus
- the polynucleotides may encode the same or a different structural protein.
- the polynucleotides may encode the same structural protein but different variants of the structural protein.
- the nucleic acid vaccine encodes the full-length glycoprotein of a rabies virus (RABV) . In some embodiments, the nucleic acid vaccine encodes a fragment of the glycoprotein of a rabies virus (RABV) . In some embodiments, the nucleic acid vaccine encodes an antigenic peptide of the glycoprotein of a rabies virus (RABV) . In some embodiments, the nucleic acid vaccine encodes a variant of the glycoprotein of a rabies virus (RABV) with the N-terminal signal peptide is removed and/or replaced.
- the nucleic acid vaccine encodes a variant of the glycoprotein of a rabies virus (RABV) wherein the C-terminal cytoplasmic domain is truncated.
- the C-terminal truncation is a complete removal (i.e., AA 482-524) or partial truncation of the cytoplasmic domain.
- the cytoplasmic domain of the glycoprotein of RABV may be removed so the c-terminal region is truncated staring at amino acid 482.
- the cytoplasmic domain of the glycoprotein of RABV may be truncated starting at amino acid 484.
- the cytoplasmic domain of the glycoprotein of RABV may be truncated starting at amino acid 492.
- the nucleic acid vaccine encodes the glycoprotein of RABV wherein the amino acids YKSG (SEQ ID NO.: 62) (i.e., AAs 516-519) in the cytoplasmic domain of the glycoprotein are deleted.
- the nucleic acid vaccine encoding the glycoprotein of RABV, a fragment, antigenic peptide or variant thereof may also include a signal peptide and/or at least one linker (e.g., GSG linker) sequence and one or more sequences in the nucleic acid vaccine may be codon optimized.
- the nucleic acid vaccine encodes the full-length matrix (M) protein of RABV. In some embodiments, the nucleic acid vaccine encodes a fragment, antigenic peptide or variant of the M protein of RABV.
- the nucleic acid vaccine encoding the M protein of RABV, a fragment or variant thereof may also include a signal peptide and/or at least one linker (e.g., GSG linker) sequence and one or more sequences in the nucleic acid vaccine may be codon optimized.
- the nucleic acid vaccine encodes the full-length phosphoprotein (P) of RABV. In some embodiments, the nucleic acid vaccine encodes an isoform, fragment, antigenic peptide or variant of the phosphoprotein of RABV.
- the nucleic acid vaccine encoding the phosphoprotein of RABV, an isoform, fragment, antigenic peptide or variant thereof may also include a signal peptide and/or at least one linker (e.g., GSG linker) sequence and one or more sequences in the nucleic acid vaccine may be codon optimized.
- the nucleic acid vaccine encodes the full-length nucleoprotein (N) of RABV. In some embodiments, the nucleic acid vaccine encodes a fragment, antigenic peptide or variant of the nucleoprotein of RABV.
- the nucleic acid vaccine encoding the N protein of RABV, a fragment, or antigenic peptide or variant thereof may also include a signal peptide and/or at least one linker (e.g., GSG linker) sequence and one or more sequences in the nucleic acid vaccine may be codon optimized.
- the nucleic acid vaccine encodes the full-length RNA polymerase (L) of RABV. In some embodiments, the nucleic acid vaccine encodes a fragment, antigenic peptide or variant of the RNA polymerase of RABV.
- the nucleic acid vaccine encoding the L protein of RABV, a fragment, or antigenic peptide or variant thereof may also include a signal peptide and/or at least one linker (e.g., GSG linker) sequence and one or more sequences in the nucleic acid vaccine may be codon optimized.
- the nucleic acid vaccine encodes two or more different structural proteins of RABV, fragments, antigenic peptides or variants thereof.
- the polynucleotides described herein encode at least one polypeptide of interest, e.g., one or more proteins, peptides, fragments or variants thereof of RABV.
- the proteins, polypeptides, peptides, fragments or variants thereof of RABV of the present disclosure may be wild type where they are derived from the infectious agent, or modified (e.g., the structural proteins or fragments and variants thereof are engineered, designed or artificial) . They may have any combination of the features described herein.
- the polynucleotides of the nucleic acid vaccines described herein encode one or more peptides or polypeptides of interest.
- Such peptides or polypeptides are structural proteins, or fragments or variants thereof of RABV for the prevention, alleviation and/or treatment of rabies.
- these peptides or polypeptides may serve as an antigen or antigenic molecule (also preferred to as immunogenic molecule) .
- nucleic acids or polynucleotides include, but are not limited to, ribonucleic acids (RNAs) , deoxyribonucleic acids (DNAs) , threose nucleic acids (TNAs) , glycol nucleic acids (GNAs) , peptide nucleic acids (PNAs) , locked nucleic acids (LNAs, including LNA having a ⁇ -D-ribo configuration, ⁇ -LNA having an ⁇ -L-ribo configuration (adiastereomer of LNA) , 2'-amino-LNA having a 2'-amino functionalization, and 2'-amino- ⁇ -LNA having a 2'-amino functionalization) , ethylene nucleic acids (ENA) , cyclohexenyl nucleic acids (CeNA) or hybrids or combinations thereof.
- RNAs ribonucleic acids
- DNAs deoxyribonucleic acids
- TAAs glyco
- IVT enzymatic synthesis methods may be used to make linear polynucleotides (referred to as “IVT polynucleotides” ) encoding one or more proteins, peptides, fragments or variants thereof of RABV of the present disclosure.
- the nucleic acid vaccines may include “chimeric polynucleotides” which have portions or regions which differ in size and/or encoded protein (e.g., structural protein of RABV) .
- a “chimera” is an entity having two or more incongruous or heterogeneous parts or regions.
- a “part” or “region” of a polynucleotide is defined as any portion of the polynucleotide which is less than the entire length of the polynucleotide.
- the chimeric polynucleotide of the present disclosure may comprise a region encoding a heterogeneous signal peptide such as a signal peptide of the light chain of Immunoglobulin.
- the nucleic acid vaccine includes polynucleotides from about 30 to about 100,000 nucleotides in length (e.g., from 30 to 50, from 30 to 100, from 30 to 250, from 30 to 500, from 30 to 1,000, from 30 to 1,500, from 30 to 3,000, from 30 to 5,000, from 30 to 7,000, from 30 to 10,000, from 30 to 25,000, from 30 to 50,000, from 30 to 70,000, from 100 to 250, from 100 to 500, from 100 to 1,000, from 100 to 1,500, from 100 to 3,000, from 100 to 5,000, from 100 to 7,000, from 100 to 10,000, from 100 to 25,000, from 100 to 50,000, from 100 to 70,000, from 100 to 100,000, from 500 to 1,000, from 500 to 1,500, from 500 to 2,000, from 500 to 3,000, from 500 to 5,000, from 500 to 7,000, from 500 to 10,000, from 500 to 25,000, from 500 to 50,000, from 500 to 70,000, from 500 to 100,000, from 1,000 to 1,500, from 500 to 2,000, from 500 to 3,000, from
- the nucleic acid vaccine includes at least one polynucleotide encoding at least one peptide or polypeptide of interest.
- the polynucleotides may be non-coding.
- the length of a region encoding at least one peptide or polypeptide of interest of the polynucleotides of the nucleic acid vaccine is greater than about 30 nucleotides in length (e.g., at least or greater than about 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450,500, 600, 700, 800, 900, 1,000, 1, 100, 1, 200, 1, 300, 1, 400, 1,500, 1, 600, 1, 700, 1, 800, 1, 900, 2,000, 2,500, and 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, 10,000, 20,000, 30,000, 40,000, 50,000, 60,000, 70,000, 80,000, 90,000 or up to and including 100,000 nucleotides) .
- a region may be referred to as a “coding region” or “region encoding. ”
- the polynucleotides of the nucleic acid vaccine is or functions as a messenger RNA (mRNA) .
- mRNA messenger RNA
- the term “messenger RNA (mRNA) ” refers to any polynucleotide which encodes at least one peptide or polypeptide of interest and which is capable of being translated to produce the encoded peptide or polypeptide of interest in vitro, in vivo, in situ or ex vivo.
- the shortest length of a region of the polynucleotide of the nucleic acid vaccine can be the length of a nucleic acid sequence that is sufficient to encode for a dipeptide, a tripeptide, a tetrapeptide, a pentapeptide, a hexapeptide, a heptapeptide, an octapeptide, a nonapeptide, or a decapeptide.
- the length may be sufficient to encode a peptide of 2-30 amino acids, e.g., 5-30, 10-30, 2-25, 5-25, 10-25, or 10-20 amino acids.
- the length may be sufficient to encode for a peptide of at least 11, 12, 13, 14, 15, 17, 20, 25 or 30 amino acids, or a peptide that is no longer than 40 amino acids, e.g., no longer than 35, 30, 25, 20, 17, 15, 14, 13, 12, 11 or 10 amino acids.
- dipeptides that the polynucleotide sequences can encode include, but are not limited to, carnosine and anserine.
- the region of the polynucleotide of the nucleic acid vaccine encoding one or more proteins, peptides, fragments or variants thereof of RABV for the prevention, alleviation and/or treatment of rabies may be greater than about 30 nucleotides in length.
- the length may be, but is not limited to, at least or greater than about 30, 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450,500, 600, 700, 800, 900, 1,000, 1, 100, 1, 200, 1, 300, 1, 400, 1,500, 1, 600, 1, 700, 1, 800, 1, 900, 2,000, 2,500, and 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, 10,000, 20,000, 30,000, 40,000, 50,000, 60,000, 70,000, 80,000, 90,000 or up to and including 100,000 nucleotides.
- the region includes from about 30 to about 100,000 nucleotides (e.g., from 30 to 50, from 30 to 100, from 30 to 250, from 30 to 500, from 30 to 1,000, from 30 to 1,500, from 30 to 3,000, from 30 to 5,000, from 30 to 7,000, from 30 to 10,000, from 30 to 25,000, from 30 to 50,000, from 30 to 70,000, from 100 to 250, from 100 to 500, from 100 to 1,000, from 100 to 1,500, from 100 to 3,000, from 100 to 5,000, from 100 to 7,000, from 100 to 10,000, from 100 to 25,000, from 100 to 50,000, from 100 to 70,000, from 100 to 100,000, from 500 to 1,000, from 500 to 1,500, from 500 to 2,000, from 500 to 3,000, from 500 to 5,000, from 500 to 7,000, from 500 to 10,000, from 500 to 25,000, from 500 to 50,000, from 500 to 70,000, from 500 to 100,000, from 1,000 to 1,500, from 1,000, from 500 to 2,000, from 500 to 3,000, from 500 to 5,000, from 500 to 7,000
- the nucleic acid vaccines described herein may be an mRNA vaccine.
- the mRNA vaccine includes at least one mRNA molecule which, when translated, produce at least one peptide or polypeptide of interest for the prevention, alleviation and/or treatment of rabies.
- an mRNA molecule generally includes at least a coding region, a 5' untranslated region (UTR) , a 3' UTR, a 5' cap and a poly-A tail.
- the mRNA includes a region to initiate translation.
- This region may include any translation initiation sequence or signal including a Start codon.
- the region includes a Start codon.
- the Start codon may be “ATG, ” “ACG, ” “AGG, ” “ATA, ” “ATT, ” “CTG, ” “GTG, ” “TTG, ” “AUG, ” “AUA, ” “AUU, ” “CUG, ” “GUG, ” or “UUG” .
- the mRNA includes a region to stop translation.
- This region may include any translation termination sequence or signal including a Stop codon.
- the region includes a Stop codon.
- the Stop codon may be “TGA, ” “TAA, ” “TGA, ” “TAG, ” “UGA, ” “UAA, ” “UGA” or “UAG. ”
- the regions to initiate or terminate translation may independently range from 3 to 40, e.g., 5-30, 10-20, 15, or at least 4, or 30 or fewer nucleotides in length. Additionally, these regions may comprise, in addition to a Start and/or Stop codon, one or more signal and/or restriction sequences.
- a masking agent may be used to mask a first start codon or alternative start codon in order to increase the chance that translation will initiate on a start codon or alternative start codon downstream to the masked start codon or alternative start codon.
- the start codon may be removed from the polynucleotide sequence in order to have the translation of the polynucleotide begin on a codon which is not the start codon. Translation of the polynucleotide may begin on the codon following the removed start codon or on a downstream start codon or an alternative start codon.
- the polynucleotide sequence where the start codon is removed may further comprise at least one masking agent for the downstream start codon and/or alternative start codons in order to control or attempt to control the initiation of translation, the length of the polynucleotide and/or the structure of the polynucleotide.
- the coding region of the polynucleotide of the nucleic acid vaccine may encode at least one peptide or polypeptide of interest.
- peptides or polypeptides of interest include one or more proteins, polypeptides, peptides, fragments or variants thereof of RABV for the prevention, alleviation and/or treatment of rabies and diseases caused by rabies viral infection.
- the polynucleotides of the nucleic acid vaccines described herein may comprise one or more regions or parts which act or function as an untranslated region (UTR) .
- UTR untranslated region
- Wild type UTRs of a gene are transcribed but not translated. In mRNA, the 5 'UTR starts at the transcription start site and continues to the start codon but does not include the start codon; whereas, the 3'UTR starts immediately following the stop codon and continues until the transcriptional termination signal. While not wishing to be bound by theory, UTRs may have a role in the stability and translation of the nucleic acid molecule. Variants ofUTRs may be utilized where one or more nucleotides (e.g., A, T/U, C or G) are added or removed to the termini, of the UTR.
- nucleotides e.g., A, T/U, C or G
- the UTRs of the polynucleotide of the nucleic acid vaccine may range independently from 15-1,000 nucleotides in length (e.g., greater than 30, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, and 900 nucleotides or at least 30, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450,500, 600, 700, 800, 900, and 1,000 nucleotides) .
- Wild type 5'UTRs include features which play roles in translation initiation as these 5’ UTRs include sequences such as Kozak sequences which are known to be involved in how the ribosome initiates translation of many genes. 5' UTRs also have been known to form secondary structures which are involved in elongation factor binding. Other non-UTR sequences (e.g., introns or portions of intron sequences) may also be used as regions or subregions which may increase protein production as well as polynucleotide levels.
- 3'UTRs Natural or wild type 3'UTRs are known to have stretches of Adenosines and Uridines embedded in them. These AU rich signatures are particularly prevalent in genes with high rates of turnover. Introduction, removal or modification of 3'UTR AU rich elements (AREs) can be used to modulate the stability of polynucleotides of the nucleic acid vaccines.
- AREs 3'UTR AU rich elements
- the UTR from any gene may be incorporated into the regions of the polynucleotides of the nucleic acid vaccines.
- artificial UTRs which are not variants of wild type regions, may also be used in the polynucleotides of the nucleic acid vaccines.
- These UTRs or portions thereof may be placed in the same orientation as in the transcript from which they were selected or may be altered in orientation or location.
- the term “altered” as it relates to a UTR sequence means that the UTR has been changed in some way in relation to a reference sequence.
- a 5' or 3' UTR may be inverted, shortened, lengthened, made with one or more other 5' UTRs or 3' UTRs from a different parental sequence.
- flanking regions are selected from a family of transcripts whose proteins share a common function, structure, feature of property.
- polypeptides of interest may belong to a family of proteins which are expressed in a particular cell, tissue or at some time during development.
- the UTRs from any of these genes may be swapped for any other UTR of the same or different family of proteins to create a new polynucleotide.
- a “family of proteins” is used in the broadest sense to refer to a group of two or more polypeptides of interest which share at least one function, structure, feature, localization, origin, or expression pattern.
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 5’ UTR having a sequence of SEQ ID NO: 55 (DNA) or SEQ ID NO: 56 (RNA) .
- the 5’ UTR of the polynucleotides of the nucleic acid vaccines disclosed herein consist of the nucleic acid sequence of SEQ ID NO: 55 (DNA) or SEQ ID NO: 56 (RNA) .
- the 5’ UTR is directly 5’ of the start codon of the sequence encoding the RABV polypeptide of the nucleic acid vaccine.
- the 5’ UTR is directly 5’ of the start codon of the sequence encoding the signal peptide of the nucleic acid vaccine.
- the 5’ UTR is 1, 2, 3, 4, 5, 6 or more nucleotides 5’ of the start codon of the sequence encoding the RABV polypeptide of the nucleic acid vaccine; e.g., a spacer sequence of 1, 2, 3, 4, 5, 6 or more nucleotides separates the 5’ UTR from the start codon of the sequence encoding the RABV polypeptide of the nucleic acid vaccine.
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 5’ UTR having a sequence with at least 80%sequence identity to the nucleic acid sequence of SEQ ID NO: 55 (DNA) or SEQ ID NO: 56(RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 5’ UTR having a sequence with at least 85%sequence identity to the nucleic acid sequence of SEQ ID NO: 55 (DNA) or SEQ ID NO: 56 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 5’ UTR having a sequence with at least 90%sequence identity to the nucleic acid sequence of SEQ ID NO: 55 (DNA) or SEQ ID NO: 56 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 5’ UTR having a sequence with at least 91%sequence identity to the nucleic acid sequence of SEQ ID NO: 55 (DNA) or SEQ ID NO: 56 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 5’ UTR having a sequence with at least 92%sequence identity to the nucleic acid sequence of SEQ ID NO: 55 (DNA) or SEQ ID NO: 56 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 5’ UTR having a sequence with at least 93%sequence identity to the nucleic acid sequence of SEQ ID NO: 55 (DNA) or SEQ ID NO: 56 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 5’ UTR having a sequence with at least 94%sequence identity to the nucleic acid sequence of SEQ ID NO: 55 (DNA) or SEQ ID NO: 56 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 5’ UTR having a sequence with at least 95%sequence identity to the nucleic acid sequence of SEQ ID NO: 55 (DNA) or SEQ ID NO: 56 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 5’ UTR having a sequence with at least 96%sequence identity to the nucleic acid sequence of SEQ ID NO: 55 (DNA) or SEQ ID NO: 56 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 5’ UTR having a sequence with at least 97%sequence identity to the nucleic acid sequence of SEQ ID NO: 55 (DNA) or SEQ ID NO: 56 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 5’ UTR having a sequence with at least 98%sequence identity to the nucleic acid sequence of SEQ ID NO: 55 (DNA) or SEQ ID NO: 56 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 5’ UTR having a sequence with at least 99%sequence identity to the nucleic acid sequence of SEQ ID NO: 55 (DNA) or SEQ ID NO: 56 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 5’ UTR having a sequence with at least 100%sequence identity to the nucleic acid sequence of SEQ ID NO: 55 (DNA) or SEQ ID NO: 56 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 3’ UTR having a sequence of SEQ ID NO: 57 (DNA) or SEQ ID NO: 58 (RNA) .
- the 3’ UTR of the polynucleotides of the nucleic acid vaccines disclosed herein consist of the nucleic acid sequence of SEQ ID NO: 57 (DNA) or SEQ ID NO: 58 (RNA) .
- the 3’ UTR is directly 3’ of the last codon of the sequence encoding the RABV polypeptide of the nucleic acid vaccine.
- the 3’ UTR is 1, 2, 3, 4, 5, 6 or more nucleotides 3’ of the last codon of the sequence encoding the RABV polypeptide of the nucleic acid vaccine; e.g., a spacer sequence of 1, 2, 3, 4, 5, 6 or more nucleotides separates the 3’ UTR from the last codon of the sequence encoding the RABV polypeptide of the nucleic acid vaccine.
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 3’ UTR having a sequence with at least 80%sequence identity to the nucleic acid sequence of SEQ ID NO: 57 (DNA) or SEQ ID NO: 58 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 3’ UTR having a sequence with at least 85%sequence identity to the nucleic acid sequence of SEQ ID NO: 57 (DNA) or SEQ ID NO: 58 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 3’ UTR having a sequence with at least 90%sequence identity to the nucleic acid sequence of SEQ ID NO: 57 (DNA) or SEQ ID NO: 58 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 3’ UTR having a sequence with at least 91%sequence identity to the nucleic acid sequence of SEQ ID NO: 57 (DNA) or SEQ ID NO: 58 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 3’ UTR having a sequence with at least 92%sequence identity to the nucleic acid sequence of SEQ ID NO: 57 (DNA) or SEQ ID NO: 58 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 3’ UTR having a sequence with at least 93%sequence identity to the nucleic acid sequence of SEQ ID NO: 57 (DNA) or SEQ ID NO: 58 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 3’ UTR having a sequence with at least 94%sequence identity to the nucleic acid sequence of SEQ ID NO: 57 (DNA) or SEQ ID NO: 58 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 3’ UTR having a sequence with at least 95%sequence identity to the nucleic acid sequence of SEQ ID NO: 57 (DNA) or SEQ ID NO: 58 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 3’ UTR having a sequence with at least 96%sequence identity to the nucleic acid sequence of SEQ ID NO: 57 (DNA) or SEQ ID NO: 58 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 3’ UTR having a sequence with at least 97%sequence identity to the nucleic acid sequence of SEQ ID NO: 57 (DNA) or SEQ ID NO: 58 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 3’ UTR having a sequence with at least 98%sequence identity to the nucleic acid sequence of SEQ ID NO: 57 (DNA) or SEQ ID NO: 58 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 3’ UTR having a sequence with at least 99%sequence identity to the nucleic acid sequence of SEQ ID NO: 57 (DNA) or SEQ ID NO: 58 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 3’ UTR having a sequence with at least 100%sequence identity to the nucleic acid sequence of SEQ ID NO: 57 (DNA) or SEQ ID NO: 58 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 3’ UTR having a sequence of SEQ ID NO: 59 (DNA) or SEQ ID NO: 60 (RNA) .
- the 3’ UTR of the polynucleotides of the nucleic acid vaccines disclosed herein consist of the nucleic acid sequence of SEQ ID NO: 59 (DNA) or SEQ ID NO: 60 (RNA) .
- the 3’ UTR is directly 3’ of the last codon of the sequence encoding the RABV polypeptide of the nucleic acid vaccine.
- the 3’ UTR is 1, 2, 3, 4, 5, 6 or more nucleotides 3’ of the last codon of the sequence encoding the RABV polypeptide of the nucleic acid vaccine; e.g., a spacer sequence of 1, 2, 3, 4, 5, 6 or more nucleotides separates the 3’ UTR from the last codon of the sequence encoding the RABV polypeptide of the nucleic acid vaccine.
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 3’ UTR having a sequence with at least 80%sequence identity to the nucleic acid sequence of SEQ ID NO: 59 (DNA) or SEQ ID NO: 60 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 3’ UTR having a sequence with at least 85%sequence identity to the nucleic acid sequence of SEQ ID NO: 59 (DNA) or SEQ ID NO: 60 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 3’ UTR having a sequence with at least 90%sequence identity to the nucleic acid sequence of SEQ ID NO: 59 (DNA) or SEQ ID NO: 60 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 3’ UTR having a sequence with at least 91%sequence identity to the nucleic acid sequence of SEQ ID NO: 59 (DNA) or SEQ ID NO: 60 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 3’ UTR having a sequence with at least 92%sequence identity to the nucleic acid sequence of SEQ ID NO: 59 (DNA) or SEQ ID NO: 60 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 3’ UTR having a sequence with at least 93%sequence identity to the nucleic acid sequence of SEQ ID NO: 59 (DNA) or SEQ ID NO: 60 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 3’ UTR having a sequence with at least 94%sequence identity to the nucleic acid sequence of SEQ ID NO: 59 (DNA) or SEQ ID NO: 60 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 3’ UTR having a sequence with at least 95%sequence identity to the nucleic acid sequence of SEQ ID NO: 59 (DNA) or SEQ ID NO: 60 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 3’ UTR having a sequence with at least 96%sequence identity to the nucleic acid sequence of SEQ ID NO: 59 (DNA) or SEQ ID NO: 60 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 3’ UTR having a sequence with at least 97%sequence identity to the nucleic acid sequence of SEQ ID NO: 59 (DNA) or SEQ ID NO: 60 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 3’ UTR having a sequence with at least 98%sequence identity to the nucleic acid sequence of SEQ ID NO: 59 (DNA) or SEQ ID NO: 60 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 3’ UTR having a sequence with at least 99%sequence identity to the nucleic acid sequence of SEQ ID NO: 59 (DNA) or SEQ ID NO: 60 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 3’ UTR having a sequence with at least 100%sequence identity to the nucleic acid sequence of SEQ ID NO: 59 (DNA) or SEQ ID NO: 60 (RNA) .
- the polynucleotides of the nucleic acid vaccines disclosed herein may comprise a 5’ cap structure.
- the 5'cap structure of a natural mRNA is involved in nuclear export, increasing mRNA stability and binds the mRNA Cap Binding Protein (CBP) , which is responsible for mRNA stability in the cell and translation competency through the association of CBP with poly (A) binding protein to form the mature cyclic mRNA species.
- CBP mRNA Cap Binding Protein
- the cap further assists the removal of 5'proximal introns removal during mRNA splicing.
- the 5’ terminal capping region of the polynucleotide of the nucleic acid vaccine may comprise a single cap or a series of nucleotides forming the cap.
- the capping region may be from 1 to 10, e.g., 2-9, 3-8, 4-7, 1-5, 5-10, or at least 2, or 10 or fewer nucleotides in length.
- the capping region may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 nucleotides.
- the cap is absent.
- cap analogs which herein are also referred to as synthetic cap analogs, chemical caps, chemical cap analogs, or structural or functional cap analogs may be used in the nucleic acid vaccines.
- Cap analogs which may be chemically (e.g., non-enzymatically) or enzymatically synthesized, differ from natural (e.g., endogenous, wild-type or physiological) 5'-caps in their chemical structure, but they retain cap function.
- the 5'terminal caps of the polynucleotides of the nucleic acid vaccines may include endogenous caps or cap analogs.
- 5'terminal caps may comprise a guanine analog.
- Useful guanine analogs include, but are not limited to, inosine, N1-methyl-guanosine (m1G) , 2'-fluoro-guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine, and 2-azido-guanosine.
- 5′capping can be generated via enzymatic or other synthetic processes. Endogenous mRNA molecules are 5′-end capped generating a 5′-ppp-5′-triphosphate linkage between a terminal guanosine cap residue and the 5′-terminal transcribed sense nucleotide of the mRNA molecule. This 5′-guanylate cap can then be methylated to generate an N7-methyl-guanylate residue.
- the ribose sugars of the terminal and/or ante-terminal transcribed nucleotides of the 5′ end of the mRNA can optionally also be 2′-O-methylated.
- 5′-decapping through hydrolysis and cleavage of the guanylate cap structure can target a nucleic acid molecule, such as an mRNA molecule, for degradation.
- Polynucleotides, e.g., mRNAs, of the nucleic acid vaccine described herein may be modified to include a non-hydrolyzable cap structure preventing decapping and thus increasing mRNA half-life. Because cap structure hydrolysis requires cleavage of 5′-ppp-5′ phosphorodiester linkages, modified nucleotides may be used during the capping reaction.
- a vaccinia virus capping enzyme available from, e.g., New England Biolabs (Ipswich, MA) may be used with ⁇ -thio-guanosine nucleotides according to the manufacturer′sinstructions to create a phosphorothioate linkage in the 5′-ppp-5′ cap. Additional modified guanosine nucleotides may be used such as ⁇ -methyl-phosphonate and seleno-phosphate nucleotides.
- Additional modifications include, but are not limited to, 2′-O-methylation of the ribose sugars of 5′-terminal and/or 5′-ante-terminal nucleotides of the mRNA (as mentioned above) on the 2′-hydroxyl group of the sugar ring.
- Multiple distinct 5′-cap structures can be used to generate the 5′-cap of a nucleic acid molecule, such as an mRNA molecule.
- Cap analogs which herein are also referred to as synthetic cap analogs, chemical caps, chemical cap analogs, or structural or functional cap analogs, differ from natural (i.e., endogenous, wild-type or physiological) 5′-caps in their chemical structure, while retaining cap function.
- Cap analogs may be chemically (e.g., non-enzymatically) or enzymatically synthesized and linked to a nucleic acid molecule, such as an mRNA molecule.
- the Anti-Reverse Cap Analog (ARCA) cap contains two guanines linked by a 5′-5′-triphosphate group, wherein one guanine contains an N7 methyl group as well as a 3′-O-methyl group (i.e., N7, 3′-O-dimethyl-guanosine-5′-triphosphate-5′-guanosine (m7G-3′mppp-G; which may equivalently be designated 3′O-Me-m7G (5′) ppp (5′) G) .
- N7, 3′-O-dimethyl-guanosine-5′-triphosphate-5′-guanosine m7G-3′mppp-G; which may equivalently be designated 3′O-Me-m7G (5′) ppp (5′) G
- the 3′-O atom of the other, unmodified, guanine becomes linked to the 5′-terminal nucleotide of the capped nucleic acid molecule (e.g., an mRNA) .
- the N7-and 3′-O-methlyated guanine provide the terminal moiety of the capped nucleic acid molecule (e.g., mRNA) .
- mCAP is similar to ARCA but has a 2′-O-methyl group on guanosine (i.e., N7, 2′-O-dimethyl-guanosine-5′-triphosphate-5′-guanosine, m7Gm-ppp-G) .
- cap analogs allow for the concomitant capping of a nucleic acid molecule in an in vitro transcription reaction, up to 20%of transcripts can remain uncapped. This, as well as the structural differences of cap analogs from endogenous 5′-cap structures may lead to reduced translational competency and reduced cellular stability.
- polynucleotides e.g., mRNAs
- mRNAs can be capped post-transcriptionally, using enzymes.
- recombinant Vaccinia Virus Capping Enzyme and recombinant 2′-O-methyltransferase enzyme can create a canonical 5′-5′-triphosphate linkage between the 5′-terminal nucleotide of an mRNA and a guanine cap nucleotide wherein the cap guanine contains an N7 methylation and the 5′-terminal nucleotide of the mRNA contains a 2′-O-methyl.
- the Cap 1 structure is termed the Cap 1 structure.
- the Cap 1 structure provides a higher translational-competency and cellular stability and a reduced activation of cellular pro-inflammatory cytokines, as compared, e.g., to other 5′cap analog structures known in the art.
- Cap structures include 7mG (5′) ppp (5′) N, pN2p (Cap 0) , 7mG (5′) ppp (5′) N1mpNp (Cap 1) , and 7mG (5′) -ppp (5′) N1mpN2mp (Cap 2) .
- the polynucleotide of the nucleic acid vaccine described herein comprises a Cap 1 structure.
- polynucleotides e.g., mRNA
- the polynucleotides may be capped post-transcriptionally, and because this process is more efficient, up to 100%of the polynucleotides, e.g., mRNA, may be capped. This is in contrast to ⁇ 80%when a cap analog is linked to an mRNA in the course of an in vitro transcription reaction.
- the polynucleotides of the nucleic acid vaccines may contain an internal ribosome entry site (IRES) sequence. While not wishing to be bound by theory, IRES plays an important role in initiating protein synthesis in absence of the 5'cap structure. An IRES may act as the sole ribosome binding site or may serve as one of multiple ribosome binding sites of an mRNA.
- IRES internal ribosome entry site
- the polynucleotide of the nucleic acid vaccine e.g., the mRNA includes a tailing region.
- Non-liming examples of a tailing region include a poly-A sequence, a poly-C sequence, and/or a polyA-G quartet.
- the mRNA includes a chain terminating nucleoside.
- chain terminating nucleosides include 2'-O methyl, F and locked nucleic acids (LNA) .
- the sequence of the tailing region of the polynucleotide of the nucleic acid vaccine may range from absent to 500 nucleotides in length (e.g., at least 60, 70, 80, 90, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, or 500 nucleotides) . If the tailing region is a poly-A tail, the length may be described in units of or as a function of poly-A Binding Protein binding.
- poly-A tails may also be added after the construct is exported from the nucleus.
- a long chain of adenine nucleotides may be added to a polynucleotide such as an mRNA molecule during RNA processing in order to increase stability.
- a polynucleotide such as an mRNA molecule
- the 3' end of the transcript may be cleaved to free a 3' hydroxyl.
- poly-A polymerase adds a chain of adenine nucleotides to the RNA.
- polyadenylation adds a poly-A tail that can be between, for example, approximately 80 to approximately 250 residues long, including approximately 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240 or 250 residues long.
- the length of a poly-A tail when present, is greater than 30 nucleotides in length (e.g., at least or greater than about 30, 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450,500, 600, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,500, and 3,000 nucleotides) .
- the poly-A tail region thereof includes from about 30 to about 3,000 nucleotides (e.g., from 30 to 50, from 30 to 100, from 30 to 250, from 30 to 500, from 30 to 750, from 30 to 1,000, from 30 to 1,500, from 30 to 2,000, from 30 to 2,500, from 50 to 100, from 50 to 250, from 50 to 500, from 50 to 750, from 50 to 1,000, from 50 to 1,500, from 50 to 2,000, from 50 to 2,500, from 50 to 3,000, from 100 to 500, from 100 to 750, from 100 to 1,000, from 100 to 1,500, from 100 to 2,000, from 100 to 2,500, from 100 to 3,000, from 500 to 750, from 500 to 1,000, from 500 to 1,500, from 500 to 2,000, from 500 to 2,500, from 500 to 3,000, from 1,000 to 1,500, from 1,000 to 2,000, from 1,000 to 2,500, from 1,000 to 3,000, from 1,500 to 2,000, from 1,500 to 2,500, from 1,500 to 3,000, from 1,000 to 1,500, from 1,000 to
- the poly-A tail is approximately 97 nucleotides in length (SEQ ID NO: 61) .
- the poly-A tail is approximately 100 nucleotides in length (SEQ ID NO: 63) .
- the poly-A tail is designed relative to the length of the overall polynucleotide or the length of a particular region of the polynucleotide. This design may be based on the length of a coding region, the length of a particular feature or region or based on the length of the ultimate product expressed from the polynucleotides.
- the poly-A tail may be 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100%greater in length than the polynucleotide or feature thereof.
- the poly-A tail may also be designed as a fraction of the polynucleotides to which it belongs.
- the poly-A tail may be 10, 20, 30, 40, 50, 60, 70, 80, or 90%or more of the total length of the construct, a construct region or the total length of the construct minus the poly-A tail.
- engineered binding sites and conjugation of polynucleotides for Poly-A binding protein may enhance expression.
- spacer regions may be present in the polynucleotide such as, but not limited to, the polyadenylation sequence. There may be one or more such spacer regions present.
- a spacer region may be between 3-25, i.e., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleotides.
- the spacer region may be derived from another sequence such as, but not limited to, a restriction site.
- the restriction site may be Spel and may comprise the sequence ACTAGT.
- Polynucleotides including the regions thereof, may have a “patterned polyadenylation sequence. ” Patterned polyadenylation sequences are those polynucleotides having a pattern of residues or regions of residues within, across or among the polynucleotide regions.
- Patterns of the polyadenylation sequence are those which start and stop within a defined region. Patterns of the polyadenylation sequence across a part or region are those patterns which start in on part or region and end in another adjacent part or region. Patterns of the polyadenylation sequence among parts or regions are those which begin and end in one part or region and are repeated in a different part or region, which is not necessarily adjacent to the first region or part.
- the regions or subregions of pattern may have simple alternating patterns such as ABAB [AB] n where each “A” and each “B” represent different sequences (e.g., adenosine residues, restriction sites, spacer sequences) .
- Different patterns may also be mixed together to form a second order pattern.
- a single alternating pattern may be combined with a triple alternating pattern to form a second order alternating pattern A’ B’ .
- One example would be [ABABAB] [AAABBBAAABBB] [ABABAB] [AAABBBAAABBB] [ABABAB] [AAABBBAAABBB] , where [ABABAB] is A’ and [AAABBBAAABBB] is B’.
- Patterns may include three or more different sequences to form an ABCABC [ABC] n pattern. These three component patterns may also be multiples, such as AABBCCAABBCC [AABBCC] n and may be designed as combinations with other patterns such as ABCABCAABBCCABCABCAABBCC, and may be higher order patterns.
- Regions or subregions of position, percent, and population modifications need not reflect an equal contribution from each category of sequence (e.g., adenosine residues, restriction sites, spacer sequences) . They may form series such as “1-2-3-4” , “1-2-4-8” , where each integer represents the number of units of a particular sequence type. Alternatively, they may be odd only, such as ‘1-3-3-1-3-1-5” or even only “2-4-2-4-6-4-8” or a mixture of both odd and even number of units such as “1-3-4-2-5-7-3-3-4” .
- the tailing region includes a spacer sequence as part of the tailing sequence.
- the polynucleotides of the nucleic acid vaccines may also encode additional features which may facilitate the trafficking of the polypeptides to therapeutically relevant sites.
- One such feature which aids in protein trafficking is the signal sequence.
- a “signal sequence” or “signal peptide” is a polynucleotide or polypeptide, respectively, which is from about 9 to 200 nucleotides (3-60 amino acids) in length which is incorporated at the 5' terminus of the coding region or the N-terminus polypeptide encoded, respectively.
- addition of these sequences results in trafficking of the encoded polypeptide to the endoplasmic reticulum through one or more secretory pathways.
- the polynucleotides of the nucleic acid vaccines described herein include a signal sequence comprising SEQ ID NO: 52 (DNA) or SEQ ID NO: 53 (RNA) . In some embodiments, the polynucleotides of the nucleic acid vaccines described herein encode a signal sequence comprising SEQ ID NO: 54.
- the polynucleotides of the nucleic acid vaccines, their regions or parts or subregions may be codon optimized. Codon optimization methods are known in the art and may be useful in efforts to achieve one or more of several goals. These goals include, but are not limited to, match codon frequencies in target and host organisms to ensure proper folding, alter GC content to increase mRNA stability or reduce secondary structures, minimize tandem repeat codons or base runs that may impair gene construction or expression, customize transcriptional and translational control regions, insert or remove protein trafficking sequences, remove/add post translation modification sites in encoded protein (e.g.
- Codon optimization tools, algorithms and services are known in the art, non-limiting examples include, but are not limited to, services from GeneArt (Life Technologies) , DNA2.0 (Menlo Park Calif. ) and/or proprietary methods.
- the ORF sequence is optimized using optimization algorithms. Codon options for each amino acid are given in Table 5.
- the nucleic acid vaccine is vectorized after codon optimization.
- vectors include, but are not limited to, plasmids, viruses, cosmids, and artificial chromosomes.
- Nucleic acid vaccines of the present disclosure may include one or more modifications.
- modification or, as appropriate, “modified” refer to modification with respect to A, G, U or C ribonucleotides. Generally, herein, these terms are not intended to refer to the ribonucleotide modifications in naturally occurring 5′-terminal mRNA cap moieties.
- modification refers to a modification as compared to the canonical set of 20 amino acids.
- nucleoside is defined as a compound containing a sugar molecule (e.g., a pentose or ribose) or a derivative thereof in combination with an organic base (e.g., a purine or pyrimidine) or a derivative thereof (also referred to herein as “nucleobase” ) .
- organic base e.g., a purine or pyrimidine
- nucleotide is defined as a nucleoside including a phosphate group or other backbone linkage (internucleoside linkage) .
- nucleic acid vaccines of the present disclosure comprise one or more modifications which render the nucleic acid molecules, when introduced to a cell, more resistant to degradation in the cell and/or more stable in the cell as compared to unmodified polynucleotides.
- the polynucleotides of the nucleic acid vaccines described herein can include any useful modification, such as to the sugar, the nucleobase, or the internucleoside linkage (e.g., to a linking phosphate/to a phosphodiester linkage/to the phosphodiester backbone) .
- One or more atoms of a pyrimidine nucleobase may be replaced or substituted, for example, with optionally substituted amino, optionally substituted thiol, optionally substituted alkyl (e.g., methyl or ethyl) , optionally substituted or halo (e.g., chloro or fluoro) atoms or groups.
- modifications are present in each of the sugar and the internucleoside linkage.
- Modifications according to the present disclosure may be modifications of ribonucleic acids (RNAs) to deoxyribonucleic acids (DNAs) , threose nucleic acids (TNAs) , glycol nucleic acids (GNAs) , peptide nucleic acids (PNAs) , locked nucleic acids (LNAs) or hybrids thereof. Additional modifications are described herein.
- the modifications include 2’ -O-Methyl-modified or 2’ -O-Methoxyethyl-modified nucleotides (2’ -OMe and 2’ -MOE modifications, respectively) .
- the polynucleotides of the nucleic acid vaccines described herein may comprise at least one modification described herein.
- polynucleotides of the nucleic acid vaccines described herein can include a combination of modifications to the sugar, the nucleobase, and/or the internucleoside linkage.
- RNA polynucleotides e.g., RNA polynucleotides, such as mRNA polynucleotides
- Modifications of polynucleotides include, but are not limited to, any modifications as described in PCT Publication WO2017070626, the contents of which are incorporated herein by reference in their entirety, including, for example, modification or deletion of nucleotides (or codons) encoding one or more N-linked glycosylation site in a translated polypeptide.
- Modifications that are useful in the vaccines of the present disclosure may also comprise any modifications as described in PCT Publication WO2018200892, the contents of which are incorporated herein by reference in their entirety.
- the vaccines of the present disclosure may further comprise features or modifications as described in PCT patent application publications WO2020255063, WO2020182869, WO2016011222, WO2016011226, WO2016005004, WO2016000792, WO2015176737, WO2015085318, WO2015048744, and WO2015034925, and United States patent application publications US20200254086, US20200206362, US20180311336 and US20180303929; the contents of each of which are incorporated herein by reference in their entireties.
- the polynucleotides can include modifications as follows.
- the internucleoside linkages of the polynucleotides may be partially or fully modified.
- the polynucleotides may comprise modifications to one or more nucleobases.
- the polynucleotides may comprise 5-methylcytosines in place of all cytosine nucleobases/cytidine nucleotides.
- the polynucleotides may have one or more modifications to one or more of the sugar subunits of a nucleoside.
- the sugar modification can be one or more locked nucleic acids (LNAs) or 2’ -O-Methoxyethyl-modified ( “2’ -MOE” ) modifications.
- LNAs locked nucleic acids
- 2’ -MOE 2’ -O-Methoxyethyl-modified
- the polynucleotides can be designed with a patterned array of sugar, nucleobase or linkage modifications. In some embodiments, the polynucleotides can comprise modifications to maximize stability. In some embodiments, the polynucleotides can be fully 2’ -MOE-sugar modified.
- the modified nucleosides and nucleotides can include a modified nucleobase.
- nucleobases found in RNA include, but are not limited to, adenine, guanine, cytosine, and uracil.
- nucleobases found in DNA include, but are not limited to,adenine, guanine, cytosine, and thymine.
- the modified nucleobase is a modified uracil.
- Exemplary nucleobases and nucleosides having a modified uracil include pseudouridine ( ⁇ ) , pyridin-4-one ribonucleoside, 5-aza-uridine, 6-aza-uridine, 2-thio-5-aza-uridine, 2-thio-uridine (s 2 U) , 4-thio-uridine (s 4 U) , 4-thio-pseudouridine, 2-thio-pseudouridine, 5-hydroxy-uridine (ho 5 U) , 5-aminoallyl-uridine, 5-halo-uridine (e.g., 5-iodo-uridine or 5-bromo-uridine) , 3-methyl-uridine (m 3 U) , 5-methoxy-uridine (mo 5 U) , uridine 5-oxyacetic acid (cmo 5 U) , uridine 5-oxyacetic acid methyl ester (mcmo 5 U)
- the modified nucleobase is a modified cytosine.
- exemplary nucleobases and nucleosides having a modified cytosine include 5-aza-cytidine, 6-aza-cytidine, pseudoisocytidine, 3-methyl-cytidine (m 3 C) , N4-acetyl-cytidine (ac 4 C) , 5-formyl-cytidine (f 5 C) , N4-methyl-cytidine (m 4 C) , 5-methyl-cytidine (m 5 C) , 5-halo-cytidine (e.g., 5-iodo-cytidine) , 5-hydroxymethyl-cytidine (hm 5 C) , 1-methyl-pseudoisocytidine, pyrrolo-cytidine, pyrrolo-pseudoisocytidine, 2-thio-cytidine (s 2 C) , 2-thio-5-methyl-cyl
- the modified nucleobase is a modified adenine.
- exemplary nucleobases and nucleosides having a modified adenine include 2-amino-purine, 2, 6-diaminopurine, 2-amino-6-halo-purine (e.g., 2-amino-6-chloro-purine) , 6-halo-purine (e.g., 6-chloro-purine) , 2-amino-6-methyl-purine, 8-azido-adenosine, 7-deaza-adenine, 7-deaza-8-aza-adenine, 7-deaza-2-amino-purine, 7-deaza-8-aza-2-amino-purine, 7-deaza-2, 6-diaminopurine, 7-deaza-8-aza-2, 6-diaminopurine, 1-methyl-adenosine (m 1 A) , 2-methyl-adenine (m 2 A) , N6-methyl-adeno
- the modified nucleobase is a modified guanine.
- exemplary nucleobases and nucleosides having a modified guanine include inosine (I) , 1-methyl-inosine (m 1 I) , wyosine (imG) , methylwyosine (mimG) , 4-demethyl-wyosine (imG-14) , isowyosine (imG2) , wybutosine (yW) , peroxywybutosine (o 2 yW) , hydroxywybutosine (OHyW) , undermodified hydroxywybutosine (OHyW*) , 7-deaza-guanosine, queuosine (Q) , epoxyqueuosine (oQ) , galactosyl-queuosine (galQ) , mannosyl-queuosine (manQ) , 7-cyano-7-d
- the nucleobase of the nucleotide can be independently selected from a purine, a pyrimidine, a purine or pyrimidine analog.
- the nucleobase can each be independently selected from adenine, cytosine, guanine, uracil, or hypoxanthine.
- the nucleobase can also include, for example, naturally-occurring and synthetic derivatives of a base, including pyrazolo [3, 4-d] pyrimidines, 5-methylcytosine (5-me-C) , 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil) , 4-thiouracil, 8-halo (e.g., 8-bromo) , 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substitute
- nucleotide modifications may be introduced at various positions in a polynucleotide described herein.
- nucleotide analogs or other modification may be located at any position (s) of a polynucleotide such that the function of the polynucleotide is not substantially decreased.
- the polynucleotides of the present disclosure may contain from about 1%to about 100%modified nucleotides (either in relation to overall nucleotide content, or in relation to one or more types of nucleotide, i.e.
- any one or more ofA, G, T/U or C) or any intervening percentage e.g., from 1%to 20%, from 1%to 25%, from 1%to 50%, from 1%to 60%, from 1%to 70%, from 1%to 80%, from 1%to 90%, from 1%to 95%, from 10%to 20%, from 10%to 25%, from 10%to 50%, from 10%to 60%, from 10%to 70%, from 10%to 80%, from 10%to 90%, from 10%to 95%, from 10%to 100%, from 20%to 25%, from 20%to 50%, from 20%to 60%, from 20%to 70%, from 20%to 80%, from 20%to 90%, from 20%to 95%, from 20%to 100%, from 50%to 60%, from 50%to 70%, from 50%to 80%, from 50%to 90%, from 50%to 95%, from 50%to 100%, from 70%to 80%, from 70%to 90%, from 70%to 95%, from 70%to 100%, from 80%to 90%, from 80%to 95%, from 90%to 100%, and from 95%to 100%
- the polynucleotides of the nucleic acid vaccines described herein may be modified to be a circular nucleic acid.
- the termini of the polynucleotides may be linked by chemical reagents or enzymes, producing circular polynucleotides that have no free ends.
- Circular polynucleotides are expected to be more stable than linear counterparts and to be resistant to digestion with exonucleases.
- Circular polynucleotides may further comprise other structural and/or chemical modifications with respect to A, G, T/U or C ribonucleotides/deoxyribonucleotides.
- the polynucleotides are at least 50%modified, e.g., at least 50%of the nucleotides are modified. In some embodiments, the polynucleotides are at least 75%modified, e.g., at least 75%of the nucleotides are modified. It is to be understood that since a nucleotide (sugar, base and phosphate moiety, e.g., linkage) may each be modified, any modification to any portion of a nucleotide, or nucleoside, will constitute a modification.
- the polynucleotides are at least 10%modified in only one component of the nucleotide, with such component being the nucleobase, sugar, or linkage between nucleosides.
- modifications may be made to at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%or 100%of the nucleobases, sugars, or linkages of a polynucleotide described herein.
- the uracil nucleosides of the polynucleotide of the nucleic acid vaccine are all modified.
- the modifications may be the same or different.
- the guanine nucleosides of the polynucleotide of the nucleic acid vaccine are all modified.
- the modifications may be the same or different.
- the guanine nucleosides of the polynucleotide of the nucleic acid vaccine are all modified.
- the modifications may be the same or different.
- the cytosine nucleosides of the polynucleotide of the nucleic acid vaccine are all modified.
- the modifications may be the same or different.
- the adenine nucleosides of the polynucleotide of the nucleic acid vaccine are all modified. The modifications may be the same or different.
- the polynucleotide of the nucleic acid vaccine is modified to comprise N1-methyl-pseudouridine nucleotides.
- modified nucleosides and nucleotides which may be incorporated into polynucleotides (e.g., RNA or mRNA, as described herein) , can be modified on the sugar of the ribonucleic acid.
- the 2′hydroxyl group (OH) can be modified or replaced with a number of different substituents.
- substitutions at the 2′-position include, but are not limited to, H, halo, optionally substituted C 1-6 alkyl; optionally substituted C 1-6 alkoxy; optionally substituted C 6-10 aryloxy; optionally substituted C 3-8 cycloalkyl; optionally substituted C 3-8 cycloalkoxy; optionally substituted C 6-10 aryloxy; optionally substituted C 6-10 aryl-C 1-6 alkoxy, optionally substituted C 1-12 (heterocyclyl) oxy; a sugar (e.g., ribose, pentose, or any described herein) ; a polyethyleneglycol (PEG) , -O (CH 2 CH 2 O) n CH 2 CH 2 OR, where R is H or optionally substituted alkyl, and n is an integer from 0 to 20 (e.g., from 0 to 4, from 0 to 8, from 0 to 10,from 0 to 16, from 1 to 4, from 1 to 8, from 1 to 10,
- the polynucleotide such as the mRNA of the nucleic acid vaccine described herein comprises at least one sugar modification.
- RNA includes the sugar group ribose, which is a 5-membered ring having an oxygen.
- modified nucleotides include replacement of the oxygen in ribose (e.g., with S, Se, or alkylene, such as methylene or ethylene) ; addition of a double bond (e.g., to replace ribose with cyclopentenyl or cyclohexenyl) ; ring contraction of ribose (e.g., to form a 4-membered ring of cyclobutane or oxetane) ; ring expansion of ribose (e.g., to form a 6-or 7-membered ring having an additional carbon or heteroatom, such as for anhydrohexitol, altritol, mannitol, cyclohexanyl, cyclohexenyl, and morpholino that also has a phosphoramidate backbone) ; multicyclic forms (e.g., tricyclo; and“unlocked” forms, such as glycol nucleic
- the sugar group can also contain one or more carbons that possess the opposite stereochemical configuration than that of the corresponding carbon in ribose.
- polynucleotide molecules as described herein, including mRNAs can include nucleotides containing, e.g., arabinose, as the sugar.
- Nonlimiting examples of the sugar modification may include the modifications provided in Table 6.
- the polynucleotides of the present disclosure can have one or more nucleotides carrying a modification as provided in Table 6.
- each of the nucleotides of a polynucleotide described herein carries any one of the modifications as provided in Table 6, or none of the modifications as provided in Table 6.
- At least one of the 2' positions of the sugar (OH in RNA or H in DNA) of a nucleotide of the polynucleotides is substituted with-OMe, referred to as 2’ -OMe.
- at least one of the 2' positions of the sugar (OH in RNA or H in DNA) of a nucleotide of the polynucleotides is substituted with-F, referred to as 2’ -F.
- the polynucleotides of the present disclosure can include any modification to the internucleoside linkage (e.g., to a linking phosphate/to a phosphodiester linkage/to the phosphodiester backbone) .
- the phrases “phosphate” and “phosphodiester” are used interchangeably.
- Backbone phosphate groups can be modified by replacing one or more of the oxygen atoms with a different substituent.
- the modified nucleosides and nucleotides can include the wholesale replacement of an unmodified phosphate moiety with another internucleoside linkage as described herein.
- modified phosphate groups include, but are not limited to, phosphorothioate, methylphosphonates phosphoroselenates, boranophosphates, boranophosphate esters, hydrogen phosphonates, phosphoramidates, phosphorodiamidates, alkyl or aryl phosphonates, and phosphotriesters.
- Phosphorodithioates have both non-linking oxygens replaced by sulfur.
- the phosphate linker can also be modified by the replacement of a linking oxygen with nitrogen (bridged phosphoramidates) , sulfur (bridged phosphorothioates) , and carbon (bridged methylene-phosphonates) .
- the ⁇ -thio substituted phosphate moiety is provided to confer stability to RNA and DNA polynucleotides through the unnatural phosphorothioate backbone linkages.
- Phosphorothioate DNA and RNA have increased nuclease resistance and subsequently a longer half-life in a cellular environment.
- Phosphorothioate linked polynucleotide molecules are expected to also reduce the innate immune response through weaker binding/activation of cellular innate immune molecules.
- a modified nucleoside includes an alpha-thio-nucleoside (e.g., 5′-O- (1-thiophosphate) -adenosine, 5′-O- (1-thiophosphate) -cytidine ( ⁇ -thio-cytidine) , 5′-O- (1-thiophosphate) -guanosine, 5′-O- (1-thiophosphate) -uridine, or 5′-O- (1-thiophosphate) -pseudouridine) .
- alpha-thio-nucleoside e.g., 5′-O- (1-thiophosphate) -adenosine, 5′-O- (1-thiophosphate) -cytidine ( ⁇ -thio-cytidine) , 5′-O- (1-thiophosphate) -guanosine, 5′-O- (1-thiophosphate) -uridine, or 5′-O- (1-thio
- the polynucleotides comprise at least one phosphorothioate linkage or methylphosphonate linkage between nucleotides.
- the polynucleotides comprise at least one 5’ - (E) -vinylphosphonate (5’ -E-VP) , a phosphate mimic, as a modification.
- the polynucleotide (e.g., mRNA) of the nucleic acid vaccine for rabies may be modified.
- Nucleic acid vaccines of the present disclosure may vary in their valency. “Valency” refers to the number of antigenic components in the nucleic acid vaccine or the polynucleotide of the nucleic acid vaccines. The antigenic components of the nucleic acid vaccine may be on the same polynucleotide or they may be on different polynucleotides. In some embodiments, the nucleic acid vaccine may be monovalent. In some embodiments, the nucleic acid vaccine may be divalent. In some embodiments, the nucleic acid vaccine may be trivalent.
- the nucleic acid vaccine may be multivalent which may comprise 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more than 25 antigens or antigenic moieties such as, but not limited to, antigenic peptides.
- antigenic peptides may be one or more fragments or variants of the structural proteins of RABV.
- cDNA encoding the polynucleotides of the nucleic acid vaccines described herein may be transcribed using an in vitro transcription (IVT) system.
- the system typically comprises a transcription buffer, nucleotide triphosphates (NTPs) , an RNase inhibitor and a polymerase.
- NTPs may be manufactured in house, may be selected from a supplier, or may be synthesized as described herein.
- the NTPs may be selected from, but are not limited to, those described herein including natural and unnatural (modified) NTPs.
- the polymerase may be selected from, but is not limited to, T7 RNA polymerase, T3 RNA polymerase and polymerase variants.
- the DNA template is removed from the IVT reaction, using a DNase I enzyme.
- the digested DNA and nucleotides are then removed during oligo dT purification of the mRNA.
- This purification method is based on affinity of the poly-A tail of the mRNA to the poly-dT column bed. Centrifugation may be used but may not be required to remove the digested DNA and nucleotides.
- a reverse phase column e.g., SDVB
- ultrafiltration may be utilized, followed by one or more filtration steps.
- DNA may be measured to confirm that the DNA has been removed by using PCR for a region of the plasmid outside of the region transcribed into mRNA.
- diafiltration methods may be used followed by one or more filtration steps to remove any bioburden (e.g., biomolecules, or other biomaterial) .
- RNA polymerases or variants may be used in the synthesis of the polynucleotides of the nucleic acid vaccine described herein.
- RNA polymerases may be modified by inserting or deleting amino acids of the RNA polymerase sequence.
- Polynucleotide or nucleic acid synthesis reactions may be carried out by enzymatic methods utilizing polymerases.
- Polymerases catalyze the creation of phosphodiester bonds between nucleotides in a polynucleotide or nucleic acid chain.
- DNA polymerase I polymerase I
- a polymerase family including the Klenow fragments of E. Coli, Bacillus DNA polymerase I, Thermus aquaticus (Taq) DNA polymerases, and the T7 RNA and DNA polymerases, is among the best studied of these families.
- DNA polymerase a or B polymerase family, including all eukaryotic replicating DNA polymerases and polymerases from phages T4 and RB69. Although they employ similar catalytic mechanism, these families of polymerases differ in substrate specificity, substrate analog-incorporating efficiency, degree and rate for primer extension, mode of DNA synthesis, exonuclease activity, and sensitivity against inhibitors.
- polynucleotides of the nucleic acid vaccines described herein may be manufactured in whole or in part using solid phase techniques.
- Solid-phase chemical synthesis of polynucleotides or nucleic acids is an automated method wherein molecules are immobilized on a solid support and synthesized step by step in a reactant solution. Impurities and excess reagents are washed away and no purification is required after each step. The automation of the process is amenable on a computer-controlled solid-phase synthesizer. Solid-phase synthesis allows rapid production of polynucleotides or nucleic acids in a relatively large scale that leads to the commercial availability of some polynucleotides or nucleic acids.
- automated solid-phase synthesis is used where the chain is synthesized in 3' to 5' direction.
- the hydroxyl group in the 3' end of a nucleoside is tethered to a solid support via a chemically cleavable or light-cleavable linker.
- Activated nucleoside monomers such as 2'-deoxynucleosides (dA, dC, dG and dT) , ribonucleosides (A, C, G, and U) , or chemically modified nucleosides, are added to the support-bound nucleoside sequentially.
- a cleaving agent such as ammonia or ammonium hydroxide is added to remove all the protecting groups and release the polynucleotide chains from the solid support.
- Light may also be applied to cleave the polynucleotide chain.
- the product can then be further purified with high pressure liquid chromatography (HPLC) or electrophoresis.
- HPLC high pressure liquid chromatography
- the synthesis of polynucleotides of the nucleic acid vaccines described herein by the sequential addition of monomer building blocks may be carried out in a liquid phase.
- a covalent bond is formed between the monomers or between a terminal functional group of the growing chain and an incoming monomer.
- Functional groups not involved in the reaction must be temporarily protected.
- the reaction mixture has to be purified before adding the next monomer building block.
- the functional group at one terminal of the chain has to be deprotected to be able to react with the next monomer building blocks.
- a liquid phase synthesis is labor-and time-consuming and cannot not be automated. Despite the limitations, liquid phase synthesis is still useful in preparing short polynucleotides in a large scale. Because the system is homogenous, it does not require a large excess of reagents and is cost-effective in this respect.
- the polynucleotides of the nucleic acid vaccines described herein may be quantified in exosomes or when derived from one or more bodily fluid.
- bodily fluids include peripheral blood, serum, plasma, ascites, urine, cerebrospinal fluid (CSF) , sputum, saliva, bone marrow, synovial fluid, aqueous humor, amniotic fluid, cerumen, breast milk, bronchoalveolar lavage fluid, semen, prostatic fluid, cowper’s fluid or pre-ejaculatory fluid, sweat, fecal matter, hair, tears, cyst fluid, pleural and peritoneal fluid, pericardial fluid, lymph, chyme, chyle, bile, interstitial fluid, menses, pus, sebum, vomit, vaginal secretions, mucosal secretion, stool water, pancreatic juice, lavage fluids from sinus cavities, bronchopulmonary aspirates, blastocyl cavity fluid
- exosomes may be retrieved from an organ selected from the group consisting of lung, heart, pancreas, stomach, intestine, bladder, kidney, ovary, testis, skin, colon, breast, prostate, brain, esophagus, liver, and placenta.
- the exosome quantification method a sample of not more than 2 mL is obtained from the subject and the exosomes isolated by size exclusion chromatography, density gradient centrifugation, differential centrifugation, nanomembrane ultrafiltration, immunosorbent capture, affinity purification, microfluidic separation, or combinations thereof.
- the level or concentration of a polynucleotide may be an expression level, presence, absence, truncation or alteration of the administered construct. It is advantageous to correlate the level with one or more clinical phenotypes or with an assay for a human disease biomarker.
- the assay may be performed using construct specific probes, cytometry, qRT-PCR, real-time PCR, PCR, flow cytometry, electrophoresis, mass spectrometry, or combinations thereof while the exosomes may be isolated using immunohistochemical methods such as enzyme linked immunosorbent assay (ELISA) methods. Exosomes may also be isolated by size exclusion chromatography, density gradient centrifugation, differential centrifugation, nanomembrane ultrafiltration, immunosorbent capture, affinity purification, microfluidic separation, or combinations thereof.
- immunohistochemical methods such as enzyme linked immunosorbent assay (ELISA) methods.
- Exosomes may also be isolated by size exclusion chromatography, density gradient centrifugation, differential centrifugation, nanomembrane ultrafiltration, immunosorbent capture, affinity purification, microfluidic separation, or combinations thereof.
- the polynucleotide may be quantified using methods such as, but not limited to, ultraviolet visible spectroscopy (UV/Vis) .
- UV/Vis ultraviolet visible spectroscopy
- a non-limiting example of a UV/Vis spectrometer is a spectrometer (ThermoFisher, Waltham, Mass. ) .
- the quantified polynucleotide may be analyzed in order to determine if the polynucleotide may be of proper size, check that no degradation of the polynucleotide has occurred.
- Degradation of the polynucleotide may be checked by methods such as, but not limited to, agarose gel electrophoresis, HPLC based purification methods such as, but not limited to, strong anion exchange HPLC, weak anion exchange HPLC, reverse phase HPLC (RP-HPLC) , and hydrophobic interaction HPLC (HIC-HPLC) , liquid chromatography-mass spectrometry (LCMS) , capillary electrophoresis (CE) and capillary gel electrophoresis (CGE) .
- HPLC based purification methods such as, but not limited to, strong anion exchange HPLC, weak anion exchange HPLC, reverse phase HPLC (RP-HPLC) , and hydrophobic interaction HPLC (HIC-HPLC) , liquid chromatography-mass spectrometry (LCMS) , capillary electrophoresis (CE) and capillary gel electrophoresis (CGE) .
- HPLC based purification methods such as, but not limited
- Purification of the polynucleotides of the nucleic acid vaccines described herein may include, but is not limited to, polynucleotide clean-up, quality assurance and quality control. Clean-up may be performed by methods known in the arts such as, but not limited to, beads (Beckman Coulter Genomics, Danvers, Mass. ) , poly-T beads, LNA TM oligo-T capture probes ( Inc, Vedbaek, Denmark) or HPLC based purification methods such as, but not limited to, strong anion exchange HPLC, weak anion exchange HPLC, reverse phase HPLC (RP-HPLC) , and hydrophobic interaction HPLC (HIC-HPLC) .
- beads Beckman Coulter Genomics, Danvers, Mass.
- poly-T beads poly-T beads
- LNA TM oligo-T capture probes Inc, Vedbaek, Denmark
- HPLC based purification methods such as, but not limited to, strong anion exchange HPLC, weak anion exchange HP
- purified when used in relation to a polynucleotide such as a “purified polynucleotide” refers to one that is separated from at least one contaminant.
- a “contaminant” is any substance which makes another unfit, impure or inferior.
- a purified polynucleotide e.g., DNA and RNA
- a quality assurance and/or quality control check may be conducted using methods such as, but not limited to, gel electrophoresis, UV absorbance, or analytical HPLC.
- nucleic acid vaccines described herein may be used as therapeutic or prophylactic agents such as preexposure prophylaxis and postexposure prophylaxis (PEP) .
- PEP postexposure prophylaxis
- the present disclosure provides pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier and a nucleic acid vaccine, i.e., a nucleic acid vaccine for rabies.
- the pharmaceutical compositions comprising the nucleic acid vaccine described herein can be used for preventing, alleviating and/or treating rabies.
- nucleic acid vaccines and pharmaceutical compositions thereof which may be used in combination with one or more pharmaceutically acceptable excipients.
- Pharmaceutical compositions may optionally comprise one or more additional active substances, e.g., therapeutically and/or prophylactically active substances.
- Pharmaceutical compositions of the nucleic acid vaccines described herein may be sterile and/or pyrogen-free.
- compositions are administered to humans, human patients or subjects.
- active ingredient generally refers to the nucleic acid vaccines or the polynucleotides contained therein, e.g., polynucleotides encoding one or more proteins, peptides, fragments or variants thereof of RABV for the prevention, alleviation and/or treatment of rabies, to be delivered as described herein.
- compositions are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to any other animal, e.g., to non-human animals, e.g., non-human mammals. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with merely ordinary, if any, experimentation.
- Subjects to which administration of the pharmaceutical compositions is contemplated include, but are not limited to, humans and/or other primates; mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, dogs, mice, and/or rats; and/or birds, including commercially relevant birds such as poultry, chickens, ducks, geese, and/or turkeys.
- compositions may additionally comprise a pharmaceutically acceptable excipient, which, as used herein, includes, but is not limited to, any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, and the like, as suited to the particular dosage form desired.
- a pharmaceutically acceptable excipient includes, but is not limited to, any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, and the like, as suited to the particular dosage form desired.
- excipients for formulating pharmaceutical compositions and techniques for preparing the composition are known in the art (see Remington: The Science and Practice ofPharmacy, 21 st Edition, A. R. Gennaro, Lippincott, Williams&Wilkins, Baltimore,
- any conventional excipient medium may be contemplated within the scope of the present disclosure, except insofar as any conventional excipient medium may be incompatible with a substance or its derivatives, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component (s) of the pharmaceutical composition.
- Formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with an excipient and/or one or more other accessory ingredients, and then, if necessary and/or desirable, dividing, shaping and/or packaging the product into a desired single-or multi-dose unit.
- Apharmaceutical composition in accordance with the disclosure may be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
- a “unit dose” is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
- the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
- compositions in accordance with the disclosure will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
- the composition may comprise between 0.1%and 100%, e.g., between 0.5 and 50%, between 1-30%, between 5-80%, at least 80% (w/w) active ingredient.
- the formulations described herein may contain at least one nucleic acid vaccine composition, e.g., nucleic acid vaccine for rabies, e.g., one mRNA vaccine for rabies.
- the formulations may contain 1, 2, 3, 4 or 5 nucleic acid vaccine compositions with different sequences, e.g., 1, 2, 3, 4 or 5 mRNA vaccine compositions with different sequences.
- the formulation contains at least two nucleic acid vaccine (e.g., mRNA vaccine) compositions with different sequences.
- the formulation contains at least three nucleic acid vaccine (e.g., mRNA vaccine) compositions with different sequences.
- the formulation contains at least four nucleic acid vaccine (e.g., mRNA vaccine) compositions with different sequences. In some embodiments, the formulation contains at least five nucleic acid vaccine (e.g., mRNA vaccine) compositions with different sequences.
- the nucleic acid vaccine compositions of the present disclosure can be formulated using one or more excipients to: (1) increase stability; (2) increase cell transfection; (3) permit the sustained or delayed release (e.g., from a depot formulation of the nucleic acid vaccine composition) ; (4) alter the biodistribution (e.g., target the nucleic acid vaccine composition to specific tissues or cell types) ; (5) increase the translation of encoded protein in vivo; and/or (6) alter the release profile of encoded protein in vivo.
- excipients to: (1) increase stability; (2) increase cell transfection; (3) permit the sustained or delayed release (e.g., from a depot formulation of the nucleic acid vaccine composition) ; (4) alter the biodistribution (e.g., target the nucleic acid vaccine composition to specific tissues or cell types) ; (5) increase the translation of encoded protein in vivo; and/or (6) alter the release profile of encoded protein in vivo.
- excipients of the present disclosure can include, without limitation, lipidoids, liposomes, lipid nanoparticles, polymers, lipoplexes, core-shell nanoparticles, peptides, proteins, cells transfected with nucleic acid vaccine compositions (e.g., for transplantation into a subject) , hyaluronidase, nanoparticle mimics and combinations thereof.
- the formulations of the present disclosure can include one or more excipients, each in an amount that together increases the stability of the nucleic acid vaccine compositions and/or increases cell transfection by the nucleic acid vaccine compositions.
- the nucleic acid vaccine compositions of the present disclosure may be formulated using self-assembled nucleic acid nanoparticles.
- Pharmaceutically acceptable carriers, excipients, and delivery agents for nucleic acids that may be used in the formulation with the nucleic acid vaccine compositions of the present disclosure are disclosed in PCT Patent Application Publication WO 2013/090648, the contents of which are incorporated herein by reference in their entirety.
- nucleic acid vaccine compositions of the disclosure can be formulated using one or more lipidoids.
- lipidoids The synthesis of lipidoids has been extensively described and formulations containing these compounds are particularly suited for delivery of oligonucleotides or nucleic acids (see Mahon et al., Bioconjug Chem. 2010, 21: 1448-1454; Schroeder et al., J Intern Med. 2010, 267: 9-21; Akinc et al., Nat Biotechnol. 2008, 26: 561-569; Love et al., Proc Natl Acad Sci USA. 2010, 107: 1864-1869; Siegwart et al., Proc Natl Acad Sci US A. 2011, 108: 12996-3001; the contents of all of which are incorporated herein by references in their entirety) .
- the present disclosure contemplates their formulation and use in delivering at least one pharmaceutically acceptable carrier, including nucleic acid vaccines.
- nucleic acid vaccines include nucleic acid vaccines.
- Complexes, micelles, liposomes or particles can be prepared containing these lipidoids and therefore, can result in an effective delivery of the nucleic acid vaccine compositions following the injection of a lipidoid formulation via localized and/or systemic routes of administration.
- Lipidoid complexes containing nucleic acid vaccine compositions can be administered by various means including, but not limited to, intravenous (IV) , intramuscular (IM) , subcutaneous (SC) , intraparenchymal (IPa) , intrathecal (IT) , or intracerebroventricular (ICV) administration.
- IV intravenous
- IM intramuscular
- SC subcutaneous
- IPa intraparenchymal
- IMV intracerebroventricular
- nucleic acids may be affected by many parameters, including, but not limited to, the formulation composition, nature of particle PEGylation, degree of loading, polynucleotide to lipid ratio, and biophysical parameters such as, but not limited to, particle size (Akinc et al., Mol Ther. 2009, 17: 872-879; the contents of which are herein incorporated by reference in their entirety) .
- particle size Akinc et al., Mol Ther. 2009, 17: 872-879; the contents of which are herein incorporated by reference in their entirety.
- small changes in the anchor chain length of poly (ethylene glycol) (PEG) lipids may result in significant effects on in vivo efficacy.
- Formulations with the different lipidoids including, but not limited to penta [3- (1-laurylaminopropionyl) ] -triethylenetetramine hydrochloride (TETA–5LAP; aka 98N12-5, see Murugaiah et al., Analytical Biochemistry, 2010, 401: 61; the contents of which are herein incorporated by reference in their entirety) , C12-200(including derivatives and variants) , and MD1, can be tested for in vivo activity.
- penta [3- (1-laurylaminopropionyl) ] -triethylenetetramine hydrochloride (TETA–5LAP; aka 98N12-5, see Murugaiah et al., Analytical Biochemistry, 2010, 401: 61; the contents of which are herein incorporated by reference in their entirety) , C12-200(including derivatives and variants) , and MD1 can be tested for in vivo activity.
- lipidoid referred to herein as “98N12-5” is disclosed by Akinc et al., Mol Ther. 2009, 17: 872-879 and the contents of which is incorporated herein by reference in their entirety.
- the lipidoid referred to herein as “C12-200” is disclosed by Love et al., Proc Natl Acad Sci USA. 2010, 107: 1864-1869 and Liu and Huang, Molecular Therapy. 2010, 669-670; the contents of both of which are herein incorporated herein by reference in their entirety.
- the lipidoid formulations can include particles comprising either 3 or 4 or more components in addition to the nucleic acid vaccine compositions.
- formulations with certain lipidoids include, but are not limited to, 98N12-5 and may contain 42%lipidoid, 48%cholesterol and 10%PEG (C14 alkyl chain length) .
- formulations with certain lipidoids include, but are not limited to, C12-200 and may contain 50%lipidoid, 10%disteroylphosphatidyl choline, 38.5%cholesterol, and 1.5%PEG-DMG.
- nucleic acid vaccine compositions formulated with a lipidoid for systemic intravenous administration can result in the distribution of the formulation to be greater than 90%to the liver.
- a final optimized intravenous formulation using nucleic acid vaccine compositions and comprising a lipid molar composition of 42%98N12-5, 48%cholesterol, and 10%PEG-lipid with a final weight ratio of about 7.5 to 1 total lipid to nucleic acid vaccine compositions and a C14 alkyl chain length on the PEG lipid, with a mean particle size of roughly 50–60 nm, can result in the distribution of the formulation to be greater than 90%to the liver. (see, Akinc et al., Mol Ther.
- an intravenous formulation using a C12-200 lipidoid may have a molar ratio of 50/10/38.5/1.5 of C12-200/disteroylphosphatidyl choline/cholesterol/PEG-DMG, with a weight ratio of 7 to 1 total lipid to nucleic acid and a mean particle size of 80 nm may be effective to deliver nucleic acid vaccine compositions (see, Love et al., Proc Natl Acad Sci USA. 2010, 107: 1864-1869, the contents of which are herein incorporated by reference herein in their entirety) .
- an MD1 lipidoid-containing formulation may be used to effectively deliver nucleic acid vaccine compositions to hepatocytes in vivo.
- the characteristics of optimized lipidoid formulations for intramuscular or subcutaneous routes may vary significantly depending on the target cell type and the ability of formulations to diffuse through the extracellular matrix into the blood stream. While a particle size of less than 150 nm may be desired for effective hepatocyte delivery due to the size of the endothelial fenestrae (see, Akinc et al., Mol Ther.
- lipidoid-formulated nucleic acid vaccine composition to deliver the formulation to other cells types including, but not limited to, endothelial cells, myeloid cells, and muscle cells may not be similarly size-limited.
- lipidoid formulations may have a similar component molar ratio.
- lipidoids and other components including, but not limited to, disteroylphosphatidyl choline, cholesterol and PEG-DMG, may be used to optimize the formulation of nucleic acid vaccine compositions for delivery to different cell types including, but not limited to, hepatocytes, myeloid cells, muscle cells, etc.
- the component molar ratio may include, but is not limited to, 50%C12-200, 10%disteroylphosphatidyl choline, 38.5%cholesterol, and 1.5%PEG-DMG (see Leuschner et al., Nat Biotechnol 2011, 29: 1005-1010; the contents of which are herein incorporated by reference in their entirety) .
- lipidoid formulations for the localized delivery of nucleic acids to cells via either subcutaneous or intramuscular delivery, may not require all of the formulation components desired for systemic delivery, and as such may comprise only the lipidoid and nucleic acid vaccine compositions.
- nucleic acid vaccine compositions of the disclosure can be formulated using one or more liposomes.
- compositions of nucleic acid vaccine compositions include liposomes.
- Liposomes are artificially prepared vesicles which may primarily be composed of a lipid bilayer and may be used as a delivery vehicle for the administration of nutrients and pharmaceutical formulations.
- Liposomes can be of different sizes such as, but not limited to, a multilamellar vesicle (MLV) which may be hundreds of nanometers in diameter and may contain a series of concentric bilayers separated by narrow aqueous compartments, a small unicellular vesicle (SUV) which may be smaller than 50 nm in diameter, and a large unilamellar vesicle (LUV) which may be between 50 and 500 nm in diameter.
- MLV multilamellar vesicle
- SUV small unicellular vesicle
- LUV large unilamellar vesicle
- Liposome design may include, but is not limited to,opsonins or ligands in order to improve the attachment of liposomes to unhealthy tissue or to activate events such as, but not limited to, endocytosis.
- Liposomes may contain a low or a high pH in order to improve the delivery of the pharmaceutical formulations.
- liposomes may depend on the physicochemical characteristics such as, but not limited to, the pharmaceutical formulation entrapped and the liposomal ingredients, the nature of the medium in which the lipid vesicles are dispersed, the effective concentration of the entrapped substance and its potential toxicity, any additional processes involved during the application and/or delivery of the vesicles, the optimized particle size, polydispersity and the shelf-life of the vesicles for the intended application, and the batch-to-batch reproducibility and possibility of large-scale production of safe and efficient liposomal products.
- compositions comprising the nucleic acid vaccines described herein may include, without limitation, liposomes such as those formed from 1, 2-dioleyloxy-N, N-dimethylaminopropane (DODMA) liposomes, DiLa2 liposomes from Marina Biotech (Bothell, WA) , (Marina Biotech, Bothell) , 1, 2-dilinoleyloxy-3-dimethylaminopropane (DLin-DMA) , 2, 2-dilinoleyl-4- (2-dimethylaminoethyl) - [1, 3] -dioxolane (DLin-KC2-DMA) , and MC3 (US Patent Application Publication US20100324120; the contents of which are herein incorporated by reference in their entirety) , neutral DOPC (1, 2-dioleoyl-sn-glycero-3-phosphocholine) based liposomes (e.g., siRNA delivery for ovarian
- DODMA
- compositions comprising the nucleic acid vaccines described herein may include, without limitation, liposomes such as those formed from the synthesis of stabilized plasmid-lipid particles (SPLP) or stabilized nucleic acid lipid particle (SNALP) that have been previously described and shown to be suitable for oligonucleotide delivery in vitro and in vivo (see Wheeler et al. Gene Therapy. 1999, 6: 271-281; Zhang et al. Gene Therapy. 1999, 6: 1438-1447; Jeffs et al. Pharm Res. 2005, 22: 362-372; Morrissey et al., Nat Biotechnol. 2005, 2: 1002-1007; Zimmermann et al., Nature.
- liposomes such as those formed from the synthesis of stabilized plasmid-lipid particles (SPLP) or stabilized nucleic acid lipid particle (SNALP) that have been previously described and shown to be suitable for oligonucleotide delivery in vitro and in vivo
- the liposome formulations may be composed of 3 to 4 lipid components in addition to the nucleic acid vaccine compositions.
- a liposome can contain, but is not limited to, 55%cholesterol, 20%disteroylphosphatidyl choline (DSPC) , 10%PEG-S-DSG, and 15%1, 2-dioleyloxy-N, N-dimethylaminopropane (DODMA) , as described by Jeffs et al.
- DSPC 20%disteroylphosphatidyl choline
- DODMA 2-dioleyloxy-N, N-dimethylaminopropane
- certain liposome formulations may contain, but are not limited to, 48%cholesterol, 20%DSPC, 2%PEG-c-DMA, and 30%cationic lipid, where the cationic lipid can be 1, 2-distearoyloxy-N, N-dimethylaminopropane (DSDMA) , DODMA, DLin-DMA, or 1, 2-dilinolenyloxy-3-dimethylaminopropane (DLenDMA) , as described by Heyes et al.
- the nucleic acid-lipid particle may comprise a cationic lipid comprising from about 50 mol%to about 85 mol%of the total lipid present in the particle; a non-cationic lipid comprising from about 13 mol%to about 49.5 mol%of the total lipid present in the particle; and a conjugated lipid that inhibits aggregation of particles comprising from about 0.5 mol%to about 2 mol%of the total lipid present in the particle as described in WO2009127060 to Maclachlan et al; the contents of which are incorporated herein by reference in their entirety.
- the nucleic acid-lipid particle may be any nucleic acid-lipid particle disclosed in US2006008910 to Maclachlan et al.
- the nucleic acid-lipid particle may comprise a cationic lipid described herein, a non-cationic lipid, and a conjugated lipid that inhibits aggregation of particles.
- the nucleic acid vaccine compositions of the present disclosure may be formulated in a lipid vesicle which may have crosslinks between functionalized lipid bilayers.
- the liposome may contain a sugar-modified lipid disclosed in US Pat. No.; US5595756 to Bally et al., the contents of which are incorporated herein by reference in their entirety.
- the lipid may be a ganglioside and cerebroside in an amount of about 10 mol percent.
- the nucleic acid vaccine compositions of the present disclosure may be formulated in a liposome comprising a cationic lipid.
- the liposome may have a molar ratio of nitrogen atoms in the cationic lipid to the phosphates in the nucleic acid vaccine compositions (N: P ratio) of between 1: 1 and 20: 1 as described in PCT Patent Application Publication No. WO2013006825, the contents of which are herein incorporated by reference in their entirety.
- the liposome may have a N: P ratio of greater than 20: 1 or less than 1: 1.
- the nucleic acid vaccine compositions of the present disclosure may be formulated in a lipid-polycation complex.
- the formation of the lipid-polycation complex may be accomplished by methods known in the art and/or as described in U.S. Pub. No. 20120178702, the contents of which are herein incorporated by reference in their entirety.
- the polycation may include a cationic peptide or a polypeptide such as, but not limited to, polylysine, polyornithine and/or polyarginine and the cationic peptides described in PCT Patent Application Publication No. WO2012013326; the contents of which are herein incorporated by reference in their entirety.
- the nucleic acid vaccine compositions may be formulated in a lipid-polycation complex which may further include a neutral lipid such as, but not limited to, cholesterol or dioleoyl phosphatidylethanolamine (DOPE) .
- a neutral lipid such as, but not limited to, cholesterol or dioleoyl phosphatidylethanolamine (DOPE) .
- DOPE dioleoyl phosphatidylethanolamine
- the liposome formulation may be influenced by, but not limited to, the selection of the cationic lipid component, the degree of cationic lipid saturation, the nature of the PEGylation, ratio of all components and biophysical parameters such as size.
- the liposome formulation was composed of 57.1%cationic lipid, 7.1%dipalmitoylphosphatidylcholine, 34.3%cholesterol, and 1.4%PEG-c-DMA.
- the pharmaceutical compositions may be formulated with any amphoteric liposome disclosed in PCT Patent Application Publication No.: WO 2008043575 to Panzner and US Pat. No.: US 8, 580, 297 to Essler et al. (Marina Biotech) , the contents of which are incorporated herein by reference in their entirety.
- the amphoteric liposome may comprise a mixture of lipids including a cationic amphiphile, an anionic amphiphile and optional one or more neutral amphiphiles.
- the amphoteric liposome may comprise amphoteric compounds based on amphiphilic molecules, the head groups of which being substituted with one or more amphoteric groups.
- the pharmaceutical compositions may be formulated with an amphoteric lipid comprising one or more amphoteric groups having an isoelectric point between 4 and 9, as disclosed in US Patent Application Publication No.: US20140227345 to Essler et al. (Marina Biotech) , the contents of which are incorporated herein by reference in their entirety.
- the pharmaceutical composition may be formulated with liposomes comprising a sterol derivative as disclosed in US Pat. No.: US7312206 to Panzner et al. (Novosom) , the contents of which are incorporated herein by reference in their entirety.
- the pharmaceutical composition may be formulated with amphoteric liposomes comprising at least one amphipathic cationic lipid, at least one amphipathic anionic lipid, and at least one neutral lipid, or liposomes comprise at least one amphipathic lipid with both a positive and a negative charge, and at least one neutral lipid, wherein the liposomes are stable at pH 4.2 and pH 7.5, as disclosed in US Pat. No.
- the pharmaceutical composition may be formulated with liposomes comprising a serum-stable mixture of lipids taught in US Patent Application Publication No.: US 20110076322 to Panzner et al, the contents of which are incorporated herein by reference in their entirety, capable of encapsulating the nucleic acid vaccine compositions of the present disclosure.
- the lipid mixture comprises phosphatidylcholine and phosphatidylethanolamine in a ratio in the range of about 0.5 to about 8.
- the lipid mixture may also include pH sensitive anionic and cationic amphiphiles, such that the mixture is amphoteric, being negatively charged or neutral at pH 7.4 and positively charged at pH 4.
- the drug/lipid ratio may be adjusted to target the liposomes to particular organs or other sites in the body.
- liposomes loaded with the nucleic acid vaccine compositions of the present disclosure as cargo are prepared by the method disclosed in US Patent Application Publication No.: US 20120021042 to Panzner et al., the contents of which are incorporated herein by reference in their entirety.
- the method comprises steps of admixing an aqueous solution of a polyanionic active agent and an alcoholic solution of one or more amphiphiles and buffering said admixture to an acidic pH, wherein the one or more amphiphiles are susceptible of forming amphoteric liposomes at the acidic pH, thereby to form amphoteric liposomes in suspension encapsulating the active agent.
- nucleic acid vaccine compositions of the disclosure can be formulated using one or more lipoplexes.
- the nucleic acid vaccine compositions may be formulated as a lipoplex, such as, without limitation, the ATUPLEX TM system, the DACC system, the DBTC system and other siRNA-lipoplex technology from Silence Therapeutics (London, United Kingdom) , STEMFECT TM from (Cambridge, MA) , and polyethylenimine (PEI) or protamine-based targeted and non- targeted delivery of nucleic acids (Aleku et al. Cancer Res. 2008, 68: 9788-9798; Strumberg et al.
- a lipoplex such as, without limitation, the ATUPLEX TM system, the DACC system, the DBTC system and other siRNA-lipoplex technology from Silence Therapeutics (London, United Kingdom) , STEMFECT TM from (Cambridge, MA) , and polyethylenimine (PEI) or protamine-based targeted and non- targeted delivery of nucleic acids (Aleku et al. Cancer Res. 2008, 68
- LNPs Lipid Nanoparticles
- the nucleic acid vaccine compositions of the present disclosure may be formulated in a lipid nanoparticle (LNP) .
- LNPs can be characterized as small solid or semi-solid particles possessing an exterior lipid layer with a hydrophilic exterior surface that is exposed to the non-LNP environment, an interior space which may aqueous (vesicle like) or non-aqueous (micelle like) , and at least one hydrophobic inter-membrane space.
- LNP membranes may be lamellar or non-lamellar and may be comprised of 1, 2, 3, 4, 5 or more layers.
- LNPs may comprise a cargo or a payload into their interior space, into the inter membrane space, onto their exterior surface, or any combination thereof.
- LNPs useful herein are known in the art and generally comprise cholesterol (aids in stability and promotes membrane fusion) , a phospholipid (which provides structure to the LNP bilayer and also may aid in endosomal escape) , a polyethylene glycol (PEG) derivative (which reduces LNP aggregation and “shields” the LNP from non-specific endocytosis by immune cells) , and an ionizable lipid (complexes negatively charged RNA and enhances endosomal escape) , which form the LNP-forming composition.
- cholesterol saids in stability and promotes membrane fusion
- PEG polyethylene glycol
- ionizable lipid complexes negatively charged RNA and enhances endosomal escape
- the components of the LNP may be selected based on the desired target, tropism, cargo, size, or other desired feature or property.
- the LNP may be the lipid nanoparticles described in PCT Patent Application Publication No. WO2012170930, the contents of which are herein incorporated by reference in their entirety.
- the nucleic acid vaccine compositions of the present disclosure may be formulated in a LNP that comprises at least one cationic lipid.
- the cationic lipid which may be used in formulations of the present disclosure may be selected from, but not limited to, a cationic lipid described in PCT Patent Application Publication Nos. WO2012040184, WO2011153120, WO2011149733, WO2011090965, WO2011043913, WO2011022460, WO2012061259, WO2012054365, WO2012044638, WO2010080724, WO201021865 and WO2008103276, US Patent Nos. 7,893,302, 7,404,969 and 8,283,333 and US Patent Publication No. US20100036115 and US20120202871; the contents of each of which are herein incorporated by reference in their entirety.
- the cationic lipid may be also selected from, but not limited to, formula A described in PCT Patent Application Publication Nos. WO2012040184, WO2011153120, WO2011149733, WO2011090965, WO2011043913, WO2011022460, WO2012061259, WO2012054365 and WO2012044638; the contents of each of which are herein incorporated by reference in their entirety.
- the cationic lipid may be selected from, but not limited to, formula CLI-CLXXIX of PCT Patent Application No. WO2008103276, formula CLI-CLXXIX ofUS Patent No. 7,893,302, formula CLI-CLXXXXII of US Patent No.
- the cationic lipid may be a multivalent cationic lipid such as the cationic lipid disclosed in US Patent No. 7,223,887 to Gaucheron et al., the contents of which are incorporated herein by reference in their entirety.
- the cationic lipid may have a positively-charged head group including two quaternary amine groups and a hydrophobic portion including four hydrocarbon chains as described in US Patent No. 7,223,887 to Gaucheron et al.
- the cationic lipid may be biodegradable such as the biodegradable lipids disclosed in US Patent Application Publication No.: US20130195920 to Maier et al., the contents of which are incorporated herein by reference in their entirety.
- the cationic lipid may have one or more biodegradable groups located in a lipidic moiety of the cationic lipid as described in formula I-IV in US20130195920 to Maier et al.
- the cationic lipid may also be the cationic lipids disclosed in US20130156845 to Manoharan et al.
- the cationic lipid may be selected from (20Z, 23Z) -N, N-dimethylnonacosa-20, 23-dien-10-amine, (17Z, 20Z) -N, N-dimethylhexacosa-17, 20-dien-9-amine, (1Z, 19Z) -N, N-dimethylpentacosa-l6, 19-dien-8-amine, (13Z, 16Z) -N, N-dimethyldocosa-13, 16-dien-5-amine, (12Z, 15Z) -N, N-dimethylhenicosa-12, 15-dien-4-amine, (14Z, 17Z) -N, N-dimethyltricosa-14, 17-dien-6-amine, (15Z, 18Z) -N, N-dimethyltetracosa-15, 18-dien-7-amine, (18Z, 21Z) -N, N-dimethylheptacosa-18,
- Lipid Nanoparticle (LNP) compositions Lipid Nanoparticle (LNP) compositions
- a lipid nanoparticle may be comprised of at least one cationic lipid, at least one non-cationic lipid, at least one sterol, at least one additional LNP functional component, or any combination thereof.
- a lipid nanoparticle may be comprised of at least one cationic lipid, at least one non-cationic lipid, at least one sterol, and at least one additional LNP functional component.
- the LNP may be comprised of at least one cationic lipid, at least one non-cationic lipid, and at least one sterol.
- the LNP may be comprised of at least one cationic lipid, at least one non-cationic lipid, and at least one additional LNP functional component.
- the LNP may be comprised of at least one non-cationic lipid, at least one sterol, and at least one additional LNP functional component. In some embodiments, the LNP may be comprised of at least one cationic lipid and at least one non-cationic lipid. In some embodiments, the LNP may be comprised of at least one cationic lipid and at least one sterol. In some embodiments, the LNP may be comprised of at least one cationic lipid and at least one additional LNP functional component. In some embodiments, the LNP may be comprised of at least one non-cationic lipid and at least one sterol.
- the LNP may be comprised of at least one non-cationic lipid and at least one additional LNP functional component. In some embodiments, the LNP may be comprised of at least one sterol and at least one additional LNP functional component. In some embodiments, the LNP may be comprised of at least one cationic lipid. In some embodiments, the LNP may be comprised of at least one non-cationic lipid. In some embodiments, a LNP may be comprised of a sterol. In some embodiments, the LNP may be comprised of an additional LNP functional component.
- the at least one cationic lipid may comprise any of at least one ionizable cationic lipid, at least one amino lipid, at least one saturated cationic lipid, at least one unsaturated cationic lipid, at least one zwitterionic lipid, at least one multivalent cationic lipid, or any combination thereof.
- the LNP may be essentially devoid of the at least one cationic lipid. In some embodiments, the LNP may contain no amount of the at least one cationic lipid.
- At least one cationic lipid may be selected from, but not limited to, at least one of 1, 3-Bis- (l, 2-bis-tetradecyloxy-propyl-3-dimethylethoxyammoniumbromide) -propan-2-ol ( (R) -PLC-2) , 2- (Dinonylamino) ethan-1-ol (17-10) , 2- (Didodecylamino) ethan-1-ol (17-11) , 3- (Didodecylamino) propan-1-ol (17-12) , 4- (Didodecylamino) butan-1-ol (17-13) , 2- (Hexyl ( (9Z, 12Z) -octadeca-9, 12-dien-1-yl) amino) ethan-1-ol (17-2) , 2- (Nonyl ( (9Z, 12Z) -octadeca-9, 12-dien-1-yl) amino) ethan
- the at least one non-cationic lipid comprises at least one phospholipid, at least one fusogenic lipid, at least one anionic lipid, at least one helper lipid, at least one neutral lipid, or any combination thereof.
- the LNP may be essentially devoid of the at least one non-cationic lipid. In some embodiments, the LNP may contain no amount of the at least one non-cationic lipid.
- At least one non-cationic lipid may be selected from, but is not limited to, at least one of 1, 2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18: 0 Diether PC) , DSPCbutwith3unsaturateddoublebondspertail (18: 3 PC) , Acylcarnosine (AC) , 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC) , N-oleoyl-SPM (C18: l) , N-lignocerylSPM (C24: 0) , N-nervacylC (C24: l) , cetylphosphate (Cet-P) , cholesterolhemisuccinate (CHEMS) , cholesterol (Chol) , Cholesterolhemidodecane dicarboxylicacid (Chol-C12) , 12-Cholesteryloxycarbonylaminodode
- AC
- the LNP comprises an ionizable lipid or lipid-like material.
- the ionizable lipid may be C12-200, CKK-E12, 5A2-SC8, BAMEA-016B, or 7C1.
- Other ionizable lipids are known in the art and are useful herein.
- the LNP comprises a phospholipid.
- the phospholipid helper
- the phospholipid may be DOPE, DSPC, DOTAP, or DOTMA.
- the LNP comprises a PEG derivative.
- the PEG derivative may be a lipid-anchored such as PEG is C14-PEG2000, C14-PEG1000, C14-PEG3000, C14-PEG5000, C12-PEG1000, C12-PEG2000, C12-PEG3000, C12-PEG5000, C16-PEG1000, C16-PEG2000, C16-PEG3000, C16-PEG5000, C18-PEG1000, C18-PEG2000, C18-PEG3000, or C18-PEG5000.
- the at least one sterol comprises at least one cholesterol or cholesterol derivative.
- the LNP may be essentially devoid of an at least one sterol. In some embodiments, the LNP may contain no amount of the at least one sterol.
- the at least one additional LNP functional component comprises at least one component that reduced aggregation of particles, at least one component that decreases clearing of the LNP from circulation in a subject, at least component that increases the LNP’s ability to traverse mucus layers, at least one component that decreases a subject’s immune response to administration of the LNP, at least one component that modifies membrane fluidity of the LNP, at least one component that contributes to the stability of the LNP, or any combination thereof.
- the LNP may be essentially devoid of the at least one additional LNP functional component.
- the LNP may contain no amount of the at least one additional LNP functional component.
- the additional LNP functional component may be comprised of a polymer.
- the polymer comprising the additional LNP functional component may be comprised of at least one polyethylene glycol (PEG) , at least one polypropylene glycol (PPG) , poly (2-oxazoline) (POZ) , at least one polyamide (ATTA) , at least one cationic polymer, or any combination thereof.
- the average molecular weight of the polymer moiety may be between 500 and 20,000 daltons. In some embodiments, the molecular weight of the polymer may be about 500 to 20,000, 1,000 to 20,000, 1,500 to 20,000, 2,000 to 20,000, 2,500 to 20,000, 3,000 to 20,000, 3,500 to 20,000, 4,000 to 20,000, 4,500 to 20,000, 5,000 to 20,000, 5,500 to 20,000, 6,000 to 20,000, 6,500 to 20,000, 7,000 to 20,000, 7,500 to 20,000, 8,000 to 20,000, 8,500 to 20,000, 9,000 to 20,000, 9,500 to 20,000, 10,000 to 20,000, 10,500 to 20,000, 11,000 to 20,000, 11,500 to 20,000, 12,000 to 20,000, 12,500 to 20,000, 13,000 to 20,000, 13,500 to 20,000, 14,000 to 20,000, 14,500 to 20,000, 15,000 to 20,000, 15,500 to 20,000, 16,000 to 20,000, 16,500 to 20,000, 17,000 to 20,000,
- the polymer e.g., PEG
- the lipid conjugated to the polymer includes at least one neutral lipid, at least one phospholipid, at least one anionic lipid, at least one cationic lipid, at least one cholesterol, at least one cholesterol derivative, or any combination thereof.
- the lipid conjugated to the polymer may be selected from, but is not limited to, at least one of the cationic, non-cationic, or sterol lipids listed previously.
- the at least one PEG-lipid conjugate may be selected from, but is not limited to at least one of Siglec-1L-PEG-DSPE, (R) -2, 3-bis (octadecyloxy) propyl-1- (methoxypoly (ethyleneglycol) 2000) propylcarbamate, PEG-S-DSG, PEG-S-DMG, PEG-PE, PEG-PAA, PEG-OH DSPE C18, PEG-DSPE, PEG-DSG, PEG-DPG, PEG-DOMG, PEG-DMPE Na, PEG-DMPE, PEG-DMG2000, PEG-DMG C14, PEG-DMG 2000, PEG-DMG, PEG-DMA, PEG-Ceramide C16, PEG-C-DOMG, PEG-c-DMOG, PEG-c-DMA, PEG-cDMA, PEGA, PEG750-C-DMA, PEG400, PEG2k-
- the amounts and ratios of LNP components may be varied by any amount dependent on the desired form, structure, function, cargo, target, or any combination thereof.
- the amount of each component may be expressed in various embodiments as percent of the total molar mass of all lipid or lipid conjugated components accounted for by the indicated component (mol%) ,
- the amount of each component may be expressed in various embodiments as the relative ratio of each component based on molar mass (Molar Ratio) .
- the amount of each component may be expressed in various embodiments as the weight of each component used to formulate the LNP prior to fabrication (mg or equivalent) .
- the amount of each component may be expressed in various embodiments by any other method known in the art.
- any formulation given in one representation of component amounts is expressly meant to encompass any formulation expressed in different units of component amounts, wherein those representations are effectively equivalent when converted into the same units.
- “effectively equivalent” means two or more values within about 10%of one another.
- the LNP comprises at least one cationic lipid in an amount of about 0.1 to 100 mol%. In some embodiments, the LNP comprises at least one cationic lipid in an amount of about 20 to 60 mol%. In some embodiments, the LNP comprises at least one cationic lipid in an amount of about 50 to 85 mol%. In some embodiments, the LNP comprises at least one cationic lipid in an amount of less than about 20 mol%. In some embodiments, the LNP comprises at least one cationic lipid in an amount of more than about 60 mol%or about 85 mol%. In some embodiments, the LNP comprises at least one cationic lipid in an amount of about 95 mol%or less.
- the LNP comprises a cationic lipid in an amount of less than or equal to about 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, and 5 mol%. In some embodiments, the LNP comprises at least one cationic lipid in an amount of more than or equal to about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, and 95 mol%.
- the LNP comprises at least one cationic lipid in an amount from about 20 to 30 mol%, 20 to 35 mol%, 20 to 40 mol%, 20 to 45 mol%, 20 to 50 mol%, 20 to 55 mol%, 20 to 60 mol%, 20 to 65 mol%, 20 to 70 mol%, 20 to 75 mol%, 20 to 80 mol%, 20 to 85 mol%, 20 to 90 mol%, 25 to 35 mol%, 25 to 40 mol%, 25 to 45 mol%, 25 to 50 mol%, 25 to 55 mol%, 25 to 60 mol%, 25 to 65 mol%, 25 to 70 mol%, 25 to 75 mol%, 25 to 80 mol%, 25 to 85 mol%, 25 to 90 mol%, 30 to 40 mol%, 30 to 45 mol%, 30 to 50 mol%, 30 to 55 mol%, 30 to 60 mol%, 30 to 65 mol%, 30 to 70 mol%, 30 to 75 mol%, 30 to 40 mol%
- the LNP comprises at least one non-cationic lipid in an amount of about 0.1 to 100 mol%. In some embodiments, the LNP comprises at least one non-cationic lipid in an amount of about 5 to 35 mol%. In some embodiments, the LNP comprises at least one cationic lipid in an amount of about 5 to 25 mol%. In some embodiments, the LNP comprises at least one non-cationic lipid in an amount of less than about 5 mol%. In some embodiments, the LNP comprises at least one non-cationic lipid in an amount of more than about 25 mol%or about 35 mol%. In some embodiments, the LNP comprises at least one non-cationic lipid in an amount of about 95 mol%or less.
- the LNP comprises at least one non-cationic lipid in an amount of less than or equal to about 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, and 5 mol%. In some embodiments, the LNP comprises at least one non-cationic lipid in an amount of more than or equal to about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, and 95 mol%.
- the LNP comprises at least one non-cationic lipid in an amount from about 5 to 15 mol%, 5 to 25 mol%, 5 to 35 mol%, 5 to 45 mol%, 5 to 55 mol%, 10 to 20 mol%, 10 to 30 mol%, 10 to 40 mol%, 10 to 50 mol%, 15 to 25 mol%, 15 to 35 mol%, 15 to 45 mol%, 20 to 30 mol%, 20 to 40 mol%, 20 to 50 mol%, 25 to 35 mol%, 25 to 45 mol%, 30 to 40 mol%, 30 to 50 mol%, and 35 to 45 mol%.
- the LNP comprises at least one sterol in an amount of about 0.1 to 100 mol%. In some embodiments, the LNP comprises at least one sterol in an amount of about 20 to 45 mol%. In some embodiments, the LNP comprises at least one sterol in an amount of about 25 to 55 mol%. In some embodiments, the LNP comprises at least one sterol in an amount of less than about 20 mol%. In some embodiments, the LNP comprises at least one sterol in an amount of more than about 45 mol%or about 55 mol%. In some embodiments, the LNP comprises at least one sterol in an amount of about 95 mol%or less.
- the LNP comprises at least one sterol in an amount of less than or equal to about 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, and 5 mol%. In some embodiments, the LNP comprises at least one sterol in an amount of more than or equal to about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, and 95 mol%.
- the LNP comprises at least one sterol in an amount from about 10 to 20 mol%, 10 to 30 mol%, 10 to 40 mol%, 10 to 50 mol%, 10 to 60 mol%, 15 to 25 mol%, 15 to 35 mol%, 15 to 45 mol%, 15 to 55 mol%, 15 to 65 mol%, 20 to 30 mol%, 20 to 40 mol%, 20 to 50 mol%, 20 to 60 mol%, 25 to 35 mol%, 25 to 45 mol%, 25 to 55 mol%, 25 to 65 mol%, 30 to 40 mol%, 30 to 50 mol%, 30 to 60 mol%, 35 to 45 mol%, 35 to 55 mol%, 35 to 65 mol%, 40 to 50 mol%, 40 to 60 mol%, 45 to 55 mol%, 45 to 65 mol%, 50 to 60 mol%, and 55 to 65 mol%.
- the LNP comprises at least one additional LNP functional component in an amount of about 0.1 to 100 mol%. In some embodiments, the LNP comprises at least one additional LNP functional component in an amount of about 0.5 to 15 mol%. In some embodiments, the LNP comprises at least one additional LNP functional component in an amount of about 15 to 40 mol%. In some embodiments, the LNP comprises at least one additional LNP functional component in an amount of less than about 0.1 mol%. In some embodiments, the LNP comprises at least one additional LNP functional component in an amount of more than about 15 mol%or about 40 mol%. In some embodiments, the LNP comprises at least one additional LNP functional component in an amount of about 95 mol%or less.
- the LNP comprises at least one additional LNP functional component in an amount of less than or equal to about 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, and 5 mol%. In some embodiments, the LNP comprises at least one additional LNP functional component in an amount of more than or equal to about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, and 95 mol%.
- the LNP comprises at least one additional LNP functional component in an amount from about 0.1 to 1 mol%, 0.1 to 2 mol%, 0.1 to 3 mol%, 0.1 to 4 mol%, 0.1 to 5 mol%, 0.1 to 6 mol%, 0.1 to 7 mol%, 0.1 to 8 mol%, 0.1 to 9 mol%, 0.1 to 10 mol%, 0.1 to 15 mol%, 0.1 to 20 mol%, 0.1 to 25 mol%, 1 to 2 mol%, 1 to 3 mol%, 1 to 4 mol%, 1 to 5 mol%, 1 to 6 mol%, 1 to 7 mol%, 1 to 8 mol%, 1 to 9 mol%, 1 to 10 mol%, 1 to 15 mol%, 1 to 20 mol%, 1 to 25 mol%, 2 to 3 mol%, 2 to 4 mol%, 2 to 5 mol%, 2 to 6 mol%, 2 to 7 mol%, 2 to 8 mol%, 1 to 9 mol%,
- the LNP includes about 30-60 mol%of at least one cationic lipid, about 0-30 mol%of at least one non-cationic lipid (e.g., a phospholipid) , about 18.5-48.5 mol%of at least one sterol (e.g., cholesterol) , and about 0-10 mol%of at least one additional LNP functional component (e.g., a PEGylated lipid) .
- a non-cationic lipid e.g., a phospholipid
- sterol e.g., cholesterol
- additional LNP functional component e.g., a PEGylated lipid
- the LNP includes of about 35-55 mol%of at least one cationic lipid, about 5-25 mol%of at least one non-cationic lipid (e.g., a phospholipid) , about 30-40 mol%of at least one sterol (e.g., cholesterol) , and about 0-10 mol%of at least one additional LNP functional component (e.g., a PEGylated lipid) .
- the LNP includes of about 35-45 mol%of at least one cationic lipid, about 25-35 mol%of at least one non-cationic lipid (e.g., a phospholipid) , about 20-30 mol%of at least one sterol (e.g., cholesterol) , and about 0-10 mol%of at least one additional LNP functional component (e.g., a PEGylated lipid) .
- the LNP includes of about 45-65 mol%of at least one cationic lipid, about 5-10 mol%of at least one non-cationic lipid (e.g., a phospholipid) , about 25-40 mol%of at least one sterol (e.g., cholesterol) , and about 0.5-10 mol%of at least one additional LNP functional component (e.g., a PEGylated lipid) .
- the LNP includes of about 40-60 mol%of at least one cationic lipid, about 5-15 mol%of at least one non-cationic lipid (e.g., a phospholipid) , about 35-45 mol%of at least one sterol (e.g., cholesterol) , and about 0.5-3 mol%of at least one additional LNP functional component (e.g., a PEGylated lipid) .
- a cationic lipid e.g., a phospholipid
- sterol e.g., cholesterol
- additional LNP functional component e.g., a PEGylated lipid
- the LNP includes of about 30-60 mol%of at least one cationic lipid, about 0-30 mol%of at least one non-cationic lipid (e.g., a phospholipid) , about 15-50 mol%of at least one sterol (e.g., cholesterol) , and about 0.01-10 mol%of at least one additional LNP functional component (e.g., a PEGylated lipid) .
- a cationic lipid e.g., a phospholipid
- sterol e.g., cholesterol
- additional LNP functional component e.g., a PEGylated lipid
- the LNP includes of about 10-75 mol%of at least one cationic lipid, about 0.5-50 mol%of at least one non-cationic lipid (e.g., a phospholipid) , about 5-60 mol%of at least one sterol (e.g., cholesterol) , and about 0.1-20 mol%of at least one additional LNP functional component (e.g., a PEGylated lipid) .
- the LNP includes of about 50-65 mol%of at least one cationic lipid, about 3-15 mol%of at least one non-cationic lipid (e.g., a phospholipid) , about 30-40 mol%of at least one sterol (e.g., cholesterol) , and about 0.5-2 mol%of at least one additional LNP functional component (e.g., a PEGylated lipid) .
- the LNP includes of about 50-85 mol%of at least one cationic lipid, about 3-15 mol%of at least one non-cationic lipid (e.g., a phospholipid) , about 30-40 mol%of at least one sterol (e.g., cholesterol) , and about 0.5-2 mol%of at least one additional LNP functional component (e.g., a PEGylated lipid) .
- the LNP includes of about 25-75 mol%of at least one cationic lipid, about 0.1-15 mol%of at least one non-cationic lipid (e.g., a phospholipid) , about 5-50 mol%of at least one sterol (e.g., cholesterol) , and about 0.5-20 mol%of at least one additional LNP functional component (e.g., a PEGylated lipid) .
- the LNP includes of about 50-65 mol%of at least one cationic lipid, about 5-10 mol%of at least one non-cationic lipid (e.g., a phospholipid) , about 25-35 mol%of at least one sterol (e.g., cholesterol) , and about 5-10 mol%of at least one additional LNP functional component (e.g., a PEGylated lipid) .
- a cationic lipid e.g., a phospholipid
- sterol e.g., cholesterol
- additional LNP functional component e.g., a PEGylated lipid
- the LNP includes of about 20-60 mol%of at least one cationic lipid, about 5-25 mol%of at least one non-cationic lipid (e.g., a phospholipid) , about 25-55 mol%of at least one sterol (e.g., cholesterol) , and about 0.5-15 mol%of at least one additional LNP functional component (e.g., a PEGylated lipid) .
- a cationic lipid e.g., a phospholipid
- sterol e.g., cholesterol
- additional LNP functional component e.g., a PEGylated lipid
- the nucleic acid vaccine described here is formulated in a lipid nanoparticle comprising a cationic lipid, a phospholipid, a sterol and a PEGylated lipid as described herein.
- the LNP may comprise about 20-70% (mole) of a cationic lipid in the formulation, e.g., about 30-60%, or about 30-50%, or 50%.
- the LNP may comprise about 5-20% (mole) of a phospholipid in the formulation, e.g., 5-10%, 5-15%, 10-15%or about 10%of the phospholipid.
- the LNP may comprise about 20-45% (mole) of a sterol in the formulation, e.g., 20-40%, 30-40%, or about 38%of the sterol.
- the LNP may comprise about 0.5 to 5.0%of a PEGylated lipid, e.g., about 0.5-2.0%, 1.0-3.0%, 1.5-2.0%or about 2.0%of the PEGylated lipid.
- the nucleic acid vaccine described here is formulated in a lipid nanoparticle comprising 3D-P-DMA, a phospholipid, a sterol and a PEGylated lipid.
- the nucleic acid vaccine described here is formulated in a lipid nanoparticle comprising a cationic lipid, DSPC, a sterol and a PEGylated lipid.
- the nucleic acid vaccine described here is formulated in a lipid nanoparticle comprising a cationic lipid, a phospholipid, a sterol and PEG-DMA.
- the nucleic acid vaccine described here is formulated in a lipid nanoparticle comprising a cationic lipid, a phospholipid, cholesterol and PEGylated lipid.
- the nucleic acid vaccine described here is formulated in a lipid nanoparticle comprising 3D-P-DMA, DSPC, a sterol and a PEGylated lipid.
- the nucleic acid vaccine described here is formulated in a lipid nanoparticle comprising 3D-P-DMA, a phospholipid, cholesterol and a PEGylated lipid.
- the nucleic acid vaccine described here is formulated in a lipid nanoparticle comprising 3D-P-DMA, a phospholipid, a sterol and PEG-DMA.
- the nucleic acid vaccine described here is formulated in a lipid nanoparticle comprising a cationic lipid, a phospholipid, cholesterol and PEG-DMA.
- the nucleic acid vaccine described here is formulated in a lipid nanoparticle comprising a cationic lipid, DSPC, a sterol and PEG-DMA.
- the nucleic acid vaccine described here is formulated in a lipid nanoparticle comprising a cationic lipid, DSPC, cholesterol and a PEGylated lipid.
- the nucleic acid vaccine described here is formulated in a lipid nanoparticle comprising 3D-P-DMA, DSPC, cholesterol and PEG-DMA.
- the nucleic acid vaccine described here is formulated in a lipid nanoparticle comprising about 50% (by mole) of a cationic lipid, about 10% (by mole) of a phospholipid, about 38% (by mole) of a sterol and about 1.6%of a PEGylated lipid in the formulation.
- the cationic lipid, sterol, phospholipid and PEGylated lipid is 3D-P-DMA, DSPC, Cholesterol and PEG-DMA, respectively.
- the nucleic acid vaccine described here is formulated in a lipid nanoparticle comprising about 53% (by weight) of 3D-P-DMA, about 14% (by weight) ofDSPC, about 26% (by weight) of cholesterol and about 7% (by weight) of a PEG-DMA in the formulation.
- the nucleic acid vaccine compositions described here may comprise at least one nucleic acid vaccine comprising a polynucleotide of SEQ ID NO: 41 or SEQ ID NO: 92 that is formulated in a LNP comprising about 50% (by mole) of a cationic lipid, about 10% (by mole) of a phospholipid, about 38% (by mole) of a sterol and about 2.0%of a PEGylated lipid.
- the nucleic acid vaccine compositions described here may comprise at least one nucleic acid vaccine comprising a polynucleotide of SEQ ID NO: 41 or SEQ ID NO: 92 that is formulated in a LNP comprising about 50% (by mole) of 3D-P-DMA, about 10% (by mole) ofDSPC, about 38% (by mole) of cholesterol and about 2.0%of a PEG-DMA.
- the nucleic acid vaccine compositions described here may comprise at least one nucleic acid vaccine comprising a polynucleotide of SEQ ID NO: 43 or SEQ ID NO: 94 that is formulated in a LNP comprising about 50% (by mole) of a cationic lipid, about 10% (by mole) of a phospholipid, about 38% (by mole) of a sterol and about 2.0%of a PEGylated lipid.
- the nucleic acid vaccine compositions described here may comprise at least one nucleic acid vaccine comprising a polynucleotide of SEQ ID NO: 43 or SEQ ID NO: 94 that is formulated in a LNP comprising about 50% (by mole) of 3D-P-DMA, about 10% (by mole) ofDSPC, about 38% (by mole) of cholesterol and about 2.0%of a PEG-DMA.
- the nucleic acid vaccine compositions described here may comprise at least one nucleic acid vaccine comprising a polynucleotide of SEQ ID NO: 45 or SEQ ID NO: 96 that is formulated in a LNP comprising about 50% (by mole) of a cationic lipid, about 10% (by mole) of a phospholipid, about 38% (by mole) of a sterol and about 2.0%of a PEGylated lipid.
- the nucleic acid vaccine compositions described here may comprise at least one nucleic acid vaccine comprising a polynucleotide of SEQ ID NO: 45 or SEQ ID NO: 96 that is formulated in a LNP comprising about 50% (by mole) of 3D-P-DMA, about 10% (by mole) ofDSPC, about 38% (by mole) of cholesterol and about 2.0%of a PEG-DMA.
- the nucleic acid vaccine compositions described here may comprise at least one nucleic acid vaccine comprising a polynucleotide of SEQ ID NO: 47 or SEQ ID NO: 98 that is formulated in a LNP comprising about 50% (by mole) of a cationic lipid, about 10% (by mole) of a phospholipid, about 38% (by mole) of a sterol and about 2.0%of a PEGylated lipid.
- the nucleic acid vaccine compositions described here may comprise at least one nucleic acid vaccine comprising a polynucleotide of SEQ ID NO: 47 or SEQ ID NO: 98 that is formulated in a LNP comprising about 50% (by mole) of 3D-P-DMA, about 10% (by mole) ofDSPC, about 38% (by mole) of cholesterol and about 2.0%of a PEG-DMA.
- the nucleic acid vaccine compositions described here may comprise at least one nucleic acid vaccine comprising a polynucleotide of SEQ ID NO: 49 or SEQ ID NO: 100 that is formulated in a LNP comprising about 50% (by mole) of a cationic lipid, about 10% (by mole) of a phospholipid, about 38% (by mole) of a sterol and about 2.0%of a PEGylated lipid.
- the nucleic acid vaccine compositions described here may comprise at least one nucleic acid vaccine comprising a polynucleotide of SEQ ID NO: 49 or SEQ ID NO: 100 that is formulated in a LNP comprising about 50% (by mole) of 3D-P-DMA, about 10% (by mole) of DSPC, about 38% (by mole) of cholesterol and about 2.0%of a PEG-DMA.
- the nucleic acid vaccine compositions described here may comprise at least one nucleic acid vaccine comprising a polynucleotide of SEQ ID NO: 51 or SEQ ID NO: 102 that is formulated in a LNP comprising about 50% (by mole) of a cationic lipid, about 10% (by mole) of a phospholipid, about 38% (by mole) of a sterol and about 2.0%of a PEGylated lipid.
- the nucleic acid vaccine compositions described here may comprise at least one nucleic acid vaccine comprising a polynucleotide of SEQ ID NO: 51 or SEQ ID NO: 92 that is formulated in a LNP comprising about 50% (by mole) of 3D-P-DMA, about 10% (by mole) ofDSPC, about 38% (by mole) of cholesterol and about 2.0%of a PEG-DMA.
- the LNPs can be characterized by their shape. In some embodiments, the LNPs are essentially spherical. In some embodiments, the LNPs are essentially rod-shaped (i.e., cylindrical) . In some embodiments, the LNPs are essentially disk shaped.
- the LNPs can be characterized by their size.
- the size of an LNP can be defined as the diameter of its largest circular cross section, referred to herein simply as its diameter.
- the LNPs may have a diameter between 30 nm to about 150 nm.
- the LNP may have diameters ranging between about 40 to 150 nm, 50 to 150 nm, 60 to 150 nm, about 70 to 150 nm, or 80 to 150 nm, 90 to 150 nm, 100 nm to 150 nm, 110 to 150 nm, 120 to 150 nm, 130 to 150 nm, or 140 to 150 nm.
- a population of LNPs such as those resulting from the same formulation, may be characterized by measuring the uniformity of size, shape, or mass of the particles in the population. Uniformity may be expressed in some embodiments as the polydispersity index (PI) of the population. In some embodiments uniformity may be expressed in some embodiments as the disparity of the population.
- PI polydispersity index
- a population of LNPs resulting from a given formulation will have a PI of between about 0.1 and 1.
- a population of LNPs resulting from a giving formulation will have a PI of less than about 1, less than about 0.5, less than about 0.4, less than about 0.3, less than about 0.2, less than about 0.1. In some embodiments, a population of LNPs resulting from a given formulation will have a PI of between about 0.1 to 1, 0.1 to 0.8, 0.1 to 0.6, 0.1 to 0.4, 0.1 to 0.2, 0.2 to 1, 0.2 to 0.8, 0.2 to 0.6, 0.2 to 0.4, 0.4 to 1, 0.4 to 0.8, 0.4 to 0.6, 0.6 to 1, 0.6 to 0.8, and 0.8 to 1.
- the LNP may fully or partially encapsulate a cargo, such as nucleic acid constructs of the present disclosure.
- a cargo such as nucleic acid constructs of the present disclosure.
- essentially 0%of the cargo present in the final formulation is exposed to the environment outside of the LNP (i.e., the cargo is fully encapsulated) .
- the cargo is associated with the LNP but is at least partially exposed to the environment outside of the LNP.
- the LNP may be characterized by the%of the cargo not exposed to the environment outside of the LNP, e.g., the encapsulation efficiency.
- an encapsulation efficiency of about 100% refers to an LNP formulation where essentially all the cargo is fully encapsulated by the LNP, while an encapsulation rate of about 0% refers to an LNP where essential none of the cargo is encapsulated in the LNP, such as with an LNP where the cargo is bound to the external surface of the LNP.
- an LNP may have an encapsulation efficiency of less than about 100%, less than about 95%, less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, or less than 5%.
- an LNP may have an encapsulation efficiency of between about 90 to 100%, 80 to 100%, 70 to 100%, 60 to 100%, 50 to 100%, 40 to 100%, 30 to 100%, 20 to 100%, 10 to 100%, 80 to 90%, 70 to 90%, 60 to 90%, 50 to 90%, 40 to 90%, 30 to 90%, 20 to 90%, 10 to 90%, 70 to 80%, 60 to 80%, 50 to 80%, 40 to 80%, 30 to 80%, 20 to 80%, 10 to 80%, 60 to 70%, 50 to 70%, 40 to 70%, 30 to 70%, 20 to 70%, 50 to 70%, 40 to 70%, 30 to 70%, 20 to 70%, 10 to 70%, 40 to 70%, 30 to 70%, 20 to 70%, 10 to 70%, 40 to 50%, 30 to 50%, 20 to 50%, 10 to 50%, 30 to 40%, 20 to 40%, 10 to 40%, 20 to 30%, 10 to 30%, and 10 to 20%.
- the at least one targeting agent may be presented on the external surface of the nanoparticle. In some embodiments, the at least one targeting agent may be conjugated to a lipid-component of the nanoparticle. In some embodiments, the at least one targeting agent may be conjugated to a polymer component of the nanoparticle. In some embodiments, the at least one targeting agent may be anchored to the nanoparticle via hydrophobic and hydrophilic interactions among the at least one targeting agent, the nanoparticle membrane, and the aqueous environments inside or outside the nanoparticle. In some embodiments, the at least one targeting agent is conjugated to a peptide/protein component of the nanoparticle membrane. In some embodiments, the at least one targeting agent is conjugated to a suitable linker moiety which is conjugated to a component of the nanoparticle membrane. In some embodiments, any combination of forces and bonds can result in the targeting agent being associated with the nanoparticle.
- the LNPs described herein may be formed using techniques known in the art.
- an organic solution containing the lipids is mixed together with an acidic aqueous solution containing the nucleic acid compositions in a microfluidic channel resulting in the formation of targeting system (delivery vehicle and the nucleic acid vaccine) .
- the lipid compositions are described according to the respective molar ratios of the component lipids in the formulation.
- the mol-%of the ionizable lipid may be from about 10 mol-%to about 80 mol-%.As a non-limiting example, the mol-%of the ionizable lipid may be from about 20 mol-%to about 70 mol-%. As a non-limiting example, the mol-%of the ionizable lipid may be from about 30 mol-%to about 60 mol-%. As a non-limiting example, the mol-%of the ionizable lipid may be from about 35 mol-%to about 55 mol-%.
- the mol-%of the ionizable lipid may be from about 40 mol-%to about 50 mol-%.
- the ionizable lipid mol-%of the transfer vehicle batch will be ⁇ 30%, ⁇ 25%, ⁇ 20%, ⁇ 15%, ⁇ 10%, ⁇ 5%, or ⁇ 2.5%of the target mol-%.
- transfer vehicle variability between lots will be less than 15%, less than 10%or less than 5%.
- the mol-%of the helper lipid may be from about 1 mol-%to about 50 mol-%. In some embodiments, the mol-%of the helper lipid may be from about 2 mol-%to about 45 mol-%. In some embodiments, the mol-%of the helper lipid may be from about 3 mol-%to about 40 mol-%. In some embodiments, the mol-%of the helper lipid may be from about 4 mol-%to about 35 mol-%. In some embodiments, the mol-%of the helper lipid may be from about 5 mol-%to about 30 mol-%.
- the mol-%of the helper lipid may be from about 10 mol-%to about 20 mol-%. In some embodiments, the helper lipid mol-%of the transfer vehicle batch will be ⁇ 30%, ⁇ 25%, ⁇ 20%, ⁇ 15%, ⁇ 10%, ⁇ 5%, or ⁇ 2.5%of the target mol-%.
- the mol-%of the structural lipid may be from about 10 mol-%to about 80 mol-%. In some embodiments, the mol-%of the structural lipid may be from about 20 mol-%to about 70 mol-%. In some embodiments, the mol-%of the structural lipid may be from about 30 mol-%to about 60 mol-%. In some embodiments, the mol-%of the structural lipid may be from about 35 mol-%to about 55 mol-%. In some embodiments, the mol-%of the structural lipid may be from about 40 mol-%to about 50 mol-%. In some embodiments, the structural lipid mol-%of the transfer vehicle batch will be ⁇ 30%, ⁇ 25%, ⁇ 20%, ⁇ 15%, ⁇ 10%, ⁇ 5%, or ⁇ 2.5%of the target mol-%.
- the mol-%of the PEG modified lipid may be from about 0.1 mol%to about 10 mol%. In some embodiments, the mol%of the PEG modified lipid may be from about 0.2 mol%to about 5 mol%. In some embodiments, the mol%of the PEG modified lipid may be from about 0.5 mol%to about 3 mol%. In some embodiments, the mol%of the PEG modified lipid may be from about 1 mol%to about 2 mol%. In some embodiments, the mol%of the PEG modified lipid may be about 1.5 mol%. In some embodiments, the PEG modified lipid mol-%of the transfer vehicle batch will be ⁇ 30%, ⁇ 25%, ⁇ 20%, ⁇ 15%, ⁇ 10%, ⁇ 5%, or ⁇ 2.5%of the target mol-%.
- a lipid nanoparticle formulation may be prepared by the methods described in International Publication Nos. WO2011127255 or WO2008103276, the contents of each of which is herein incorporated by reference in their entirety.
- lipid nanoparticle formulations may be as described in International Publication No. WO2019131770, the contents of which is herein incorporated by reference in its entirety.
- a lipid nanoparticle formulation may be prepared by the methods described in International Publication No. WO2020237227, the contents of each of which is herein incorporated by reference in their entirety. In some embodiments, lipid nanoparticle formulations may be as described in International Publication No. WO2020237227, the contents of which is herein incorporated by reference in its entirety.
- the lipid may be a cleavable lipid such as those described in PCT Patent Application Publication No. WO2012170889, the contents of which are herein incorporated by reference in their entirety.
- the nanoparticles described herein may comprise at least one cationic polymer described herein and/or known in the art.
- the cationic lipid may be synthesized by methods known in the art and/or as described in PCT Patent Application Publication Nos. WO2012040184, WO2011153120, WO2011149733, WO2011090965, WO2011043913, WO2011022460, WO2012061259, WO2012054365, WO2012044638, WO2010080724 and WO201021865; the contents of each of which are herein incorporated by reference in their entirety.
- the pharmaceutical compositions of the nucleic acid vaccine compositions may include at least one of the PEGylated lipids described in PCT Patent Application Publication No. WO2012099755, the contents of which are herein incorporated by reference in their entirety.
- the ratio of PEG in the lipid nanoparticle (LNP) formulations may be increased or decreased and/or the carbon chain length of the PEG lipid may be modified from C14 to C18 to alter the pharmacokinetics and/or biodistribution of the LNP formulations.
- LNP formulations may contain 1-5%of the lipid molar ratio of PEG-c-DOMG as compared to the cationic lipid, DSPC and cholesterol.
- the LNP formulations of the nucleic acid vaccine compositions may contain PEG-c-DOMG at 3%lipid molar ratio.
- the LNP formulations of the nucleic acid vaccine compositions may contain PEG-c-DOMG at 1.5%lipid molar ratio.
- the PEG-c-DOMG may be replaced with a PEG lipid such as, but not limited to, PEG-DSG (1, 2-Distearoyl-sn-glycerol, methoxypolyethylene glycol) or PEG-DPG (1, 2-Dipalmitoyl-sn-glycerol, methoxypolyethylene glycol) .
- the cationic lipid may be selected from any lipid known in the art such as, but not limited to, DLin-MC3-DMA, DLin-DMA, C12-200 and DLin-KC2-DMA.
- the LNP formulation may contain PEG-DMG 2000 (1, 2-dimyristoyl-sn-glycero-3-phophoethanolamine-N- [methoxy (polyethylene glycol) -2000] ) , a cationic lipid known in the art.
- the LNP formulation may contain PEG-DMG 2000and at least one other component.
- the LNP formulation may contain PEG-DMG 2000, DSPC and cholesterol.
- the LNP formulation may contain PEG-DMG 2000, DLin-DMA, DSPC and cholesterol.
- the LNP formulation may contain PEG-DMG 2000, DLin-DMA, DSPC and cholesterol in a molar ratio of 2: 40: 10: 48 (see e.g., Geall et al., Nonviral delivery of self-amplifying RNA vaccines, PNAS, 2012, 109 (36) : 14604-14609; herein incorporated by reference in its entirety) .
- nucleic acid vaccine compositions described herein may be formulated in a nanoparticle to be delivered by a parenteral route as described in U. S. Patent Application Publication No. US20120207845; the contents of which are herein incorporated by reference in their entirety.
- the nucleic acid vaccine compositions of the present disclosure may be formulated with a plurality of cationic lipids, such as a first and a second cationic lipid as described in US Patent Application Publication No.: US20130017223 to Hope et al., the contents of which are incorporated herein by reference in their entirety.
- the first cationic lipid can be selected on the basis of a first property and the second cationic lipid can be selected on the basis of a second property, where the properties may be determined as outlined in US20130017223.
- the first and second properties are complementary.
- nucleic acid vaccine compositions described herein may be formulated with a lipid particle comprising one or more cationic lipids and one or more second lipids, and one or more nucleic acids, wherein the lipid particle comprises a solid core, as described in US Patent Publication No. US20120276209 to Cullis et al., the contents of which are incorporated herein by reference in their entirety.
- the nucleic acid vaccine compositions of the present disclosure may be complexed with a cationic amphiphile in an oil-in-water (o/w) emulsion such as described in European Publication No.: EP2298358 to Satishchandran et al., the contents of which are incorporated herein by reference in their entirety.
- the cationic amphiphile may be a cationic lipid, modified or unmodified spermine, bupivacaine, or benzalkonium chloride and the oil may be a vegetable or an animal oil.
- At least 10%of the nucleic acid-cationic amphiphile complex is in the oil phase of the oil-in-water emulsion (see e.g., the complex described in. EP2298358 to Satishchandran et al. ) , the contents of which are incorporated herein by reference in its entirety.
- the nucleic acid vaccine compositions of the present disclosure may be formulated with a composition comprising a mixture of cationic compounds and neutral lipids.
- the cationic compounds may be formula (I) disclosed in PCT Patent Application Publication No.: WO 1999010390 to Ansell et al., the contents of which are described herein by reference in their entirety
- the neutral lipid may be selected from the group consisting of diacylphosphatidylcholine, diacylphosphatidylethanolamine, ceramide and sphingomyelin.
- the lipid formulation may comprise a cationic lipid of formula A, a neutral lipid, a sterol and a PEG or PEG-modified lipid disclosed in US Patent Publication No.: US 20120101148 to Akinc et al., the contents of which are incorporated herein by reference in their entirety.
- the LNP formulation may be formulated by the methods described in International Publication Nos. WO2011127255 or WO2008103276.
- the nucleic acid vaccine compositions of the present disclosure may be encapsulated in any of the lipid nanoparticle (LNP) formulations described in WO2011127255 and/or WO2008103276; the contents of each of which are herein incorporated by reference in their entirety.
- LNP lipid nanoparticle
- the LNP formulations described herein may comprise a polycationic composition.
- the polycationic composition may be selected from formula 1-60 of US Patent Publication No. US20050222064; the contents of which are herein incorporated by reference in their entirety.
- the LNP formulations comprising a polycationic composition may be used for the delivery of the nucleic acid vaccine compositions described herein in vivo and/or in vitro.
- the LNP formulations described herein may additionally comprise a permeability enhancer molecule.
- a permeability enhancer molecule are described in US Patent Publication No. US20050222064; the contents of which are herein incorporated by reference in their entirety.
- the nanoparticle formulations may be a carbohydrate nanoparticle comprising a carbohydrate carrier and a nucleic acid vaccine composition (e.g., a nucleic acid vaccine for rabies) .
- the carbohydrate carrier may include, but is not limited to, an anhydride-modified phytoglycogen or glycogen-type material, phtoglycogen octenyl succinate, phytoglycogen beta-dextrin, anhydride-modified phytoglycogen beta-dextrin. (See e.g., PCT Patent Application Publication No. WO2012109121; the contents of which are herein incorporated by reference in their entirety) .
- Lipid nanoparticle formulations may be improved by replacing the cationic lipid with a biodegradable cationic lipid which is known as a rapidly eliminated lipid nanoparticle (reLNP) .
- Ionizable cationic lipids such as, but not limited to, DLinDMA, DLin-KC2-DMA, and DLin-MC3-DMA, have been shown to accumulate in plasma and tissues over time and may be a potential source of toxicity.
- the rapid metabolism of the rapidly eliminated lipids can improve the tolerability and therapeutic index of the lipid nanoparticles by an order of magnitude from a 1 mg/kg dose to a 10 mg/kg dose in rat.
- ester linkage can improve the degradation and metabolism profile of the cationic component, while still maintaining the activity of the reLNP formulation.
- the ester linkage can be internally located within the lipid chain or it may be terminally located at the terminal end of the lipid chain.
- the internal ester linkage may replace any carbon in the lipid chain.
- the nucleic acid vaccine compositions are formulated as a solid lipid nanoparticle.
- a solid lipid nanoparticle may be spherical with an average diameter between 10 to 1000 nm.
- SLN possess a solid lipid core matrix that can solubilize lipophilic molecules and may be stabilized with surfactants and/or emulsifiers.
- the lipid nanoparticle may be a self-assembly lipid-polymer nanoparticle (see Zhang et al., ACS Nano, 2008, 2 (8) : 1696–1702; the contents of which are herein incorporated by reference in their entirety) .
- formulations comprising the nucleic acid vaccine compositions described herein may also be constructed or altered such that they passively or actively are directed to different cell types in vivo, including but not limited to immune cells, endothelial cells, antigen presenting cells, and leukocytes (Akinc et al. Mol Ther. 2010, 18: 1357-1364; Song et al., Nat Biotechnol. 2005, 23: 709-717; Judge et al., J Clin Invest.
- One example of passive targeting of formulations to liver cells includes the DLin-DMA, DLin-KC2-DMA and DLin-MC3-DMA-based lipid nanoparticle formulations which have been shown to bind to apolipoprotein E and promote binding and uptake of these formulations into hepatocytes in vivo (Akinc et al. Mol Ther. 2010, 18: 1357-1364; the contents of which are herein incorporated by reference in their entirety) .
- Formulations can also be selectively targeted through expression of different ligands on their surface as exemplified by, but not limited by, folate, transferrin, N-acetylgalactosamine (GalNAc) , and antibody targeted approaches (Kolhatkar et al., Curr Drug Discov Technol. 2011, 8: 197-206; Musacchio and Torchilin, Front Biosci. 2011, 16: 1388-1412; Yu et al., Mol Membr Biol. 2010, 27: 286-298; Patil et al., Crit Rev Ther Drug Carrier Syst. 2008, 25: 1-61; Benoit et al., Biomacromolecules.
- the nucleic acid vaccine compositions of the present disclosure can be formulated for controlled release and/or targeted delivery.
- controlled release refers to a pharmaceutical composition or compound release profile that conforms to a particular pattern of release to affect a therapeutic outcome.
- the nucleic acid vaccine compositions may be encapsulated into a delivery agent described herein and/or known in the art for controlled release and/or targeted delivery.
- encapsulate means to enclose, surround, or encase. As it relates to the formulation of the compositions of the disclosure, encapsulation may be substantial, complete or partial.
- substantially encapsulated means that at least greater than 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, 99.9, 99.99 or greater than 99.999%of the pharmaceutical composition of the disclosure may be enclosed, surrounded or encased within the delivery agent. “Partially encapsulated” means that less than 10, 20, 30, 4050 or less of the pharmaceutical composition or compound of the disclosure may be enclosed, surrounded or encased within the delivery agent.
- encapsulation may be determined by measuring the escape or the activity of the pharmaceutical composition of the disclosure using fluorescence and/or electron micrograph.
- At least 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, 99.9, 99.99 or greater than 99.99%of the pharmaceutical composition of the disclosure are encapsulated in the delivery agent.
- the nucleic acid vaccine compositions may be encapsulated into a lipid nanoparticle or a rapidly eliminated lipid nanoparticle and the lipid nanoparticles or a rapidly eliminated lipid nanoparticle may then be encapsulated into a polymer, hydrogel and/or surgical sealant described herein and/or known in the art.
- the polymer, hydrogel or surgical sealant may be PLGA, ethylene vinyl acetate (EVAc) , poloxamer, (Nanotherapeutics, Inc. Alachua, FL) , (Halozyme Therapeutics, San Diego CA) , surgical sealants such as fibrinogen polymers (Ethicon Inc. Cornelia, GA) , (Baxter International, Inc., Deerfield, IL) , PEG-based sealants, and (Baxter International, Inc., Deerfield, IL) .
- the lipid nanoparticle may be encapsulated into any polymer known in the art which may form a gel when injected into a subject.
- the lipid nanoparticle may be encapsulated into a polymer matrix which may be biodegradable.
- the formulations comprising the nucleic acid vaccine compositions for controlled release and/or targeted delivery may also include at least one controlled release coating.
- Controlled release coatings include, but are not limited to, polyvinylpyrrolidone/vinyl acetate copolymer, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, EUDRAGIT EUDRAGIT and cellulose derivatives such as ethylcellulose aqueous dispersions
- the controlled release and/or targeted delivery formulation may comprise at least one degradable polyester which may contain polycationic side chains.
- Degradable polyesters include, but are not limited to, poly (serine ester) , poly (L-lactide-co-L-lysine) , poly (4-hydroxy-L-proline ester) , and combinations thereof.
- the degradable polyesters may include a PEG conjugation to form a PEGylated polymer.
- the nucleic acid vaccine compositions of the present disclosure may be formulated with a targeting lipid with a targeting moiety such as the targeting moieties disclosed in US Patent Application Publication No.: US20130202652 to Manoharan et al., the contents of which are incorporated herein by reference in their entirety.
- the targeting moiety of formula I ofUS 20130202652 to Manoharan et al. may be selected in order to favor the lipid being localized with a desired organ, tissue, cell, cell type or subtype, or organelle.
- Non-limiting targeting moieties that are contemplated in the present disclosure include transferrin, anisamide, an RGD peptide, prostate specific membrane antigen (PSMA) , fucose, an antibody, or an aptamer.
- the nucleic acid vaccine compositions of the present disclosure may be encapsulated in a therapeutic nanoparticle.
- Therapeutic nanoparticles may be formulated by methods described herein and known in the art such as, but not limited to, PCT Patent Application Publication Nos. WO2010005740, WO2010030763, WO2010005721, WO2010005723, and WO2012054923, US Pub. Nos. US20110262491, US20100104645, US20100087337, US20100068285, US20110274759, US20100068286 and US20120288541 and US Pat. No.
- Therapeutic polymer nanoparticles may be identified by the methods described in US Pub No. US20120140790, the contents of which are herein incorporated by reference in their entirety.
- the therapeutic nanoparticle may be formulated for sustained release.
- sustained release refers to a pharmaceutical composition or compound that conforms to a release rate over a specific period of time. The period of time may include, but is not limited to, hours, days, weeks, months and years.
- the sustained release nanoparticle may comprise a polymer and a therapeutic agent such as, but not limited to, the nucleic acid vaccine compositions of the present disclosure (see PCT Patent Application Publication No. WO2010075072 and US Pub No. US20100216804, US20110217377 and US20120201859, the contents of each of which are herein incorporated by reference in their entirety) .
- the therapeutic nanoparticles may be formulated to be target specific.
- the therapeutic nanoparticles may include a corticosteroid (see PCT Patent Application Publication No. WO2011084518; the contents of which are herein incorporated by reference in their entirety) .
- the therapeutic nanoparticles may be formulated to be cancer specific.
- the therapeutic nanoparticles may be formulated in nanoparticles described in PCT Patent Application Publication No. WO2008121949, WO2010005726, WO2010005725, and WO2011084521, and US Pub No. US20100069426, US20120004293 and US20100104655, the contents of each of which are herein incorporated by reference in their entirety.
- the nanoparticles of the present disclosure may comprise a polymeric matrix.
- the nanoparticle may comprise two or more polymers such as, but not limited to, polyethylenes, polycarbonates, polyanhydrides, polyhydroxyacids, polypropylfumerates, polycaprolactones, polyamides, polyacetals, polyethers, polyesters, poly (orthoesters) , polycyanoacrylates, polyvinyl alcohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polycyanoacrylates, polyureas, polystyrenes, polyamines, polylysine, poly (ethylene imine) , poly (serine ester) , poly (L-lactide-co-L-lysine) , poly (4-hydroxy-L-proline ester) or combinations thereof.
- the therapeutic nanoparticle comprises a diblock copolymer.
- the diblock copolymer may include PEG in combination with a polymer such as, but not limited to, polyethylenes, polycarbonates, polyanhydrides, polyhydroxyacids, polypropylfumerates, polycaprolactones, polyamides, polyacetals, polyethers, polyesters, poly (orthoesters) , polycyanoacrylates, polyvinyl alcohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polycyanoacrylates, polyureas, polystyrenes, polyamines, polylysine, poly (ethylene imine) , poly (serine ester) , poly (L-lactide-co-L-lysine) , poly (4-hydroxy-L-proline ester) or combinations thereof.
- a polymer such as, but not limited to, polyethylenes, polycarbonates, polyanhydrides, polyhydroxyacids, poly
- the therapeutic nanoparticle comprises a PLGA-PEG block copolymer (see US Pub. No. US20120004293 and US Pat. No. 8,236,330, each of which is herein incorporated by reference in their entirety) .
- the therapeutic nanoparticle is a stealth nanoparticle comprising a diblock copolymer of PEG and PLA or PEG and PLGA (see US Pat. No 8,246,968 and PCT Patent Application Publication No. WO2012166923, the contents of each of which are herein incorporated by reference in their entirety) .
- the therapeutic nanoparticle may comprise a multiblock copolymer such as, but not limited to the multiblock copolymers described in U.S. Pat. Nos. 8,263,665 and 8,287,910; the contents of each of which are herein incorporated by reference in their entirety.
- the block copolymers described herein may be included in a polyion complex comprising a non-polymeric micelle and the block copolymer.
- a polyion complex comprising a non-polymeric micelle and the block copolymer.
- the nanoparticles for delivery of the nucleic acid vaccines described herein include block co-polymers.
- block co-polymers include those of formula I, formula II, formula III, formula IV, formula V, formula VI and formula VII ofPCT Patent Application Publication No. WO2015017519, the contents of which are herein incorporated by reference in their entirety.
- the therapeutic nanoparticle may comprise at least one acrylic polymer.
- Acrylic polymers include but are not limited to, acrylic acid, methacrylic acid, acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, amino alkyl methacrylate copolymer, poly (acrylic acid) , poly (methacrylic acid) , polycyanoacrylates and combinations thereof.
- the therapeutic nanoparticles may comprise at least one amine-containing polymer such as, but not limited to polylysine, polyethylene imine, poly (amidoamine) dendrimers, poly (beta-amino esters) (See e.g., U.S. Pat. No. 8,287,849; the contents of which are herein incorporated by reference in their entirety) and combinations thereof.
- amine-containing polymer such as, but not limited to polylysine, polyethylene imine, poly (amidoamine) dendrimers, poly (beta-amino esters) (See e.g., U.S. Pat. No. 8,287,849; the contents of which are herein incorporated by reference in their entirety) and combinations thereof.
- the therapeutic nanoparticles may comprise at least one degradable polyester which may contain polycationic side chains.
- Degradable polyesters include, but are not limited to, poly (serine ester) , poly (L-lactide-co-L-lysine) , poly (4- hydroxy-L-proline ester) , and combinations thereof.
- the degradable polyesters may include a PEG conjugation to form a PEGylated polymer.
- the therapeutic nanoparticle may include a conjugation of at least one targeting ligand.
- the targeting ligand may be any ligand known in the art such as, but not limited to, a monoclonal antibody. (Kirpotin et al, Cancer Res. 2006, 66: 6732-6740; the contents of which are herein incorporated by reference in their entirety) .
- the therapeutic nanoparticle may be formulated in an aqueous solution which may be used to target cancer (see PCT Patent Application Publication No. WO2011084513 and US Pub No. US20110294717, the contents of each of which are herein incorporated by reference in their entirety) .
- the nucleic acid vaccine compositions may be encapsulated in, linked to and/or associated with synthetic nanocarriers.
- Synthetic nanocarriers include, but are not limited to, those described in PCT Patent Application Publication Nos. WO2010005740, WO2010030763, WO201213501, WO2012149252, WO2012149255, WO2012149259, WO2012149265, WO2012149268, WO2012149282, WO2012149301, WO2012149393, WO2012149405, WO2012149411, WO2012149454 and WO2013019669, and US Pub. Nos.
- the synthetic nanocarriers may be formulated using methods known in the art and/or described herein. As a non-limiting example, the synthetic nanocarriers may be formulated by the methods described in PCT Patent Application Publication Nos. WO2010005740, WO2010030763 and WO201213501and US Pub. Nos. US20110262491, US20100104645, US20100087337 and US2012024422, the contents of each of which are herein incorporated by reference in their entirety.
- the synthetic nanocarrier formulations may be lyophilized by methods described in PCT Patent Application Publication Pub. No. WO2011072218 and US Pat. No. 8,211,473; the contents of each of which are herein incorporated by reference in their entirety.
- the synthetic nanocarriers may contain reactive groups to release the nucleic acid vaccine compositions described herein (see PCT Patent Application Publication No. WO20120952552 and US Pub No. US20120171229, the contents of each of which are herein incorporated by reference in their entirety) .
- the synthetic nanocarriers may be formulated for targeted release.
- the synthetic nanocarrier may be formulated to release the nucleic acid vaccine compositions at a specified pH and/or after a desired time interval.
- the synthetic nanoparticle may be formulated to release the nucleic acid vaccine compositions after 24 hours and/or at a pH of 4.5 (see PCT Patent Application Publication Nos. WO2010138193 and WO2010138194 and US Pub Nos. US20110020388 and US20110027217, the contents of each of which are herein incorporated by reference in their entireties) .
- the synthetic nanocarriers may be formulated for controlled and/or sustained release of the nucleic acid vaccine compositions described herein.
- the synthetic nanocarriers for sustained release may be formulated by methods known in the art, described herein and/or as described in PCT Patent Application Publication No. WO2010138192 and US Pub No. US20100303850, the contents each of which are herein incorporated by reference in their entirety.
- the nanoparticle may be optimized for oral administration.
- the nanoparticle may comprise at least one cationic biopolymer such as, but not limited to, chitosan or a derivative thereof.
- the nanoparticle may be formulated by the methods described in U.S. Pub. No. US20120282343; the contents of which are herein incorporated by reference in their entirety.
- the nucleic acid vaccine compositions of the present disclosure may be formulated in a modular composition such as described in US Pat. No. US 8,575,123 to Manoharan et al., the contents of which are herein incorporated by reference in their entirety.
- the modular composition may comprise a nucleic acid, e.g., the nucleic acid vaccine compositions of the present disclosure, at least one endosomolytic component, and at least one targeting ligand.
- the modular composition may have a formula such as any formula described in US 8,575,123 to Manoharan et al.
- the nucleic acid vaccine compositions of the present disclosure may be encapsulated in the lipid formulation to form a stable nucleic acid-lipid particle (SNALP) such as described in US Pat. No. US8,546,554 to de Fougerolles et al., the contents of which are incorporated here by reference in their entirety.
- SNALP stable nucleic acid-lipid particle
- the lipid may be cationic or non-cationic.
- the lipid to nucleic acid ratio (mass/mass ratio) (e.g., lipid to nucleic acid vaccine compositions ratio) will be in the range of from about 1: 1 to about 50: 1, from about 1: 1 to about 25: 1, from about 3: 1 to about 15: 1, from about 4: 1 to about 10: 1, from about 5: 1 to about 9: 1, or about 6: 1 to about 9: 1, or 5: 1, 6: 1, 7: 1, 8: 1, 9: 1, 10: 1, or 11: 1.
- the SNALP includes 40%2, 2-Dilinoleyl-4-dimethylaminoethyl- [1, 3] -dioxolane (Lipid A) , 10%dioleoylphosphatidylcholine (DSPC) , 40%cholesterol, 10%polyethylene glycol (PEG) -C-DOMG (mole percent) with a particle size of 63.0 ⁇ 20 nm and a 0.027 nucleic acid/lipid ratio.
- nucleic acid vaccine compositions of the present disclosure may be formulated with a nucleic acid-lipid particle comprising an endosomal membrane destabilizer as disclosed in US Pat. No. US 7,189,705 to Lam et al., the contents of which are incorporated herein by reference in their entirety.
- the endosomal membrane destabilizer may be a Ca 2+ ion.
- the nucleic acid vaccine compositions of the present disclosure may be formulated with formulated lipid particles (FLiPs) disclosed in US Pat. No. US 8,148,344 to Akinc et al., the contents of which are herein incorporated by reference in their entirety.
- FLiPs may comprise at least one of a single or double-stranded oligonucleotide, where the oligonucleotide has been conjugated to a lipophile and at least one of an emulsion or liposome to which the conjugated oligonucleotide has been aggregated, admixed or associated.
- FLiPs formulated lipid particles
- the nucleic acid vaccine compositions of the present disclosure may be delivered to a cell using a composition comprising an expression vector in a lipid formulation as described in US Pat. No. US 6,086,913 to Tam et al., the contents of which are incorporated herein by reference in their entirety.
- the composition disclosed by Tam is serum-stable and comprises an expression vector comprising first and second inverted repeated sequences from an adeno associated virus (AAV) , a rep gene from AAV, and a nucleic acid fragment.
- AAV adeno associated virus
- the expression vector in Tam is complexed with lipids.
- the nucleic acid vaccine compositions of the present disclosure may be formulated with a lipid formulation disclosed in US Pub. No. US 20120270921 to de Fougerolles et al., the contents of which are incorporated herein by reference in their entirety.
- the lipid formulation may include a cationic lipid having the formula A described in US 20120270921.
- the compositions of exemplary nucleic acid-lipid particles disclosed in Table A ofUS20120270921 may be used with the nucleic acid vaccine compositions of the present disclosure.
- the nucleic acid vaccine compositions of the present disclosure may be fully encapsulated in a lipid particle disclosed in US Pub. No. US 20120276207 to Maurer et al., the contents of which are incorporated herein by reference in their entirety.
- the particles may comprise a lipid composition comprising preformed lipid vesicles, a charged therapeutic agent, and a destabilizing agent to form a mixture of preformed vesicles and therapeutic agent in a destabilizing solvent, wherein the destabilizing solvent is effective to destabilize the membrane of the preformed lipid vesicles without disrupting the vesicles.
- the nucleic acid vaccine compositions of the present disclosure may be formulated with a conjugated lipid.
- the conjugated lipid may have a formula such as described in US Pub. No. US 20120264810 to Lin et al., the contents of which are incorporated herein by reference in their entirety.
- the conjugate lipid may form a lipid particle which further comprises a cationic lipid, a neutral lipid, and a lipid capable of reducing aggregation.
- nucleic acid vaccine compositions of the present disclosure may be formulated in a neutral liposomal formulation such as disclosed in US Pub. No. US 20120244207 to Fitzgerald et al., the contents of which are incorporated herein by reference in their entirety.
- neutral liposomal formulation refers to a liposomal formulation with a near neutral or neutral surface charge at a physiological pH.
- Physiological pH can be, e.g., about 7.0 to about 7.5, or, e.g., about 7.5, or, e.g., 7.0, 7.1, 7.2, 7.3, 7.4, or 7.5, or, e.g., 7.3, or, e.g., 7.4.
- a neutral liposomal formulation is an ionizable lipid nanoparticle (iLNP) .
- a neutral liposomal formulation can include an ionizable cationic lipid, e.g., DLin-KC2-DMA.
- the nucleic acid vaccine compositions of the present disclosure may be formulated with a charged lipid or an amino lipid.
- charged lipid is meant to include those lipids having one or two fatty acyl or fatty alkyl chains and a quaternary amino head group.
- the quaternary amine carries a permanent positive charge.
- the head group can optionally include an ionizable group, such as a primary, secondary, or tertiary amine that may be protonated at physiological pH.
- a charged lipid is referred to as an "amino lipid. "
- the amino lipid may be any amino lipid described in US Pub. No. US20110256175 to Hope et al., the contents of which are incorporated herein by reference in their entirety.
- the amino lipids may have the structure disclosed in Tables 3-7 ofHope, such as structure (II) , DLin-K-C2-DMA, DLin-K2-DMA, DLin-K6-DMA, etc.
- the resulting pharmaceutical preparations may be lyophilized according to Hope.
- the amino lipids may be any amino lipid described in US 20110117125 to Hope et al., the contents of which are incorporated herein by reference in their entirety, such as a lipid of structure (I) , DLin-K-DMA, DLin-C-DAP, DLin-DAC, DLin-MA, DLin-S-DMA, etc.
- the amino lipid may have the structure (I) , (II) , (III) , or (IV) , or 4- (R) -DLin-K-DMA (VI) , 4-(S) -DLin-K-DMA (V) as described in PCT Patent Application Publication No. WO2009132131 to Manoharan et al., the contents of which are incorporated herein by reference in their entirety.
- the charged lipid used in any of the formulations described herein may be any charged lipid described in EP2509636 to Manoharan et al., the contents of which are incorporated herein by reference in their entirety.
- the nucleic acid vaccine composition s of the present disclosure may be formulated with an association complex.
- the association complex comprises one or more compounds each having a structure defined by formula (I) , a PEG-lipid having a structure defined by formula (XV) , a steroid and a nucleic acid disclosed in US Pat. No. US8,034,376 to Manoharan et al., the contents of which are incorporated herein by reference in their entirety.
- the nucleic acid vaccine compositions may be formulated with any association complex described in US Pat. No. US8,034,376., the contents of which are herein incorporated by reference in its entirety.
- the nucleic acid vaccine compositions of the present disclosure may be formulated with reverse head group lipids.
- the nucleic acid vaccine compositions may be formulated with a zwitterionic lipid comprising a headgroup wherein the positive charge is located near the acyl chain region and the negative charge is located at the distal end of the head group, such as a lipid having structure (A) or structure (I) described in PCT Patent Application Publication No. WO2011056682 to Leung et al., the contents of which are incorporated herein by reference in their entirety.
- the nucleic acid vaccine compositions of the present disclosure may be formulated in a lipid bilayer carrier.
- the nucleic acid vaccine compositions may be combined with a lipid-detergent mixture comprising a lipid mixture of an aggregation-preventing agent in an amount of about 5 mol%to about 20 mol%, a cationic lipid in an amount of about 0.5 mol%to about 50 mol%, and a fusogenic lipid and a detergent, to provide a nucleic acid-lipid-detergent mixture; and then dialyzing the nucleic acid-lipid-detergent mixture against a buffered salt solution to remove the detergent and to encapsulate the nucleic acid in a lipid bilayer carrier and provide a lipid bilayer-nucleic acid composition, wherein the buffered salt solution has an ionic strength sufficient to encapsulate of from about 40%to about 80%of the nucleic acid, described in PCT Patent Application Publication No. WO
- the nucleic acid vaccine compositions of the present disclosure may comprise (a) a nucleic acid; (b) 1.0 mole%to 45 mole%of a cationic lipid; (c) 0.0 mole%to 90 mole%of another lipid; (d) 1.0 mole%to 10 mole%of a bilayer stabilizing component; (e) 0.0 mole%to 60 mole%cholesterol; and (f) 0.0 mole%to 10 mole%of cationic polymer lipid as described in EP1328254 to Cullis et al., the contents of which are incorporated herein by reference in their entirety.
- the nucleic acid vaccine may be delivered using smaller LNPs.
- the diameter of such particles may be from below 0.1 ⁇ m or up to 100 nm such as, but not limited to, less than 0.1 ⁇ m, less than 1.0 ⁇ m, less than 5 ⁇ m, less than 10 ⁇ m, less than 15 ⁇ m, less than 20 ⁇ m, less than 25 ⁇ m, less than 30 ⁇ m, less than 35 ⁇ m, less than 40 ⁇ m, less than 50 ⁇ m, less than 55 ⁇ m, less than 60 ⁇ m, less than 65 ⁇ m, less than 70 ⁇ m, less than 75 ⁇ m, less than 80 ⁇ m, less than 85 ⁇ m, less than 90 ⁇ m, less than 95 ⁇ m,less than 100 ⁇ m, less than 125 ⁇ m, less than 150 ⁇ m, less than 175 ⁇ m, less than 200 ⁇ m, less than 225 ⁇ m, less than 250 ⁇ m, less than 275 ⁇ m, less than 300
- nucleic acid vaccine may be delivered using smaller LNPs which may comprise a diameter from about 1 nm to about 100 nm, from about 1 nm to about 10 nm, from about 1 nm to about 20 nm, from about 1 nm to about 30 nm, from about 1 nm to about 40 nm, from about 1 nm to about 50 nm, from about 1 nm to about 60 nm, from about 1 nm to about 70 nm, from about 1 nm to about 80 nm, from about 1 nm to about 90 nm, from about 5 nm to about from 100 nm, from about 5 nm to about 10 nm, from about 5 nm to about 20 nm, from about 5 nm to about 30 nm, from about 5 nm to about 40 nm, from about 5 nm to about 50 nm, from about 5 nm to about 60 nm, from about 5 nm to about 70
- the nucleic acid vaccine may be formulated in lipid nanoparticles having a diameter from about 10 nm to about 100 nm such as, but not limited to, about 10 nm to about 20 nm, about 10 nm to about 30 nm, about 10 nm to about 40 nm, about 10 nm to about 50 nm, about 10 nm to about 60 nm, about 10 nm to about 70 nm, about 10 nm to about 80 nm, about 10 nm to about 90 nm, about 20 nm to about 30 nm, about 20 nm to about 40 nm, about 20 nm to about 50 nm, about 20 nm to about 60 nm, about 20 nm to about 70 nm, about 20 nm to about 80 nm, about 20 nm to about 90 nm, about 20 nm to about 100 nm, about 30 nm to about 40 nm, about 30 nm
- the nucleic acid vaccine may be formulated in lipid nanoparticles having a diameter from 10-1000 nm.
- the nanoparticle may be 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440,
- the lipid nanoparticles may have a diameter from about 10 to 500 nm.
- the lipid nanoparticle may have a diameter greater than 100 nm, greater than 150 nm, greater than 200 nm, greater than 250 nm, greater than 300 nm,greater than 350 nm, greater than 400 nm, greater than 450 nm, greater than 500 nm, greater than 550 nm, greater than 600 nm, greater than 650 nm, greater than 700 nm, greater than 750 nm, greater than 800 nm, greater than 850 nm, greater than 900 nm, greater than 950 nm or greater than 1000 nm.
- the nucleic acid vaccine compositions of the disclosure can be formulated using natural and/or synthetic polymers.
- Non-limiting examples of polymers which may be used for delivery include, but are not limited to, DYNAMIC (Arrowhead Research Corp., Pasadena, CA) formulations from Bio (Madison, WI) and Roche Madison (Madison, WI) , PHASERX TM polymer formulations such as, without limitation, SMARTT POLYMER TECHNOLOGY TM ( Seattle, WA) , DMRI/DOPE, poloxamer, adjuvant from Vical (San Diego, CA) , chitosan, cyclodextrin from Calando Pharmaceuticals (Pasadena, CA) , dendrimers and poly (lactic-co-glycolic acid) (PLGA) polymers, RONDEL TM (RNAi/Oligonucleotide Nanoparticle Delivery) polymers (Arrowhead Research Corporation, Pasadena, CA) and pH responsive co-block
- chitosan-based formulation includes a core of positively charged chitosan and an outer portion of negatively charged substrate (U.S. Pub. No. US20120258176; the contents of which are herein incorporated by reference in their entirety) .
- Chitosan includes, but is not limited to N-trimethyl chitosan, mono-N-carboxymethyl chitosan (MCC) , N-palmitoyl chitosan (NPCS) , EDTA-chitosan, low molecular weight chitosan, chitosan derivatives, or combinations thereof.
- the polymers used in the present disclosure have undergone processing to reduce and/or inhibit the attachment of unwanted substances such as, but not limited to, bacteria, to the surface of the polymer.
- the polymer may be processed by methods known and/or described in the art and/or described in PCT Patent Application Publication No. WO2012150467; the contents of which are herein incorporated by reference in their entirety.
- PLGA based formulations include, but are not limited to, PLGA-based injectable depots (e.g., which is formed by dissolving PLGA in 66%N-methyl-2-pyrrolidone (NMP) and the remainder being aqueous solvent and leuprolide. Once injected, the PLGA and leuprolide peptide precipitates into the subcutaneous space) .
- the PLGA-based injectable depots may be long-acting.
- the first of these delivery approaches uses dynamic polyconjugates and has been shown in vivo in mice to effectively deliver siRNA and silence endogenous target mRNA in hepatocytes (Rozema et al., Proc Natl Acad Sci USA. 2007, 104: 12982-12887; the contents of which are herein incorporated by reference in their entirety) .
- This particular approach is a multicomponent polymer system whose key features include a membrane-active polymer to which nucleic acid, in this case siRNA, is covalently coupled via a disulfide bond and where both PEG (for charge masking) and N-acetylgalactosamine (for hepatocyte targeting) groups are linked via pH-sensitive bonds (See again, Rozema et al., Proc Natl Acad Sci USA. 2007, 104: 12982-12987) .
- the polymer complex On binding to the hepatocyte and entry into the endosome, the polymer complex disassembles in the low-pH environment, with the polymer exposing its positive charge, leading to endosomal escape and cytoplasmic release of the siRNA from the polymer.
- the polymer formulation can permit the sustained or delayed release of nucleic acid vaccine compositions (e.g., following intramuscular, subcutaneous, intraparenchymal, intrathecal, intracerebroventricular administration) .
- the altered release profile for the nucleic acid vaccine compositions can result in, for example, translation of an encoded protein, or polypeptide or peptide over an extended period of time.
- Biodegradable polymers have been previously used to protect nucleic acids from degradation and been shown to result in sustained release of payloads in vivo (Rozema et al., Proc Natl Acad Sci USA. 2007, 104: 12982-12887; Sullivan et al., Expert Opin Drug Deliv.
- the nucleic acid vaccines of the present disclosure may be formulated for controlled release.
- One form of controlled-release formulation contains the therapeutic compound or its salt dispersed or encapsulated in a slowly degrading, non-toxic, non-antigenic polymer such as copoly (lactic/glycolic) acid, as described in the pioneering work of Kent et al., US Patent No. 4,675,189, the contents of which are incorporated by reference herein in their entirety.
- the compounds, or their salts may also be formulated in cholesterol or other lipid matrix pellets, or silastomer matrix implants.
- the nucleic acid vaccines of the present disclosure may be dispersed or encapsulated in the polymers disclosed in US Patent No.
- An additional form of controlled-release formulation comprises a solution of biodegradable polymer, such as copoly (lactic/glycolic acid) or block copolymers of lactic acid and PEG, which is injected subcutaneously or intramuscularly to achieve a depot formulation for controlled release.
- biodegradable polymer such as copoly (lactic/glycolic acid) or block copolymers of lactic acid and PEG, which is injected subcutaneously or intramuscularly to achieve a depot formulation for controlled release.
- the pharmaceutical compositions may be sustained release formulations.
- the sustained release formulations may be for subcutaneous delivery.
- Sustained release formulations may include, but are not limited to, PLGA microspheres, ethylene vinyl acetate (EVAc) , poloxamer, (Nanotherapeutics, Inc. Alachua, FL) , (Halozyme Therapeutics, San Diego, CA) , surgical sealants such as fibrinogen polymers (Ethicon Inc. Cornelia, GA) , (Baxter International, Inc Deerfield, IL) , PEG-based sealants, and (Baxter International, Inc Deerfield, IL) .
- nucleic acid vaccine compositions may be formulated in PLGA microspheres by preparing the PLGA microspheres with tunable release rates (e.g., days and weeks) and encapsulating the nucleic acid vaccine compositions in the PLGA microspheres while maintaining the integrity of the nucleic acid vaccine compositions during the encapsulation process.
- EVAc are non-biodegradable, biocompatible polymers which are used extensively in pre-clinical sustained release implant applications.
- Poloxamer F-407 NF is a hydrophilic, non-ionic surfactant triblock copolymer of polyoxyethylene-polyoxypropylene-polyoxyethylene having a low viscosity at temperatures less than 5°C and forms a solid gel at temperatures greater than 15°C.
- PEG-based surgical sealants comprise two synthetic PEG components mixed in a delivery device which can be prepared in one minute, seals in 3 minutes and is reabsorbed within 30 days. and natural polymers are capable of in-situ gelation at the site of administration. They have been shown to interact with protein and peptide therapeutic candidates through ionic interaction to provide a stabilizing effect.
- Polymer formulations can also be selectively targeted through expression of different ligands as exemplified by, but not limited by, folate, transferrin, and N-acetylgalactosamine (GalNAc) (Benoit et al., Biomacromolecules. 2011, 12: 2708-2714; Rozema et al., Proc Natl Acad Sci USA. 2007, 104: 12982-12987; Davis, Mol Pharm. 2009, 6: 659-668; Davis, Nature, 2010, 464: 1067-1070; the contents of each of which are herein incorporated by reference in their entirety) .
- GalNAc N-acetylgalactosamine
- the nucleic acid vaccine compositions of the disclosure may be formulated with or in a polymeric compound.
- the polymeric compound may include at least one polymer such as, but not limited to, polyethenes, polyethylene glycol (PEG) , poly (l-lysine) (PLL) , PEG grafted to PLL, cationic lipopolymer, biodegradable cationic lipopolymer, polyethyleneimine (PEI) , cross-linked branched poly (alkylene imines) , a polyamine derivative, a modified poloxamer, a biodegradable polymer, elastic biodegradable polymer, biodegradable block copolymer, biodegradable random copolymer, biodegradable polyester copolymer, biodegradable polyester block copolymer, biodegradable polyester block random copolymer, multiblock copolymers, linear biodegradable copolymer, poly [ ⁇ - (4-aminobutyl) -L-glycolic acid
- the nucleic acid vaccine compositions of the disclosure may be formulated with the polymeric compound of PEG grafted with PLL as described in U.S. Pat. No. 6,177,274; herein incorporated by reference in its entirety.
- the formulation may be used for transfecting cells in vitro or for in vivo delivery of the nucleic acid vaccine compositions.
- the nucleic acid vaccine compositions may be suspended in a solution or medium with a cationic polymer, in a dry pharmaceutical composition or in a solution that is capable of being dried as described in U.S. Pub. Nos. US20090042829 and US20090042825; the contents of each of which are herein incorporated by reference in their entirety.
- the nucleic acid vaccine compositions of the disclosure may be formulated with a PLGA-PEG block copolymer (see US Pub. No. US20120004293 and US Pat No. 8,236,330, herein incorporated by reference in their entireties) or PLGA-PEG-PLGA block copolymers (See U.S. Pat. No. 6,004,573, herein incorporated by reference in its entirety) .
- the nucleic acid vaccine compositions of the disclosure may be formulated with a diblock copolymer of PEG and PLA or PEG and PLGA (see US Pat No 8,246,968, herein incorporated by reference in its entirety) .
- the nucleic acid vaccines compositions may be formulated with branched PEG molecules as described in or made by the methods described in PCT Patent Application Publication No. WO20180126084; the contents of which are herein incorporated by reference in their entirety.
- the branched PEG which may be used in the formulations described herein may have the formula I, formula II, formula III, formula IV, formula V, formula VI of PCT Publication No. WO20180126084, the contents of which are herein incorporated by reference in their entirety.
- Apolyamine derivative may be used to deliver nucleic acids to treat and/or prevent a disease or to be included in an implantable or injectable device (U.S. Pub. No. US20100260817; the contents of which are herein incorporated by reference in their entirety) .
- the nucleic acid vaccine compositions of the present disclosure may be formulated using the polyamine derivative described in U. S. Pub. No. US20100260817; the contents of which are incorporated herein by reference in their entirety.
- the nucleic acid vaccine compositions of the present disclosure may be delivered using a polyamide polymer such as, but not limited to, a polymer comprising a 1, 3-dipolar addition polymer prepared by combining a carbohydrate diazide monomer with a dialkyne unite comprising oligoamines (U.S. Pat. No. 8,236,280; the contents of which are herein incorporated by reference in their entirety) .
- a polyamide polymer such as, but not limited to, a polymer comprising a 1, 3-dipolar addition polymer prepared by combining a carbohydrate diazide monomer with a dialkyne unite comprising oligoamines (U.S. Pat. No. 8,236,280; the contents of which are herein incorporated by reference in their entirety) .
- the nucleic acid vaccine compositions of the present disclosure may be formulated with at least one polymer and/or derivatives thereof described in PCT Patent Application Publication Nos. WO2011115862, WO2012082574 and WO2012068187 and U.S. Pub. No. US20120283427, the contents of each of which are herein incorporated by reference in their entireties.
- the nucleic acid vaccine compositions of the present disclosure may be formulated with a polymer of formula Z as described in WO2011115862; the contents of which are herein incorporated by reference in their entirety.
- the nucleic acid vaccine compositions may be formulated with a polymer of formula Z, Z’ or Z” as described in PCT Patent Application Publication Nos.
- the polymers formulated with the nucleic acid vaccine compositions of the present disclosure may be synthesized by the methods described in PCT Patent Application Publication Nos. WO2012082574 or WO2012068187, the contents of each of which are herein incorporated by reference in their entireties.
- the nucleic acid vaccine compositions of the disclosure may be formulated with at least one acrylic polymer.
- Acrylic polymers include but are not limited to, acrylic acid, methacrylic acid, acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, amino alkyl methacrylate copolymer, poly (acrylic acid) , poly (methacrylic acid) , polycyanoacrylates and combinations thereof.
- Formulations of nucleic acid vaccine compositions of the disclosure may include at least one amine-containing polymer such as, but not limited to polylysine, polyethylene imine, poly (amidoamine) dendrimers or combinations thereof.
- amine-containing polymer such as, but not limited to polylysine, polyethylene imine, poly (amidoamine) dendrimers or combinations thereof.
- the nucleic acid vaccine compositions of the disclosure may be formulated in a pharmaceutical compound including a poly (alkylene imine) , a biodegradable cationic lipopolymer, a biodegradable block copolymer, a biodegradable polymer, or a biodegradable random copolymer, a biodegradable polyester block copolymer, a biodegradable polyester polymer, a biodegradable polyester random copolymer, a linear biodegradable copolymer, PAGA, a biodegradable cross-linked cationic multi-block copolymer or combinations thereof.
- the biodegradable cationic lipopolymer may be made by methods known in the art and/or described in U.S. Pat.
- the poly (alkylene imine) may be made using methods known in the art and/or as described in U.S. Pub. No. US20100004315, which is herein incorporated by reference in its entirety.
- the biodegradable polymer, biodegradable block copolymer, the biodegradable random copolymer, biodegradable polyester block copolymer, biodegradable polyester polymer, or biodegradable polyester random copolymer may be made using methods known in the art and/or as described in U.S. Pat. Nos.
- the linear biodegradable copolymer may be made using methods known in the art and/or as described in U.S. Pat. No. 6,652,886; the contents of which are each incorporated herein by reference in their entirety.
- the PAGA polymer may be made using methods known in the art and/or as described in U.S. Pat. No. 6,217,912; the contents of which are herein incorporated by reference in their entirety.
- the PAGA polymer may be copolymerized to form a copolymer or block copolymer with polymers such as but not limited to, poly-L-lysine, polyargine, polyornithine, histones, avidin, protamines, polylactides and poly (lactide-co-glycolides) .
- the biodegradable cross-linked cationic multi-block copolymers may be made my methods known in the art and/or as described in U.S. Pat. No. 8,057,821 or U.S. Pub. No. US2012009145; the contents of each of which are herein incorporated by reference in their entireties.
- the multi-block copolymers may be synthesized using linear polyethyleneimine (LPEI) blocks which have distinct patterns as compared to branched polyethyleneimines.
- LPEI linear polyethyleneimine
- the composition or pharmaceutical composition may be made by the methods known in the art, described herein, or as described in U.S. Pub. No. US20100004315 or U.S. Pat. Nos. 6,267,987 and 6,217,912; the contents of each of which are herein incorporated by reference in their entireties.
- the nucleic acid vaccine compositions of the disclosure may be formulated with at least one degradable polyester which may contain polycationic side chains.
- Degradable polyesters include, but are not limited to, poly (serine ester) , poly (L-lactide- co-L-lysine) , poly (4-hydroxy-L-proline ester) , and combinations thereof.
- the degradable polyesters may include a PEG conjugation to form a PEGylated polymer.
- the nucleic acid vaccine compositions of the disclosure may be formulated with at least one crosslinkable polyester.
- Crosslinkable polyesters include those known in the art and described in US Pub. No. US20120269761; the contents of which herein are incorporated by reference in their entirety.
- the polymers described herein may be conjugated to a lipid-terminating PEG.
- PLGA may be conjugated to a lipid-terminating PEG forming PLGA-DSPE-PEG.
- PEG conjugates for use with the present disclosure include those described in PCT Patent Application Publication No. WO2008103276; the contents of which are herein incorporated by reference in their entirety.
- the polymers may be conjugated using a ligand conjugate such as, but not limited to, the conjugates described in U.S. Pat. No. 8,273,363; the contents of which are herein incorporated by reference in their entirety.
- the nucleic acid vaccine compositions described herein may be conjugated with another compound.
- conjugates are described in US Pat. Nos. 7,964,578 and 7,833,992; the contents of each of which are herein incorporated by reference in their entireties.
- the nucleic acid vaccine compositions of the present disclosure may be conjugated with conjugates of formula 1-122 as described in US Pat. Nos. 7,964,578 and 7,833,992; the contents of each of which are herein incorporated by reference in their entireties.
- the nucleic acid vaccine compositions described herein may be conjugated with a metal such as, but not limited to, gold. (See e.g., Giljohann et al. Journ. Amer. Chem.
- nucleic acid vaccine compositions described herein may be conjugated and/or encapsulated in gold-nanoparticles (PCT Application Publication No. WO201216269 and U.S. Pub. No. US20120302940; the contents of each of which are herein incorporated by reference in their entirety) .
- a gene delivery composition may include a nucleotide sequence and a poloxamer.
- the nucleic acid vaccine compositions of the present disclosure may be used in a gene delivery composition with the poloxamer described in U.S. Pub. No. US20100004313; the contents of which are each incorporated herein by reference in their entirety.
- the polymer formulations comprising the nucleic acid vaccines of the present disclosure may be stabilized by contacting the polymer formulation, which may include a cationic carrier, with a cationic lipopolymer which may be covalently linked to cholesterol and polyethylene glycol groups.
- the polymer formulation may be contacted with a cationic lipopolymer using the methods described in U.S. Pub. No. US20090042829; the contents of which are herein incorporated by reference in their entirety.
- the cationic carrier may include, but is not limited to, polyethylenimine, poly (trimethylenimine) , poly (tetramethylenimine) , polypropylenimine, aminoglycoside-polyamine, dideoxy-diamino-b-cyclodextrin, spermine, spermidine, poly (2-dimethylamino) ethyl methacrylate, poly (lysine) , poly (histidine) , poly (arginine) , cationized gelatin, dendrimers, chitosan, 1, 2-Dioleoyl-3-Trimethylammonium-Propane (DOTAP) , N- [1- (2, 3-dioleoyloxy) propyl] -N, N, N-trimethylammonium chloride (DOTMA) , 1- [2- (oleoyloxy) ethyl] -2-oleyl-3- (2-hydroxyethyl) imidazolini
- the nucleic acid vaccine compositions of the disclosure may be formulated in a polyplex of one or more polymers (U. S. Pub. Nos. US20120237565 and US20120270927; the contents of each of which are herein incorporated by reference in their entirety) .
- the polyplex comprises two or more cationic polymers.
- the cationic polymer may comprise a poly (ethylene imine) (PEI) such as linear PEI.
- the nucleic acid vaccine compositions of the disclosure can also be formulated as a nanoparticle using a combination of polymers, lipids, and/or other biodegradable agents, such as, but not limited to, calcium phosphate.
- Components may be combined in a core-shell, hybrid, and/or layer-by-layer architecture, to allow for fine-tuning of the nanoparticle so delivery of the nucleic acid vaccine compositions may be enhanced (Wang et al., Nat Mater. 2006, 5: 791-796; Fuller et al., Biomaterials. 2008, 29: 1526-1532; DeKoker et al., Adv Drug Deliv Rev. 2011, 63: 748-761; Endres et al., Biomaterials.
- the nanoparticle may comprise a plurality of polymers such as, but not limited to hydrophilic-hydrophobic polymers (e.g., PEG-PLGA) , hydrophobic polymers (e.g., PEG) and/or hydrophilic polymers (PCT Application Publication No. WO20120225129; the contents of which are herein incorporated by reference in their entirety) .
- hydrophilic-hydrophobic polymers e.g., PEG-PLGA
- hydrophobic polymers e.g., PEG
- hydrophilic polymers PCT Application Publication No. WO20120225129
- Biodegradable calcium phosphate nanoparticles in combination with lipids and/or polymers may be used to deliver nucleic acid vaccine compositions in vivo.
- a lipid coated calcium phosphate nanoparticle which may also contain a targeting ligand such as anisamide, may be used to deliver the nucleic acid vaccine compositions of the present disclosure.
- a targeting ligand such as anisamide
- This delivery system combines both a targeted nanoparticle and a component to enhance the endosomal escape, calcium phosphate, in order to improve delivery of the siRNA.
- calcium phosphate with a PEG-polyanion block copolymer may be used to delivery nucleic acid vaccine compositions of the disclosure (Kazikawa et al., J Contr Rel. 2004, 97: 345-356; Kazikawa et al., J Contr Rel. 2006, 111: 368-370; the contents of each of which are herein incorporated by reference in their entirety) .
- a PEG-charge-conversional polymer (Pitella et al., Biomaterials. 2011, 32: 3106-3114; the contents of which are herein incorporated by reference in their entirety) may be used to form a nanoparticle to deliver the nucleic acid vaccine compositions of the present disclosure.
- the PEG-charge-conversional polymer may improve upon the PEG-polyanion block copolymers by being cleaved into a polycation at acidic pH, thus enhancing endosomal escape.
- a core-shell nanoparticle may be used to form a nanoparticle to deliver the nucleic acid vaccine compositions of the present disclosure.
- the use of core-shell nanoparticles has additionally focused on a high-throughput approach to synthesize cationic cross-linked nanogel cores and various shells (Siegwart et al., Proc Natl Acad Sci USA. 2011, 108: 12996-13001; the contents of which are herein incorporated by reference in their entirety) .
- the complexation, delivery, and internalization of the polymeric nanoparticles can be precisely controlled by altering the chemical composition in both the core and shell components of the nanoparticle.
- the core-shell nanoparticles may efficiently deliver nucleic acid vaccine compositions to mouse hepatocytes after they covalently attach cholesterol to the nanoparticle.
- the nanoparticles described herein may be nanoparticles which include at least one ligand, and the ligand may be a peptide, a nucleic acid aptamer, which is a small molecular weight (8-13 Kda) single-stranded RNA or DNA with low nanomolar binding affinities toward their targets, a peptide aptamer, an antibody, a small molecule ligand such as, but not limited to, folate, anisamide, and galactose. (Leng et al. Journal of Drug Delivery. 2017, 17, Article ID 6971297; the contents of which are herein incorporated by reference in their entirety) .
- a hollow lipid core comprising a middle PLGA layer and an outer neutral lipid layer containing PEG may be used to delivery of the nucleic acid vaccine compositions of the present disclosure.
- the lipid- polymer-lipid hybrid nanoparticle may be used to deliver the nucleic acid vaccine compositions described herein (Shi et al, Angew Chem Int Ed. 2011, 50: 7027-7031; the contents of which are herein incorporated by reference in their entirety) .
- Core-shell nanoparticles for use with the nucleic acid vaccine compositions of the present disclosure may be formed by the methods described in U.S. Pat. No. 8,313,777; the contents of which are herein incorporated by reference in their entirety.
- the core-shell nanoparticles may comprise a core of the nucleic acid vaccine compositions described herein and a polymer shell.
- the polymer shell may be any of the polymers described herein and are known in the art.
- the polymer shell may be used to protect the nucleic acid vaccine compositions in the core. (see, e.g., US Publication No. 20120321719; the contents of which are herein incorporated by reference in their entirety) .
- the polymer used with the formulations described herein may be a modified polymer (such as, but not limited to, a modified polyacetal) as described in PCT Application Publication No. WO2011120053; the contents of which are herein incorporated by reference in their entirety.
- a modified polymer such as, but not limited to, a modified polyacetal
- the nucleic acid vaccine compositions may be delivered to the cell or cytosol of a target cell by contacting the cell with a membrane-destabilizing polymer and a conjugate of the nucleic acid vaccine composition, a targeting ligand and an optional linker.
- a membrane-destabilizing polymer and a conjugate of the nucleic acid vaccine composition, a targeting ligand and an optional linker.
- membrane-destabilizing polymers are taught in International PCT Application Publication No. WO2020093061, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, the membrane-destabilizing polymers of formula XX therein.
- pharmaceutical formulations may additionally comprise a pharmaceutically acceptable excipient, which, as used herein, includes, but are not limited to, any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, flavoring agents, stabilizers, anti-oxidants, osmolality adjusting agents, pH adjusting agents and the like, as suited to the particular dosage form desired.
- a pharmaceutically acceptable excipient includes, but are not limited to, any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, flavoring agents, stabilizers, anti-oxidants, osmolality adjusting agents, pH adjusting agents and the like, as
- a pharmaceutically acceptable excipient may be at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%pure.
- an excipient is approved for use for humans and for veterinary use.
- an excipient may be approved by United States Food and Drug Administration.
- an excipient may be of pharmaceutical grade.
- an excipient may meet the standards of the United States Pharmacopoeia (USP) , the European Pharmacopoeia (EP) , the British Pharmacopoeia, and/or the International Pharmacopoeia.
- compositions include, but are not limited to, inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Such excipients may optionally be included in pharmaceutical compositions.
- the composition may also include excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and/or perfuming agents.
- Exemplary diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and/or combinations thereof.
- Exemplary granulating and/or dispersing agents include, but are not limited to, potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly (vinylpyrrolidone) (crospovidone) , sodium carboxymethyl starch (sodium starch glycolate) , carboxymethyl cellulose, crosslinked sodium carboxymethyl cellulose (croscarmellose) , methylcellulose, pregelatinized starch (starch 1500) , microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate sodium lauryl sulfate, quaternary ammonium compounds, etc., and/or combinations thereof.
- Exemplary surface active agents and/or emulsifiers include, but are not limited to,natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrex, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, wax, and lecithin) , colloidal clays (e.g. bentonite (aluminum silicate) and (magnesium aluminum silicate) ) , long chain amino acid derivatives, high molecular weight alcohols (e.g.
- natural emulsifiers e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrex, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, wax, and lecithin
- colloidal clays e.g. bentonite (aluminum silicate) and
- stearyl alcohol cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol) , carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer) , carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose) , sorbitan fatty acid esters (e.g.
- polyoxyethylene ethers e.g., polyoxyethylene lauryl ether
- poly (vinyl-pyrrolidone) diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, 68, 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof.
- Exemplary binding agents include, but are not limited to, starch (e.g. cornstarch and starch paste) ; gelatin; sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol) ; amino acids (e.g., glycine) ; natural and synthetic gums (e.g.
- acacia sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly (vinyl-pyrrolidone) , magnesium aluminum silicate and larch arabogalactan) ; alginates; polyethylene oxide; polyethylene glycol; inorganic calcium salts; silicic acid; polymethacrylates; waxes; water; alcohol; etc. ; and combinations thereof.
- Exemplary preservatives may include, but are not limited to, antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and/or other preservatives. Oxidation is a potential degradation pathway for mRNA, especially for liquid mRNA formulations. In order to prevent oxidation, antioxidants can be added to the formulation.
- antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, acorbyl palmitate, benzyl alcohol, butylated hydroxyanisole, EDTA, m-cresol, methionine, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, thioglycerol and/or sodium sulfite.
- Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) , citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and/or trisodium edetate.
- EDTA ethylenediaminetetraacetic acid
- antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and/or thimerosal.
- Exemplary antifungal preservatives include, but are not limited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and/or sorbic acid.
- Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and/or phenyl ethyl alcohol.
- Exemplary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and/or phytic acid.
- preservatives include, but are not limited to, tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA) , butylated hydroxytoluene (BHT) , ethylenediamine, sodium lauryl sulfate (SLS) , sodium lauryl ether sulfate (SLES) , sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, methylparaben, NEOLONE TM , KATHON TM , and/or
- the pH of the pharmaceutical solutions are maintained between pH 5 and pH 8 to improve stability.
- exemplary buffers to control pH may include, but are not limited to sodium phosphate, sodium citrate, sodium succinate, histidine (or histidine-HCl) , sodium carbonate, and/or sodium malate.
- the exemplary buffers listed above may be used with additional monovalent counterions (including, but not limited to potassium) . Divalent cations may also be used as buffer counterions; however, these are not preferred due to complex formation and/or mRNA degradation.
- Exemplary buffering agents may also include, but are not limited to, citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, iso
- Exemplary lubricating agents include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc., and combinations thereof.
- oils include, but are not limited to, almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury
- oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and/or combinations thereof.
- Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and/or perfuming agents can be present in the composition, according to the judgment of the formulator.
- Exemplary additives include physiologically biocompatible buffers (e.g., trimethylamine hydrochloride) , chelants (such as, for example, DTPA or DTPA-bisamide) or calcium chelate complexes (as for example calcium DTPA, CaNaDTPA-bisamide) , or, optionally, calcium or sodium salts (for example, calcium chloride, calcium ascorbate, calcium gluconate or calcium lactate) .
- physiologically biocompatible buffers e.g., trimethylamine hydrochloride
- chelants such as, for example, DTPA or DTPA-bisamide
- calcium chelate complexes as for example calcium DTPA, CaNaDTPA-bisamide
- calcium or sodium salts for example, calcium chloride, calcium ascorbate, calcium gluconate or calcium lactate
- antioxidants and suspending agents can be used.
- the nucleic acid vaccine compositions described herein may comprise at least one nucleic acid vaccine that is formulated in a lipid nanoparticle (LNP) and at least one excipient.
- the excipient may be a sugar such as sucrose.
- Adjuvants may also be administered with or in combination with one or more of the nucleic acid vaccines described herein, e.g., the mRNA vaccine.
- Adjuvants may be used to enhance the immunogenicity of the nucleic acid vaccine, modify the immune response, reduce the amount of nucleic acid vaccine needed for immunization, reduced the frequency of additional or “booster” immunizations needed or to create an improved immune response in those with weakened or immunocompromised immune systems or the elderly.
- the adjuvants may be a component of the formulation containing the nucleic acid vaccine or they may be co-administered with the nucleic acid vaccines compositions. Co-administration of the adjuvant may be any method known in the art or described herein such as, but not limited to, intravenous (IV) , intramuscular (IM) , subcutaneous (SC) or intradermal (ID) .
- the adjuvant is natural or synthetic.
- the adjuvants may also be organic or inorganic.
- the adjuvant used with the nucleic acid vaccine is from a class of adjuvants such as, but not limited to carbohydrates, microorganisms, mineral salts (e.g., aluminum hydroxide, aluminum phosphate gel, or calcium phosphate gel) , emulsions (e.g., oil emulsion, surfactant based emulsion, purified saponin, and oil-in water emulsion) , inert vehicles, particulate adjuvants (e.g., unilamellar liposomal vehicles such as virosomes or a structured complex of saponions and lipids such as polylactide co-glycolide (PLG) ) , microbial derivatives, endogenous human immunomodulators, and tensoactive compounds.
- a class of adjuvants such as, but not limited to carbohydrates, microorganisms, mineral salts (e.g., aluminum hydroxide, aluminum phosphate gel, or calcium phosphate gel)
- Adjuvants may be selected for use with the nucleic acid vaccines by one of ordinary skill in the art.
- Adjuvants may be interferons, TNF-alpha, TNF-beta, chemokines (e.g., CCL21, eotaxin, HMGB1, SA100-8alpha, GCSF, GMCSF, granulysin, lactoferrin, ovalbumin, CD40L, CD28 agonists, PD1, soluble PD1, PDL1, PDL2) or interleukins (e.g., IL1, IL2, IL4, IL6, IL7, IL10, IL12, IL13, IL15, IL17, IL18, IL21, and IL23) .
- Non-limiting examples of adjuvants include Abisco-100 vaccine adjuvant, Adamantyl amide Dipeptide Vaccine Adjuvant, Adjumer TM , AF03, Albumin-heparin microparticles vaccine adjuvant, Algal Glucan, Algammulin, alhydrogel, aluminum hydroxide vaccine adjuvant, aluminum phosphate vaccine adjuvant, aluminum potassium sulfate adjuvant, Aluminum vaccine adjuvant, amorphous aluminum hydroxyphosphate sulfate adjuvant, Arlacel A, AS0, AS04, AS03, AS-2 vaccine adjuvant, B7-2 vaccine adjuvant, Bay R1005, Bordetella pertussis component Vaccine Adjuvant, Bupivacaine vaccine adjuvant, Calcium Phosphate Gel, Calcium phosphate vaccine adjuvant, Cationic Liposomal Vaccine Adjuvant, cationic liposome-DNA complex JVRS-100, Cholera toxin, Cholera toxin B subunit, Cor
- the nucleic acid vaccines described herein may be used as a vaccine and may further comprise an adjuvant which may enable the vaccine to elicit a higher immune response.
- the adjuvant could be a sub-micron oil-in-water emulsion which can elicit a higher immune response in human pediatric populations (see e.g., the adjuvanted vaccines described in US Patent Publication No. US20120027813 and U.S. Pat. No. 8,506,966, the contents of each of which are herein incorporated by reference in their entirety) .
- nucleic acid vaccine compositions including, for example, nucleic acid vaccine for rabies for any therapeutic, prophylactic (including post-exposure and pre-exposure) , pharmaceutical, diagnostic or imaging use by any appropriate route taking into consideration likely advances in the sciences of drug delivery. Delivery may be naked or formulated.
- the nucleic acid vaccine compositions of the present disclosure may be delivered to a cell naked.
- naked refers to delivering nucleic acid vaccine compositions free from agents which promote transfection.
- the nucleic acid vaccine compositions delivered to the cell may contain no modifications.
- the naked nucleic acid vaccine compositions may be delivered to the cell using routes of administration known in the art and described herein.
- the nucleic acid vaccine compositions of the present disclosure may be formulated, using the formulation components and methods described herein.
- the formulations may contain nucleic acid vaccine compositions which may be modified and/or unmodified.
- the formulations may further include, but are not limited to, cell penetration agents, a pharmaceutically acceptable carrier, a delivery agent, a bioerodible or biocompatible polymer, a solvent, and a sustained-release delivery depot.
- the formulated nucleic acid vaccine compositions may be delivered to the cell using routes of administration known in the art and described herein.
- the nucleic acid vaccine compositions may also be formulated for direct delivery to an organ or tissue in any of several ways in the art including, but not limited to,direct soaking or bathing, via a catheter, by gels, powder, ointments, creams, gels, lotions, and/or drops, by using substrates such as fabric or biodegradable materials coated or impregnated with the compositions, and the like.
- the nucleic acid vaccine compositions of the present disclosure may also be cloned into a retroviral replicating vector (RRV) and transduced to cells.
- RRV retroviral replicating vector
- compositions are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions may be decided by the attending physician within the scope of sound medical judgment.
- the specific therapeutically effective, prophylactically effective, or appropriate imaging dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
- nucleic acid vaccine e.g., nucleic acid vaccine for rabies, e.g., mRNA vaccine for rabies
- body weight about 0.001 and about 200 mg/kg, about 0.001 and about 100 mg/kg, 0.01 and about 100 mg/kg, preferably between about 0.005 and about 50 mg/kg, 0.01 and about 50 mg/kg, 0.01 and about 40 mg/kg, 0.01 and about 30 mg/kg, 0.01 and about 10 mg/kg, 0.05 and about 50 mg/kg, 0.05 and about 30 mg/kg, 0.05 and about 10 mg/kg, 0.05 and about 5 mg/kg, 0.1 and about 50 mg/kg, 0.1 and about 30 mg/kg, 0.1 and about 10 mg/kg, 0.1 and about 1 mg/kg, 1.0 and about 50 mg/kg, 1.0 and about 40 mg/kg, 1.0 to about 30 mg/kg, 10 to about 50mg/kg body weight.
- nucleic acid vaccine e.g., nucleic acid vaccine for rabies,
- the dosages may be administered about hourly, multiple times per day, daily, every other day, weekly, every other week, monthly, every other month, or on an as-needed basis.
- compositions of the nucleic acid vaccines may be administered at dosage levels sufficient to deliver from about 0.0001 mg/kg to about 100 mg/kg, from about 0.001 mg/kg to about 0.05 mg/kg, from about 0.005 mg/kg to about 0.05 mg/kg, from about 0.001 mg/kg to about 0.005 mg/kg, from about 0.05 mg/kg to about 0.5 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 40 mg/kg, from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, from about 1 mg/kg to about 25 mg/kg, from about 1 mg/kg to about 50 mg/kg, from about 10 mg/kg to about 100 mg/kg, from about 10 mg/kg to about 50 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic, diagnostic, prophylactic, or imaging effect
- the desired dosage may be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
- the desired dosage may be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations) .
- multiple administrations e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations.
- split dosing regimens such as those described herein may be used.
- compositions of the nucleic acid vaccines described herein may be administered at dosage levels sufficient to deliver to a subject, about 1 ⁇ g, 10 ⁇ g, 15 ⁇ g, 20 ⁇ g, 25 ⁇ g, 30 ⁇ g, 35 ⁇ g, 40 ⁇ g, 50 ⁇ g, 60 ⁇ g, 70 ⁇ g, 80 ⁇ g, 90 ⁇ g, or 100 ⁇ g of the nucleic acid composition.
- the nucleic acid vaccines may be administered in split-dose regimens.
- a “split dose” is the division of single unit dose or total daily dose into two or more doses, e.g., two or more administrations of the single unit dose.
- a “single unit dose” is a dose of any therapeutic administered in one dose/at one time/single route/single point of contact, i.e., single administration event.
- a “total daily dose” is an amount given or prescribed in 24-hour period. It may be administered as a single unit dose.
- the nucleic acid vaccines described herein are administered to a subject in split doses.
- the nucleic acid vaccines may be formulated in buffer only or in a formulation described herein.
- the nucleic acid vaccine compositions described herein may be administered to a subject in two separate phases, a loading dosing phase and a maintenance dosing phase.
- the dosing regimen may comprise an initial higher loading dose of the nucleic acid vaccine that is given to the subject first time at the beginning of a course of prevention, alleviation and/or treatment, e.g., first dose for preventing rabies, and a lower maintenance dose following the first loading dose.
- the loading dose and the maintenance dose have the same amount of the nucleic acid vaccines of the present disclosure.
- more than one maintenance doses are administered to the subject.
- the multiple maintenance doses may be administered biweekly, every three weeks, every four weeks, monthly, bimonthly, every three months, every four months, every five months, or every six months.
- the maintenance doses of the nucleic acid vaccines may also be referred to as booster doses.
- a “booster dose” (or “booster shot” ) is an extra or supplemental dose of a vaccine after an initial primer dose.
- the booster dose may have the same amount of the nucleic acid vaccine as the initial loading dose.
- the booster dose has an amount of the nucleic acid vaccine that is smaller than the original amount of the nucleic acid vaccine in the initial dose.
- the subject may receive one, two, three, four or more booster doses.
- the nucleic acid vaccine is administered post-exposure as 3 to 5 injections.
- the nucleic acid vaccine is administered post-exposure as 3 to 5 injections over the course of 1 to 5 weeks.
- the nucleic acid vaccine is administered post-exposure as 3 to 5 injections over the course of 1 to 3 weeks.
- the nucleic acid vaccine is administered post-exposure as 3 to 5 injections over the course of the first 5 weeks post-exposure.
- the nucleic acid vaccine is administered post-exposure as 3 to 5 injections over the course of first 3 weeks post-exposure.
- the nucleic acid vaccine is administered post-exposure as 3 to 5 injections over the course of first 2 weeks post-exposure.
- the nucleic acid vaccine is administered post-exposure as 3 injections.
- the nucleic acid vaccine is administered post-exposure as 3 injections over the course of 1 to 3 weeks. In some embodiments, the nucleic acid vaccine is administered post-exposure as 3 injections over the course of the first 3 weeks post-exposure.
- the nucleic acid vaccine is administered post-exposure as 3 injections over the course of 1 to 5 weeks. In some embodiments, the nucleic acid vaccine is administered post-exposure as 3 injections over the course of the first 5 weeks post-exposure.
- the nucleic acid vaccine is administered post-exposure as 3 injections over the course of 14 days.
- the nucleic acid vaccine is administered on day 1, day 3 and day 14.
- the nucleic acid vaccine is administered on day 1, day 5 and day 14.
- the nucleic acid vaccine is administered on day 1, day 7 and day 14.
- the nucleic acid vaccine is administered post-exposure as 2 injections.
- the nucleic acid vaccine is administered post-exposure as 2 injections over the course of 1 to 3 weeks. In some embodiments, the nucleic acid vaccine is administered post-exposure as 2 injections over the course of the first 3 weeks post-exposure.
- the nucleic acid vaccine is administered post-exposure as 2 injections over the course of 1 to 5 weeks. In some embodiments, the nucleic acid vaccine is administered post-exposure as 2 injections over the course of the first 5 weeks post-exposure.
- the nucleic acid vaccine is administered post-exposure as 2 injections over the course of 14 days.
- the nucleic acid vaccine is administered on day 1 and day 3.
- the nucleic acid vaccine is administered on day 1 and day 5.
- the nucleic acid vaccine is administered on day 1 and day 7.
- the nucleic acid vaccine is administered on day 1 and day 14.
- Such administration can be used as a chronic or acute treatment or prevention of a clinic-concerning condition.
- the amount of drug that may be combined with the carrier to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
- a typical preparation will contain from about 5%to about 95%active compound (w/w) .
- such preparations contain from about 20%to about 80%, 30%to about 70%, 40%to about 60%, or about 50%active compound.
- the preparations used in the present disclosure will include about 5-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, 90-99%, or greater than 99%of the active ingredient.
- a maintenance dose of a compound, composition or combination of the present disclosure may be administered, ifnecessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
- the delivery of the nucleic acid vaccines may be naked or formulated.
- the nucleic acid vaccines described herein may be delivered to a cell naked.
- naked refers to delivering nucleic acid vaccines free from agents which promote transfection.
- the nucleic acid vaccines delivered to the cell may contain no modifications.
- the naked nucleic acid vaccines may be delivered to the cell using routes of administration known in the art and described herein.
- the nucleic acid vaccines described herein may be formulated, using the methods described herein.
- the formulations may further include, but are not limited to, cell penetration agents, a pharmaceutically acceptable carrier, a delivery agent, a bioerodible or biocompatible polymer, a solvent, and a sustained-release delivery depot.
- the formulated nucleic acid vaccines may be delivered to the cell using routes of administration known in the art and described herein.
- compositions may also be formulated for direct delivery to an organ or tissue in any of several ways in the art including, but not limited to, direct soaking or bathing, via a catheter, by gels, powder, ointments, creams, gels, lotions, and/or drops, by using substrates such as fabric or biodegradable materials coated or impregnated with the compositions, and the like.
- the nucleic acid vaccine compositions of the present disclosure may be administered by any route which results in a prophylactic or therapeutically effective outcome. These include, but are not limited to enteral (into the intestine) , gastroenteral, epidural (into the dura matter) , oral (by way of the mouth) , transdermal, peridural, intracerebral (into the cerebrum) , intracerebroventricular (into the cerebral ventricles) , epicutaneous (application onto the skin) , intradermal, (into the skin itself) , subcutaneous (under the skin) , nasal administration (through the nose) , intravenous (into a vein) , intravenous bolus, intravenous drip, intraarterial (into an artery) , intramuscular (into a muscle) , intracardiac (into the heart) , intraosseous infusion (into the bone marrow) , intrathecal (into the spinal canal) , intra
- enteral
- nucleic acid vaccines described herein may be accomplished by a single administration of a controlled release system containing sufficient active ingredient for the desired release period.
- a controlled release system containing sufficient active ingredient for the desired release period.
- Various controlled release systems such as monolithic or reservoir-type microcapsules, depot implants, polymeric hydrogels, osmotic pumps, vesicles, micelles, liposomes, transdermal patches, iontophoretic devices and alternative injectable dosage forms may be utilized for this purpose. Localization at the site to which delivery of the active ingredient is desired is an additional feature of some controlled release devices, which may prove beneficial in the treatment of certain disorders.
- the nucleic acid vaccines described herein may be administered intranasally similar to the administration of live vaccines.
- the polynucleotide may be administered intramuscularly or intradermally similarly to the administration of inactivated vaccines known in the art.
- delivery across the barrier of the skin would be enhanced using electrodes (e.g., iontophoresis) , electroporation, or the application of short, high-voltage electrical pulses to the skin, radiof requencies, ultrasound (e.g., sonophoresis) , microprojections (e.g., microneedles) , jet injectors, thermal ablation, magnetophoresis, lasers, velocity, or photomechanical waves.
- the drug can be included in single-layer drug-in-adhesive, multi-layer drug-in- adhesive, reservoir, matrix, or vapor style patches, or could utilize patchless technology.
- Delivery across the barrier of the skin could also be enhanced using encapsulation, a skin lipid fluidizer, or a hollow or solid microstructured transdermal system (MTS, such as that manufactured by 3M) , jet injectors.
- Additives to the formulation to aid in the passage of therapeutic compounds through the skin include prodrugs, chemicals, surfactants, cell penetrating peptides, permeation enhancers, encapsulation technologies, enzymes, enzyme inhibitors, gels, nanoparticles and peptide or protein chaperones.
- nucleic acid vaccines described herein with a polymeric formulation comprising biodegradable polymers that can form a depot formulation upon administration, is suitable to achieve very long duration of action formulations.
- the absorption across the nasal mucous membrane may be further enhanced by surfactants, such as, for example, glycocholic acid, cholic acid, taurocholic acid, ethocholic acid, deoxycholic acid, chenodeoxycholic acid, dehdryocholic acid, glycodeoxycholic acid, cycledextrins and the like in an amount in the range of between about 0.1 and 15 weight percent, between about 0.5 and 4 weight percent, or about 2 weight percent.
- surfactants such as, for example, glycocholic acid, cholic acid, taurocholic acid, ethocholic acid, deoxycholic acid, chenodeoxycholic acid, dehdryocholic acid, glycodeoxycholic acid, cycledextrins and the like in an amount in the range of between about 0.1 and 15 weight percent, between about 0.5 and 4 weight percent, or about 2 weight percent.
- absorption enhancers reported to exhibit greater efficacy with decreased irritation is the class of alkyl maltosides, such as tetradecylmaltoside (Arnold, JJ et al., JPharm Sci, 2004, 93: 2205-13; Ahsan, F et al., Pharm Res, 2001, 18: 1742-46, and references therein, all of which are hereby incorporated by reference in their entirety) .
- alkyl maltosides such as tetradecylmaltoside (Arnold, JJ et al., JPharm Sci, 2004, 93: 2205-13; Ahsan, F et al., Pharm Res, 2001, 18: 1742-46, and references therein, all of which are hereby incorporated by reference in their entirety) .
- the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
- This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol.
- suitable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono-or diglycerides.
- Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
- These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant such as Ph. Helv or a similar alcohol.
- compositions of the present disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions.
- carriers that are commonly used include lactose and corn starch.
- Lubricating agents such as magnesium stearate, are also typically added.
- useful diluents include lactose and dried corn starch.
- aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
- compositions of present disclosure may also be administered in the form of suppositories for rectal administration.
- These compositions can be prepared by mixing the active ingredient of the present disclosure with a suitable non-irritating excipient that is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
- suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
- Topical administration of the pharmaceutical compositions of the present disclosure is especially useful when the desired treatment involves areas or organs readily accessible by topical application.
- the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
- Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
- the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier.
- Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
- the pharmaceutical compositions of the present disclosure may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topical transdermal patches are also included in the present disclosure.
- compositions of the present disclosure may be administered by nasal aerosol or inhalation.
- Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
- a number of formulations offer advantages.
- Adsorption of the therapeutic agents to readily dispersed solids such as diketopiperazines (for example, Technosphere particles (Pfutzner, A and Forst, T, 2005, Expert Opin Drug Deliv 2: 1097-1106) or similar structures gives a formulation that results in rapid initial uptake of the therapeutic compound.
- Lyophilized powders, especially glassy particles, containing the therapeutic compound and an excipient are useful for delivery to the lung with good bioavailability, for example, see (inhaled insulin, Pfizer, Inc. and Aventis Pharmaceuticals Inc. ) and (inhaled insulin, Mannkind, Corp. ) .
- Apharmaceutical composition described herein can be formulated into a dosage form described herein, such as a topical, intranasal, intratracheal, or injectable (e.g., intravenous, intraocular, intravitreal, intramuscular, intracardiac, intraperitoneal, subcutaneous) .
- injectable e.g., intravenous, intraocular, intravitreal, intramuscular, intracardiac, intraperitoneal, subcutaneous
- Liquid dosage forms for parenteral administration include, but are not limited to,pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and/or elixirs.
- liquid dosage forms may comprise inert diluents commonly used in the art including, but not limited to, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils) , glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
- compositions may be mixed with so
- Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art and may include suitable dispersing agents, wetting agents, and/or suspending agents.
- Sterile injectable preparations may be sterile injectable solutions, suspensions, and/or emulsions in nontoxic parenterally acceptable diluents and/or solvents, for example, a solution in 1, 3-butanediol.
- the acceptable vehicles and solvents that may be employed include, but are not limited to, water, Ringer’s solution, U. S. P., and isotonic sodium chloride solution.
- Sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil can be employed including synthetic mono-or diglycerides.
- Fatty acids such as oleic acid can be used in the preparation of injectables.
- Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, and/or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
- the rate of polynucleotides release can be controlled.
- biodegradable polymers include, but are not limited to, poly (orthoesters) and poly (anhydrides) .
- Depot injectable formulations may be prepared by entrapping the nucleic acid vaccine in liposomes or microemulsions which are compatible with body tissues.
- Formulations described herein as being useful for pulmonary delivery may also be used for intranasal delivery of a pharmaceutical composition.
- Another formulation suitable for intranasal administration may be a coarse powder comprising the active ingredient and having an average particle from about 0.2 ⁇ m to 500 ⁇ m.
- Such a formulation may be administered in the manner in which snuff is taken, e.g., by rapid inhalation through the nasal passage from a container of the powder held close to the nose.
- Formulations suitable for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of active ingredient, and may comprise one or more of the additional ingredients described herein.
- a pharmaceutical composition may be prepared, packaged, and/or sold in a formulation suitable for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may, for example, contain about 0.1%to 20% (w/w) active ingredient, where the balance may comprise an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein.
- formulations suitable for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising active ingredient.
- Such powdered, aerosolized, and/or aerosolized formulations when dispersed, may have an average particle and/or droplet size in the range from about 0.1 nm to about 200 nm, and may further comprise one or more of any additional ingredients described herein.
- Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient (s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type may be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
- nucleic acid vaccine pharmaceutical compositions described herein may be characterized using one or more of bioavailability, therapeutic window, volume of distribution, biological effect and detection of polynucleotides by mass spectrometry.
- the nucleic acid vaccines when formulated into a composition with a delivery agent as described herein, can exhibit an increase in bioavailability as compared to a composition lacking a delivery agent as described herein.
- bioavailability refers to the systemic availability of a given amount of nucleic acid vaccines administered to a mammal. Bioavailability can be assessed by measuring the area under the curve (AUC) or the maximum serum or plasma concentration of the unchanged form of a compound following administration of the compound to a mammal. AUC is a determination of the area under the curve plotting the serum or plasma concentration of a compound along the ordinate (Y-axis) against time along the abscissa (X-axis) .
- the AUC for a particular compound can be calculated using methods known to those of ordinary skill in the art and as described in G. S. Banker, Modem Pharmaceutics, Drugs and the Pharmaceutical Sciences, v. 72, Marcel Dekker, N. Y, Inc., 1996, herein incorporated by reference in its entirety.
- the Cmax value is the maximum concentration of the compound achieved in the serum or plasma of a mammal following administration of the compound to the mammal.
- the Cmax value of a particular compound can be measured using methods known to those of ordinary skill in the art.
- the phrases “increasing bioavailability” or “improving the pharmacokinetics, ” as used herein mean that the systemic availability of a first nucleic acid vaccine, measured as AUC, Cmax, or Cmin, in a mammal is greater, when co-administered with a delivery agent as described herein, than when such co-administration does not take place.
- the bioavailability of the nucleic acid vaccines can increase by at least about 2%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100%.
- liquid formulations of nucleic acid vaccines may have various in vivo half-life, requiring modulation of doses to yield a prophylactic or therapeutic effect.
- nucleic acid vaccine formulations may be designed to improve bioavailability and/or prophylactic or therapeutic effect during repeat administrations. Such formulations may enable sustained release of nucleic acid vaccines and/or reduce nucleic acid vaccine degradation rates by nucleases.
- suspension formulations are provided comprising nucleic acid vaccines, water immiscible oil depots, surfactants and/or co-surfactants and/or co-solvents. Combinations of oils and surfactants may enable suspension formulation with nucleic acid vaccines.
- nucleic acid vaccines in a water immiscible depot may be used to improve bioavailability through sustained release of polynucleotides from the depot to the surrounding physiologic environment and/or prevent polynucleotide degradation by nucleases.
- cationic nanoparticles comprising combinations of divalent and monovalent cations may be formulated with nucleic acid vaccines. Such nanoparticles may form spontaneously in solution over a given period (e.g. hours, days, etc. ) . Such nanoparticles do not form in the presence of divalent cations alone or in the presence of monovalent cations alone.
- the delivery of nucleic acid vaccines in cationic nanoparticles or in one or more depot comprising cationic nanoparticles may improve nucleic acid vaccine bioavailability by acting as a long-acting depot and/or reducing the rate of degradation by nucleases.
- nucleic acid vaccines when formulated into a composition with a delivery agent as described herein, can exhibit an increase in the therapeutic window of the administered nucleic acid vaccine composition as compared to the therapeutic window of the administered nucleic acid vaccine composition lacking a delivery agent as described herein.
- therapeutic window refers to the range of plasma concentrations, or the range of levels of therapeutically active substance at the site of action, with a high probability of eliciting a prophylactic or therapeutic effect.
- the therapeutic window of the nucleic acid vaccines when co-administered with a delivery agent as described herein can increase by at least about 2%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100%.
- the nucleic acid vaccines when formulated into a composition with a delivery agent as described herein, can exhibit an improved volume of distribution (Vdist) , e.g., reduced or targeted, relative to a composition lacking a delivery agent as described herein.
- the volume of distribution (Vdist) relates the amount of the drug (e.g., nucleic acid vaccine of the present disclosure) in the body to the concentration of the drug in the blood or plasma.
- the term “volume of distribution” refers to the fluid volume that would be required to contain the total amount of the drug in the body at the same concentration as in the blood or plasma: Vdist equals the amount of drug in the body/concentration of drug in blood or plasma.
- the volume of distribution would be 1 liter.
- the volume of distribution reflects the extent to which the drug is present in the extravascular tissue.
- a large volume of distribution reflects the tendency of a compound to bind to the tissue components compared with plasma protein binding.
- Vdist can be used to determine a loading dose to achieve a steady state concentration.
- the volume of distribution of the nucleic acid vaccines when co-administered with a delivery agent as described herein can decrease at least about 2%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%.
- the biological effect of the nucleic acid vaccine delivered to the animals may be categorized by analyzing the protein expression in the animals.
- the protein expression may be determined from analyzing a biological sample collected from a mammal administered the nucleic acid vaccine described herein.
- Mass spectrometry is an analytical technique that can provide structural and molecular mass/concentration information on molecules after their conversion to ions.
- the molecules are first ionized to acquire positive or negative charges and then they travel through the mass analyzer to arrive at different areas of the detector according to their mass/charge (m/z) ratio.
- Mass spectrometry is performed using a mass spectrometer which includes an ion source for ionizing the fractionated sample and creating charged molecules for further analysis.
- ionization of the sample may be performed by electrospray ionization (ESI) , atmospheric pressure chemical ionization (APCI) , photoionization, electron ionization, fast atom bombardment (FAB) /liquid secondary ionization (LSIMS) , matrix assisted laser desorption/ionization (MALDI) , field ionization, field desorption, thermospray/plasmaspray ionization, and particle beam ionization.
- ESI electrospray ionization
- APCI atmospheric pressure chemical ionization
- FAB fast atom bombardment
- LIMS liquid secondary ionization
- MALDI matrix assisted laser desorption/ionization
- field ionization field desorption
- thermospray/plasmaspray ionization and particle beam ion
- the positively charged or negatively charged ions thereby created may be analyzed to determine a mass-to-charge ratio (i.e., m/z) .
- Suitable analyzers for determining mass-to-charge ratios include quadropole analyzers, ion traps analyzers, and time-of-flight analyzers.
- the ions may be detected using several detection modes. For example, selected ions may be detected (i.e., using a selective ion monitoring mode (SIM) ) , or alternatively, ions may be detected using a scanning mode, e.g., multiple reaction monitoring (MRM) or selected reaction monitoring (SRM) .
- SIM selective ion monitoring mode
- MRM multiple reaction monitoring
- SRM selected reaction monitoring
- LC-MS/MRM Liquid chromatography-multiple reaction monitoring
- targeted MS methods are peptide sequence-based modes ofMS that focus the full analytical capacity of the instrument on tens to hundreds of selected peptides in a complex mixture. By restricting detection and fragmentation to only those peptides derived from proteins of interest, sensitivity and reproducibility are improved dramatically compared to discovery-mode MS methods.
- This method of mass spectrometry based multiple reaction monitoring (MRM) quantitation of proteins can dramatically impact the discovery and quantitation of biomarkers via rapid, targeted, multiplexed protein expression profiling of clinical samples.
- MRM multiple reaction monitoring
- the biological sample once obtained from the subject, may be subjected to enzyme digestion.
- digest means to break apart into shorter peptides.
- treating a sample to digest proteins means manipulating a sample in such a way as to break down proteins in a sample.
- enzymes include, but are not limited to, trypsin, endoproteinase Glu-C and chymotrypsin.
- a biological sample may be analyzed for protein using electrospray ionization.
- Electrospray ionization (ESI) mass spectrometry (ESIMS) uses electrical energy to aid in the transfer of ions from the solution to the gaseous phase before they are analyzed by mass spectrometry.
- Samples may be analyzed using methods known in the art (e.g., Ho et al., Clin Biochem Rev. 2003, 24 (1) : 3-12; herein incorporated by reference in its entirety) .
- the ionic species contained in solution may be transferred into the gas phase by dispersing a fine spray of charge droplets, evaporating the solvent and ejecting the ions from the charged droplets to generate a mist of highly charged droplets.
- the mist of highly charged droplets may be analyzed using at least 1, at least 2, at least 3 or at least 4 mass analyzers such as, but not limited to, a quadropole mass analyzer.
- the mass spectrometry method may include a purification step.
- the first quadrapole may be set to select a single m/z ratio so it may filter out other molecular ions having a different m/z ratio which may eliminate complicated and time-consuming sample purification procedures prior to MS analysis.
- a biological sample may be analyzed for protein in a tandem ESIMS system (e.g., MS/MS) .
- the droplets may be analyzed using a product scan (or daughter scan) , a precursor scan (parent scan) , a neutral loss or a multiple reaction monitoring.
- a biological sample may be analyzed using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MALDIMS) .
- MALDI matrix-assisted laser desorption/ionization
- MALDIMS mass spectrometry
- MALDI provides for the nondestructive vaporization and ionization of both large and small molecules, such as proteins.
- the analyte is first co-crystallized with a large molar excess of a matrix compound, which may also include, but is not limited to, an ultraviolet absorbing weak organic acid.
- matrices used in MALDI are ⁇ -cyano-4-hydroxycinnamic acid, 3, 5-dimethoxy-4-hydroxycinnamic acid and 2, 5-dihydroxybenzoic acid.
- Laser radiation of the analyte-matrix mixture may result in the vaporization of the matrix and the analyte.
- the laser induced desorption provides high ion yields of the intact analyte and allows for measurement of compounds with high accuracy.
- Samples may be analyzed using methods known in the art (e.g., Lewis, Wei and Siuzdak, Encyclopedia ofAnalytical Chemistry 2000: 5880-5894; the contents of which are herein incorporated by reference in their entirety) .
- mass analyzers used in the MALDI analysis may include a linear time-of-flight (TOF) , a TOF reflectron or a Fourier transform mass analyzer.
- nucleic acid vaccines described herein may be operably linked to one or more regulatory nucleotide sequences and encoded in an expression construct.
- Regulatory nucleotide sequences will generally be appropriate for a host cell used for expression.
- the one or more regulatory nucleotide sequences may include, but are not limited to, promoter sequences, leader or signal sequences, transcriptional start and termination sequences, and enhancer or activator sequences. Constitutive or inducible promoters as known in the art are also contemplated.
- the promoters may be either naturally occurring promoters, or hybrid promoters that combine elements of more than one promoter.
- an expression construct may be present in a cell on an episome, such as a plasmid, or the expression construct may be inserted in a chromosome.
- the expression vector includes a selectable marker gene to allow the selection of transformed host cells.
- Certain embodiments include an expression vector encoding a nucleic acid vaccine for rabies sequence operably linked to at least one regulatory sequence. Regulatory sequences for use herein include promoters, enhancers, and other expression control elements.
- an expression vector is designed considering the choice of the host cell to be transformed, the particular nucleic acid vaccine sequence to be expressed, the vector's copy number, the ability to control that copy number, or the expression of other proteins encoded by the vector, such as antibiotic markers.
- the nucleic acids described herein may be expressed in microorganisms.
- the nucleic acid may be expressed in a bacterial system, for example, in Bacillus brevis, Bacillus megaterium, Bacillus subtilis, Caulobacter crescentus, Escherichia coli and their derivatives.
- Exemplary promoters include the l-arabinose inducible araBAD promoter (PBAD) , the lac promoter, the l-rhamnose inducible rhaP BAD promoter, the T7 RNA polymerase promoter, the trc and tac promoter, the lambda phage promoter Pl, and the anhydrotetracycline-inducible tetA promoter/operator.
- PBAD l-arabinose inducible araBAD promoter
- lac promoter the lac promoter
- the l-rhamnose inducible rhaP BAD promoter the T7 RNA polymerase promoter
- the trc and tac promoter the lambda phage promoter Pl
- the anhydrotetracycline-inducible tetA promoter/operator include the l-arabinose inducible araBAD promoter (PBAD) , the lac promoter, the l-rhamnose inducible
- the nucleic acids described herein may be expressed in a yeast expression system.
- promoters which may be used in yeast vectors include the promoters for 3-phosphoglycerate kinase (Hitzeman et al., J. Biol. Chem. 255: 2073 (1980) ) ; other glycolytic enzymes (Hess et al., J. Adv. Enzyme Res. 7: 149 (1968) ; Holland et al., Biochemistry 17: 4900 (1978) ) .
- Others promoters are from, e.g., enolase, glyceraldehyde-3-phosphate dehydrogenase, hexokinase, pyruvate decarboxylase, phosphof ructokinase, glucose-6-phosphate isomerase, 3-phosphoglycerate mutase, pyruvate kinase, triosephosphate isomerase, phosphoglucose isomerase, glucokinase alcohol oxidase I (AOX1) , alcohol dehydrogenase 2, isocytochrome C, acid phosphatase, degradative enzymes associated with nitrogen metabolism, and the aforementioned glyceraldehyde-3-phosphate dehydrogenase, and enzymes responsible for maltose and galactose utilization.
- enolase e.g., enolase, glyceraldehyde-3-phosphate dehydrogenase, hex
- Any plasmid vector containing a yeast-compatible promoter and termination sequences, with or without an origin of replication, is suitable.
- Certain yeast expression systems are commercially available, for example, from Clontech Laboratories, Inc. (Palo Alto, Calif., e.g., Pyex 4T family of vectors for S. cerevisiae) , Invitrogen (Carlsbad, Calif., e.g., Ppicz series Easy Select Pichia Expression Kit) and Stratagene (La Jolla, Calif., e.g. ESP. TM. Yeast Protein Expression and Purification System for S. pombe and Pesc vectors for S. cerevisiae) .
- the nucleic acids described herein may be expressed in mammalian expression systems.
- mammalian promoters include, for example, promoters from the following genes: ubiquitin/S27a promoter of the hamster (WO 97/15664) , Simian vacuolating virus 40 (SV40) early promoter, adenovirus major late promoter, mouse metallothionein-I promoter, the long terminal repeat region of Rous Sarcoma Virus (RSV) , mouse mammary tumor virus promoter (MMTV) , Moloney murine leukemia virus Long Terminal repeat region, and the early promoter of human Cytomegalovirus (CMV) .
- RSV Rous Sarcoma Virus
- MMTV mouse mammary tumor virus promoter
- CMV Cytomegalovirus
- heterologous mammalian promoters are the actin, immunoglobulin or heat shock promoter (s) .
- a yeast alcohol oxidase promoter is used.
- promoters for use in mammalian host cells can be obtained from the genomes of viruses such as polyoma virus, fowlpox virus (UK 2, 211, 504 published 5 Jul. 1989) , bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis-B virus and Simian Virus 40 (SV40) .
- viruses such as polyoma virus, fowlpox virus (UK 2, 211, 504 published 5 Jul. 1989) , bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis-B virus and Simian Virus 40 (SV40) .
- heterologous mammalian promoters are used. Examples include the actin promoter, an immunoglobulin promoter, and heat-shock promoters.
- the early and late promoters of SV40 are conveniently obtained as an SV40 restriction
- the nucleic acids described herein may be expressed in insect cell expression systems.
- Eukaryotic expression systems employing insect cell hosts may rely on either plasmid or baculoviral expression systems.
- Typical insect host cells are derived from the fall army worm (Spodopterafrugiperda) .
- Spodopterafrugiperda fall army worm
- these cells are infected with a recombinant form of the baculovirus Autographa californica nuclear polyhedrosis virus which has the gene of interest expressed under the control of the viral polyhedron promoter.
- Other insects infected by this virus include a cell line known commercially as "High 5" (Invitrogen) which is derived from the cabbage looper (Trichoplusia ni) .
- Baculovirus sometimes used is the Bombyx mori nuclear polyhedorsis virus which infect the silkworm (Bombyx mori) .
- Numerous baculovirus expression systems are commercially available, for example, from Thermo Fisher (Bac-N-Blue TM k or BAC-TO-BAC TM Systems) , Clontech (BacPAK TM Baculovirus Expression System) , Novagen (Bac Vector System TM ) , or others from Pharmingen or Quantum Biotechnologies.
- Another insect cell host is the common fruit fly, Drosophila melanogaster, for which a transient or stable plasmid-based transfection kit is offered commercially by Thermo Fisher (The DES TM System) .
- cells are transformed with vectors that express a nucleic acid described herein. Transformation techniques for inserting new genetic material into eukaryotic cells, including animal and plant cells, are well known. Viral vectors may be used for inserting expression cassettes into host cell genomes. Alternatively, the vectors may be transfected into the host cells. Transfection may be accomplished by methods as described in the art such as, but not limited to, calcium phosphate precipitation, electroporation, optical transfection, protoplast fusion, impalefection, and hydrodynamic delivery.
- the methods of use can be assessed using any endpoint indicating a benefit to the subject, including, without limitation, (1) inhibition, to some extent, of disease progression, including stabilization, slowing down and complete arrest; (2) reduction in the number of disease episodes and/or symptoms; (3) inhibition (i.e., reduction, slowing down or complete stopping) of a disease cell infiltration into adjacent peripheral organs and/or tissues; (4) inhibition (i.e.
- the nucleic acid vaccines described herein may be used to protect, treat or cure infection arising from contact with an infectious agent such as, but not limited to, viruses, bacteria, fungi, parasites and protozoa.
- an infectious agent such as, but not limited to, viruses, bacteria, fungi, parasites and protozoa.
- the infectious agent is a virus and the virus is rabies virus and/or a variant thereof.
- the variants of rabies virus are VOI, VOC and VOHC variants.
- rabies virus strains and variants include but are not limited to Pasteur virus, strain ERA, strain SAD B19, strain PM1503, strain China/DRV, strain China/RMV, strain Flury, strain India, strain Nishigahara RCEH, strain CVS-11, isolate Human/Algeria/1991, strain Vnukovo-32, and strain silver-haired bat-associated.
- nucleic acid vaccines described herein may be used as prophylactic agents where the nucleic acid vaccines are administered to a subject, and wherein the nucleic acid vaccine polynucleotide is translated in vivo to produce one or more proteins, peptides, fragments or variants thereof of RABV for the prevention of rabies.
- nucleic acid vaccines described herein may be used as therapeutic agents where the nucleic acid vaccines are administered to a subject, and wherein the nucleic acid vaccine polynucleotide is translated in vivo to produce one or more proteins, peptides, fragments or variants thereof of RABV for the alleviation of one or more symptoms of rabies such as fever, headache, prickling and itching, cerebral dysfunction, anxiety, confusion and agitation.
- rabies such as fever, headache, prickling and itching, cerebral dysfunction, anxiety, confusion and agitation.
- the administration may be in combination with an anti-viral or anti-bacterial agent or a small molecule compound described herein or known in the art.
- nucleic acid vaccines described herein may be used to protect against and/or prevent the transmission of an emerging or engineered threat which may be known or unknown.
- a polypeptide e.g., one or more proteins, peptides, fragments or variants thereof of RABV
- the translated polypeptide may be used for the prevention, alleviation and/or treatment of rabies.
- Such translation can be in vitro, in vivo, ex vivo, or in culture.
- the cell, tissue or organism may be contacted with an effective amount of a composition or pharmaceutical composition containing the nucleic acid vaccine which includes a polynucleotide with at least one region encoding the polypeptide of interest (e.g., one or more proteins, polypeptides, peptides, fragments or variants thereof of RABV for the treatment and/or prevention of rabies) .
- a composition or pharmaceutical composition containing the nucleic acid vaccine which includes a polynucleotide with at least one region encoding the polypeptide of interest (e.g., one or more proteins, polypeptides, peptides, fragments or variants thereof of RABV for the treatment and/or prevention of rabies) .
- the effective amount of the nucleic acid vaccine described herein provided to a cell, a tissue or a subject may be enough for immune prophylaxis.
- an “effective amount” of the composition of the nucleic acid vaccine is provided based, at least in part, on the target tissue, target cell type, means of administration, physical characteristics of the polynucleotide (e.g., size, and the number of unmodified and modified nucleosides) and other components of the nucleic acid vaccine.
- An effective amount of the composition containing the nucleic acid vaccine described herein is one that provides an induced or boosted immune response as a function of production in the cell of one or more proteins, polypeptides, peptides, fragments or variants thereof of RABV as compared to an untreated cell. Increased production may be demonstrated by increased cell transfection (i.e., the percentage of cells transfected with the nucleic acid vaccine) , increased protein translation from the polynucleotide or altered innate immune response of the host cell.
- a nucleic acid vaccine composition containing a polynucleotide that has at least one translatable region encoding the polypeptide (e.g., one or more proteins, polypeptides, peptides, fragments or variants thereof of RABV) is administered to the subject using the delivery methods described herein.
- the polynucleotide is provided in an amount and under other conditions such that the polynucleotide is translated in the cell.
- the cell in which the polynucleotide is localized, or the tissue in which the cell is present, may be targeted with one or more rounds of nucleic acid vaccine administration.
- the administered nucleic acid vaccine comprising polynucleotides directs production of one or more polypeptides that provide a functional immune system-related activity which is substantially absent in the cell, tissue or organism in which the polypeptide is translated.
- the missing functional activity may be enzymatic, structural, or gene regulatory in nature.
- the administered polynucleotides direct production of one or more polypeptides that increases a functional activity related to the immune system which is present but substantially deficient in the cell in which the polypeptide is translated.
- the polypeptide translated from the nucleic acid vaccine may antagonize, directly or indirectly, the activity of a biological moiety present in, on the surface of, or secreted from the cell.
- biological moieties that may be antagonized include a nucleic acid, a carbohydrate, a protein toxin such as shiga and tetanus toxins, lipids (e.g., cholesterol) , a lipoprotein (e.g., low density lipoprotein) , or a small molecule toxin (e.g., cholera, botulinum, and diphtheria toxins) .
- the biological molecule which may be antagonized may be an endogenous protein that may have an undesirable activity such as, but not limited to, cytotoxic or cytostatic activity.
- the proteins described herein may be engineered for localization within the cell, potentially within a specific compartment such as the cytoplasm or nucleus, or are engineered for secretion from the cell or translocation to the plasma membrane of the cell.
- the polynucleotides of the nucleic acid vaccines and their encoded polypeptides may be used for treatment of any of a variety of diseases, disorders, and/or conditions, including but not limited to viral infections (e.g., infections caused by RABV and/or a variant thereof) .
- viral infections e.g., infections caused by RABV and/or a variant thereof
- the subject to whom the nucleic acid vaccine may be administered suffers from or may be at risk of developing a disease, disorder, or deleterious condition.
- GWAS genome-wide association studies
- the agents can be administered simultaneously, for example in a combined unit dose (e.g., providing simultaneous delivery of both agents) .
- the agents can also be administered at a specified time interval, such as, but not limited to, an interval of minutes, hours, days or weeks.
- the agents may be concurrently bioavailable, e.g., detectable, in the subject.
- the agents may be administered essentially simultaneously, for example two unit dosages administered at the same time, or a combined unit dosage of the two agents.
- the agents may be delivered in separate unit dosages.
- the agents may be administered in any order, or as one or more preparations that includes two or more agents.
- At least one administration of one of the agents may be made within minutes, one, two, three, or four hours, or even within one or two days of the other agent, e.g., the second agent.
- combinations can achieve synergistic results, e.g., greater than additive results, e.g., at least 25, 50, 75, 100, 200, 300, 400, or 500%greater than additive results.
- the nucleic acid vaccine described herein may be administrated with other prophylactic or therapeutic compounds.
- the prophylactic or therapeutic compound may be an adjuvant or a booster.
- the term “booster” refers to an extra administration of the prophylactic composition.
- a booster (or booster vaccine) may be given after an earlier administration of the prophylactic composition.
- the time of administration between the initial administration of the prophylactic composition and the booster may be, but is not limited to, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 15 minutes, 20 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 1 day, 36 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 14 days, 21 days, 28 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 18 months, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years,
- the nucleic acid vaccines may be formulated by the methods described herein.
- the formulation may comprise a nucleic acid vaccine or polynucleotide which can have a therapeutic and/or prophylactic effect on more than one disease, disorder or condition.
- the formulation may comprise polynucleotides encoding one or more proteins, polypeptide, peptides, fragments or variants thereof of RABV for the treatment and/or prevention of rabies.
- the nucleic acid vaccines described herein may be used for pre-exposure prophylaxis.
- people who are veterinarians, veterinary technicians, animal control officers, wildlife rehabilitators, zoo employees, certain laboratory workers, and others who have regular contact with potentially rabid animal species may receive one or more doses of nucleic acid vaccines described herein.
- People who travel internationally to areas with endemic canine rabies and may contact RABV carrying animals like dogs may receive the nucleic acid vaccines described herein.
- two or three doses of the nucleic acid vaccines described herein may be administered.
- the nucleic acid vaccines described herein may be used for post-exposure prophylaxis (PEP) .
- the nucleic acid vaccines described herein may be used in combination with rabies immune globulin (such as human rabies immune globulin (HRIG) ) for PEP.
- HRIG human rabies immune globulin
- a dose of the nucleic acid vaccine described herein may be given to the patient right after the rabies viral infection.
- nucleic acid vaccines described herein may be used for research in many applications, such as, but not limited to, identifying and locating intracellular and extracellular proteins, protein interaction, signal pathways and cell biology.
- the nucleic acid vaccines comprising the polynucleotides described herein may act as a single composition as a vaccine.
- a “vaccine” refers to a composition, a substance or preparation that stimulates, induces, causes or improves immunity in an organism, e.g., an animal organism, for example, a mammalian organism (e.g., a human) .
- a vaccine provides immunity against one or more diseases or disorders in the organism, including prophylactic and/or therapeutic immunity.
- Exemplary vaccines include one or more agents that resembles an infectious agent, e.g., a disease-causing microorganism, and can be made, for example, from live, attenuated, modified, weakened or killed forms of disease-causing microorganisms, or antigens derived therefrom, including combinations of antigenic components.
- a vaccine stimulates, induces causes or improves immunity in an organism or causes or mimics infection in the organism without inducing any disease or disorder.
- a vaccine introduces an antigen into the tissues, extracellular space or cells of a subject and elicits an immune response, thereby protecting the subject from a particular disease or pathogen infection.
- the nucleic acid vaccines described herein may encode an antigen and when the polynucleotides are expressed in cells, a desired immune response is achieved.
- the nucleic acid vaccines described herein may encode one or more proteins, polypeptides, antigenic peptides, fragments or variants thereof of RABV and when the polynucleotides are expressed in cells, a desired immune response against RABV is achieved to treat and/or prevent rabies and/or other indications caused by rabies viral infection.
- Nucleic acid vaccines may be administered prophylactically or therapeutically as part of an active immunization scheme to healthy individuals or early in infection during the incubation phase or during active infection after onset of symptoms.
- nucleic acid vaccines described herein may also be administered as a second line treatment after the standard first line treatments such as antibiotics and antivirals have failed to induce passive immunity.
- the nucleic acid vaccines described herein are useful in settings where resistance to first line treatments has developed and disease persists and induces chronic disease.
- Nucleic acid vaccines may be administered as part of a treatment regimen for latent viral infections, such as rabies viral infections.
- one or more polynucleotides are administered which ultimately produce proteins which result a produces a desired immune response against RABV to treat and/or prevent rabies and/or other indications caused by rabies viral infection.
- RNA molecules are considered to be significantly safer than DNA vaccines, as RNAs are more easily degraded. They are cleared quickly out of the organism and cannot integrate into the genome and influence the cell’s gene expression in an uncontrollable manner. It is also less likely for RNA vaccines to cause severe side effects like the generation of autoimmune disease or anti-DNA antibodies (Bringmann A. et al., Journal of Biomedicine and Biotechnology (2010) , vol. 2010, article ID623687) . Transfection with RNA requires only insertion into the cell’s cytoplasm, which is easier to achieve than into the nucleus. However, RNA is susceptible to RNase degradation and other natural decomposition in the cytoplasm of cells.
- RNA vaccines have been described to increase the stability and shelf life of RNA vaccines.
- US Pub. No. US 20050032730 to Von Der Mulbe et al. discloses improving the stability of mRNA vaccine compositions by increasing G(guanosine) /C (cytosine) content of the mRNA molecules.
- U.S. Pat. No. 5,580,859 to Feigner et al. teaches incorporating polynucleotide sequences coding for regulatory proteins that bind to and regulate the stabilities of mRNA. While not wishing to be bound by theory, it is believed that the nucleic acid vaccines described herein may result in improved stability and therapeutic efficacy due at least in part to the specificity, purity and selectivity of the construct designs.
- modified nucleosides may be introduced into the nucleic acid vaccines described herein to activate the innate immune response.
- activating molecules are useful as adjuvants when combined with polypeptides and/or other vaccines.
- the activating molecules contain a translatable region which encodes for a polypeptide sequence useful as a vaccine, thus providing the ability to be a self-adjuvant.
- the polynucleotides encoding an immunogen may be delivered to cells to trigger multiple innate response pathways (see PCT Patent Application Publication Nos. WO2012006377 and US Patent Publication No. US20130177639; the contents of each of which are herein incorporated by reference in their entirety) .
- the nucleic acid vaccines described herein may be delivered to a vertebrate in a dose amount large enough to be immunogenic to the vertebrate (see PCT Patent Application Publication Nos. WO2012006372 and WO2012006369 and US Publication Nos. US20130149375 and US20130177640; the contents of each of which are herein incorporated by reference in their entirety) .
- the nucleic acid vaccines described herein may be delivered to a mammal (e.g., human) in a dose amount large enough to be immunogenic for stimulating an immune response in the mammal.
- the immune response can defend a viral infection, thereby, prevent and/or treat a disease.
- the nucleic acid vaccines described herein may treat and/or prevent rabies and/or other indications caused by rabies virus infection.
- the nucleic acid vaccines may be used to induce neutralizing antibodies in a subject.
- the neutralization activity of the neutralizing antibodies induced by the present nucleic acid vaccines may correlate to the resulting effectiveness (e.g., immune protection) of the vaccines described herein.
- the nucleic acid vaccines described herein induce antigen specific immune responses in vaccinated subjects which can neutralize rabies virus particles and therefore prevent rabies viral infections.
- the nucleic acid vaccines described herein induce potent neutralizing antibody titers.
- the nucleic acid vaccines described herein can produce 10 times, or 9X, or 8X, or 7X, or 6X, or 5X, or 4X, or 3X more neutralizing antibody titers than other vaccines.
- functional neutralizing antibody titers may be stable for at least 3 months, at least 6 months, at least 9 months, at least 1 year, at least 2 years, at least 3 years, at least 4 years, at least 5 years, at least 6 years, at least 7 years, at least 8 years, at least 9 years, at least 10 years, at least 11 years, at least 12 years, at least 13 years, at least 15 years or more than 15 years.
- the nucleic acid vaccines described herein induce T-cell responses. In some embodiments, the nucleic acid vaccines described herein induce antigen specific CD4+T-cell responses. In some embodiments, the nucleic acid vaccines described herein induce antigen specific CD8+T-cell responses. In some embodiments, the T-cell responses are higher than those induced by conventional vaccines. In some embodiments, the T-cell responses are equal to or higher than those induced by conventional vaccines.
- the nucleic acid vaccines described herein may be immunostimulatory.
- the polynucleotide sequence of the nucleic acid vaccine may further comprise a sequence region encoding a cytokine that promotes the immune response, such as a monokine, lymphokine, interleukin or chemokine, such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13,IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32, IL-33, INF-a, INF- ⁇ , GM-CFS, G-CFS, M-CFS, LT-
- a cytokine
- compositions comprising the nucleic acid vaccines described herein may further comprise one or more substances to increase their immunostimulatory capacity, if desired.
- compositions comprising the nucleic acid vaccines described herein may further comprise one or more immune stimulating compounds such as compounds that bind to toll-like receptors, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12 and/or TLR13.
- immune stimulating compounds such as compounds that bind to toll-like receptors, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12 and/or TLR13.
- the nucleic acid vaccines described herein and pharmaceutical compositions comprising the nucleic acid vaccines described herein may be used to induce immune responses in the prevention and treatment of rabies and other diseases caused by rabies viral infection.
- the nucleic acid vaccines described herein may encode at least one polypeptide of interest (e.g., one or more proteins, polypeptides, peptides, fragments or variants thereof of RABV) and may be provided to an individual in order to stimulate the immune system to protect against the disease-causing agents.
- the biological activity and/or effect from an infectious agent may be inhibited and/or abolished by providing neutralizing antibodies which have the ability to bind and neutralize the infectious agent; the neutralizing antibodies produced from the immune system stimulated by the polypeptides translated from the nucleic acid vaccines.
- nucleic acid vaccines described herein and pharmaceutical compositions comprising the nucleic acid vaccines described herein may be utilized in various settings depending on the prevalence of the infection or the degree or level of unmet medical need.
- the nucleic acid vaccines described herein may be utilized to treat and/or prevent rabies and/or other indications caused by rabies viral infection.
- nucleic acid vaccines described herein may be used for the treatment and/or prevention of rabies and other indications caused by rabies viral infection.
- the nucleic acid vaccines described herein can prevent infection by rabies virus, such as pre-exposure prevention.
- the nucleic acid vaccines described herein can be used to prevent fatal symptoms caused by rabies viral infections.
- the nucleic acid vaccines described herein encoding one or more antigen proteins of RABV can be used to induce immune responses against rabies viral infections, especially the fatal infections in developing countries.
- the nucleic acid vaccines described herein can protect against lethal intracerebral infection by rabies virus.
- the nucleic acid vaccines described herein can be used for post exposure treatment of rabies viral infection.
- the nucleic acid vaccines described herein can be combined with rabies immune globulin (such as human rabies immune globulin) .
- the nucleic acid vaccines described herein can be administered to a subject prior to infection with the rabies virus or within 6 hours, 12 hours, 1 days, 2 days, 3 days or between 1 to 10 days after rabies viral infection.
- the nucleic acid vaccines described herein can be first administered to a subject within 6 hours, 12 hours, 1 days, 2 days, 3 days or between 1 to 10 days after rabies viral infection and then repeat administration can occur within 6 hours, 12 hours, 1 days, 2 days, 3 days or between 1 to 10 days after the first administration.
- the nucleic acid vaccine can be first administered to a subject prior to infection with the rabies virus and the second administration is given about 7 days after the first administration. Both administrations may be intramuscular administrations.
- the nucleic acid vaccine can be first administered to a subject after suspicion of a possible rabies virus infection and the second administration is given about 7 days after the first administration. Both administrations may be intramuscular administrations.
- the nucleic acid vaccines described herein may be used to prevent and/or treat one or more rabies symptoms in a subject.
- the symptoms of rabies may include but are not limited to nonspecific symptoms like lethargy, fever, vomiting, weakness, headache, prickling and anorexia, progressive symptoms like cerebral dysfunction, cranial nerve dysfunction, ataxia, weakness, delirium, abnormal behavior, hallucinations, hydrophobia (fear of water) , insomnia, paralysis, seizures, difficulty breathing, difficulty swallowing, excessive salivation, abnormal behavior, aggression, and/or self-mutilation.
- the subject may be a human being and/or a host animal.
- a single dose of the nucleic acid vaccines described herein may provide protection for at least 3 months, at least 6 months, at least 1 year, at least 2 years, at least 3 years, at least 4 years, at least 5 years, at least 6 years, at least 7 years, at least 8 years, at least 9 years, at least 10 years, at least 11 years, at least 12 years, at least 13 years, at least 15 years or more than 15 years.
- the nucleic acid vaccines described herein may be administered to a subject as a single dose followed by a second dose at specific intervals, and optionally a third, fourth, a fifth or more doses subsequent thereto.
- the first dose and the subsequent doses may be the same or different.
- at least one dose of the nucleic acid vaccines described herein is administered to a subject, preferably from 1 to 15 doses, or from 2 to 10 doses, or from 2 to 8 doses, or from 2 to 6 doses, or from 2 to 4 doses, or from 3 to 6 doses, or from 3 to 5 doses.
- 3 doses of the nucleic acid vaccines described herein are administered.
- 4 doses of the nucleic acid vaccines described herein are administered. In one embodiment, 5 doses of the nucleic acid vaccines described herein are administered. In one embodiment, 6 doses of the nucleic acid vaccines described herein are administered. In one embodiment, 7 doses of the nucleic acid vaccines described herein are administered. In one embodiment, 8 doses of the nucleic acid vaccines described herein are administered. In one embodiment, 9 doses of the nucleic acid vaccines described herein are administered. In one embodiment, 10 doses of the nucleic acid vaccines described herein are administered.
- the doses are administered to a subject in a specific time period.
- the doses may be administered between 10 days to 6 months, or 10 days to 3 months, or 10 days to 120 days, or 10 days to 60 days, or 10 days to 30 days, or 20 days to 60 days, or 20 days to 3 days, or from 5 days to 20 days, or from 7 days to 21 days, or from 15 days to 30 days, or from 15 days to 21 days.
- the interval between the administration of two or more doses of the nucleic acid vaccines described herein is at least 7 days, at least 14 days or at least 28 days.
- the nucleic acid vaccines described herein may be used to prevent rabies viral infection in cats, ferrets, dogs and other pets. In some embodiments, the nucleic acid vaccines described herein may be used to prevent rabies viral infection in human. With the very rapid nucleic acid-based vaccine production process, the nucleic acid vaccines described herein ensure human rabies prevention and animal rabies control around the world.
- a single injection of a nucleic acid vaccine may provide adequate protection and control. In some embodiments, more than one injection of a nucleic acid vaccine may need to ensure adequate prevention and control.
- a vaccination scheme or plan may be developed for providing memory booster vaccinations across years, strains, or groups thereof to establish and maintain memory in a population. Any combination of a prior vaccine component strain can be utilized to create or design a memory booster vaccine.
- the nucleic acid vaccines described herein may be used to provide immune protections in vaccinated subjects; the immune protections may be greater than the immune protection provided by conventional rabies vaccines, for examples at least 10 times, 9 times, 8 times, 7 times, 6 times, 5 times, 4 times, 3 times or 2 times greater.
- the induced neutralization activity from the present nucleic acid vaccines may increase the recovery rate of those exposed to RABV.
- the nucleic acid vaccines described herein may be better designed, as compared to current anti-rabies vaccines, to produce the appropriate protein conformation on translation as the nucleic acid vaccines co-opt natural cellular machinery. Unlike traditional vaccines which are manufactured ex vivo and may trigger unwanted cellular responses, the nucleic acid vaccines are presented to the cellular system in a more native fashion.
- the nucleic acid vaccines described herein co-opt the natural cellular machinery to produce the appropriate protein conformation on translation. Unlike traditional vaccines which are manufactured ex vivo and may trigger unwanted cellular responses, the nucleic acid vaccines described herein are introduced to the cellular system in a way that is closer to the native way or the way normal cellular processing occurs. Additionally, formulations may be used to shield or target delivery of the nucleic acid vaccines to specific cells or tissues in the subject.
- nucleic acid vaccines compositions may be created which include polynucleotides that encode one or more proteins, polypeptides, antigenic peptides, fragments or variants thereof of RABV.
- nucleic acid vaccines compositions may be created which include polynucleotides that encode one or more proteins, polypeptides, antigenic peptides, fragments or variants thereof of the Pasteur vaccine strain.
- nucleic acid vaccines compositions may be created which include polynucleotides that encode one or more proteins, polypeptides, antigenic peptides, fragments or variants thereof of the Flury strain.
- nucleic acid vaccines compositions may be created which include polynucleotides that encode one or more proteins, polypeptides, antigenic peptides, fragments or variants thereof of the ERA rabies strain.
- nucleic acid vaccines compositions may be created which include polynucleotides that encode one or more proteins, polypeptides, antigenic peptides, fragments or variants thereof of the Chinese rabies vaccine strain.
- nucleic acid vaccines compositions may be created which include polynucleotides that encode one or more proteins, polypeptides, antigenic peptides, fragments or variants thereof of a new rabies viral strain emerged.
- the nucleic acid vaccine of the present disclosure comprises a RNA polynucleotide encoding the full-length glycoprotein of the Pasteur vaccine strain, i.e., SEQ ID NO: 41 or SEQ ID NO.: 92.
- the nucleic acid vaccine of the present disclosure comprises a RNA polynucleotide encoding a variant of the glycoprotein of the Pasteur vaccine strain, selected from the group consisting of SEQ ID NOs.: 43, 45, 47, 49, 51, 94, 96, 98, 100, and 102.
- the nucleic acid vaccine of the present disclosure comprises a LNP formulated RNA polynucleotide encoding the full-length glycoprotein of the Pasteur vaccine strain, i.e., SEQ ID NO.: 41 or SEQ ID NO.: 92.
- the nucleic acid vaccine of the present disclosure comprises a LNP formulated RNA polynucleotide encoding a variant of the glycoprotein of the Pasteur vaccine strain, selected from the group consisting of SEQ ID NOs.: 43, 45, 47, 49, 51, 94, 96, 98, 100, and 102.
- methods for use of the nucleic acid vaccines described herein to induce a protective immune response in a subject is provided.
- the protective immune response can protect a subject against a rabies viral infection.
- a dosing regimen of the nucleic acid vaccines described herein is provided.
- the dose may range from 0.1 ⁇ g to 100 mg, or from 0.1 ⁇ g to 10 mg, or from 0.1 ⁇ g to 1mg, or from 0.1 ⁇ g to 500 ⁇ g, or from 1 ⁇ g to 500 ⁇ g, or from 10 ⁇ g to 500 ⁇ g, or from 1 mg to 10 mg, or from 10 mg to 100 mg.
- kits for conveniently and/or effectively carrying out methods of the present disclosure.
- kits will comprise sufficient amounts and/or numbers of components to allow a user to perform multiple treatments of a subject (s) and/or to perform multiple experiments.
- kits for modulating the expression of genes in vitro or in vivo comprising nucleic acid vaccine compositions of the present disclosure or a combination of nucleic acid vaccine compositions of the present disclosure, nucleic acid vaccine compositions modulating other genes, siRNAs, miRNAs or other oligonucleotide molecules.
- the kit may further comprise packaging and instructions and/or a delivery agent to form a formulation, e.g., for administration to a subject in need of treatment using the nucleic acid vaccine compositions described herein.
- the delivery agent may comprise a saline, a buffered solution, a lipidoid, a dendrimer or any suitable delivery agent.
- the buffer solution may include sodium chloride, calcium chloride, phosphate and/or EDTA.
- the buffer solution may include, but is not limited to, saline, saline with 2mM calcium, 5%sucrose, 5%sucrose with 2mM calcium, 5%Mannitol, 5%Mannitol with 2mM calcium, Ringer’s lactate, sodium chloride, sodium chloride with 2mM calcium and mannose (See U. S. Pub. No. 20120258046; herein incorporated by reference in its entirety) .
- the buffer solutions may be precipitated or it may be lyophilized.
- the amount of each component may be varied to enable consistent, reproducible higher concentration saline or simple buffer formulations.
- the components may also be varied in order to increase the stability of nucleic acid vaccine compositions in the buffer solution over a period of time and/or under a variety of conditions.
- the present disclosure provides for devices which may incorporate nucleic acid vaccine compositions of the present disclosure. These devices can contain a stable formulation available to be immediately delivered to a subject in need thereof, such as a human patient.
- Non-limiting examples of the devices include a pump, a catheter, a needle, a transdermal patch, a pressurized olfactory delivery device, electroporation devices, iontophoresis devices, multi-layered microfluidic devices.
- the devices may be employed to deliver nucleic acid vaccine compositions of the present disclosure according to single, multi-or split-dosing regiments.
- the devices may be employed to deliver nucleic acid vaccine compositions of the present disclosure across biological tissue, intradermal, subcutaneously, or intramuscularly. More examples of devices suitable for delivering oligonucleotides are disclosed in International Publication WO 2013/090648, the contents of which are incorporated herein by reference in their entirety.
- Administered in combination means that two or more agents are administered to a subject at the same time or within an interval such that there may be an overlap of an effect of each agent on the patient. In some embodiments, they are administered within about 60, 30, 15, 10, 5, or 1 minute of one another. In some embodiments, the administrations of the agents are spaced sufficiently closely together such that a combinatorial (e.g., a synergistic) effect is achieved.
- Adjuvant means a substance that enhances a subject’s immune response to an antigen.
- the nucleic acid vaccines described herein may optionally comprise one or more adjuvants.
- animal refers to any member of the animal kingdom. In some embodiments, “animal” refers to humans at any stage of development. In some embodiments, “animal” refers to non-human animals at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, or a pig) . In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, and worms. In some embodiments, the animal is a transgenic animal, genetically-engineered animal, or a clone.
- Antigen refers to a composition, for example, a substance or agent which causes an immune response in an organism, e.g., causes the immune response of the organism to produce antibodies against the substance or agent in particular, which provokes an adaptive immune response in an organism.
- Antigens can be any immunogenic substance including, in particular, proteins, polypeptides, polysaccharides, nucleic acids, lipids and the like. Exemplary antigens are derived from infectious agents.
- Such agents can include parts or subunits of infectious agents, for example, coats, coat components, e.g., coat protein or polypeptides, surface components, e.g., surface proteins or polypeptides, capsule components, cell wall components, flagella, fimbrae, and/or toxins or toxoids) of infectious agents, for example, bacteria, viruses, and other microorganisms.
- infectious agents for example, coats, coat components, e.g., coat protein or polypeptides, surface components, e.g., surface proteins or polypeptides, capsule components, cell wall components, flagella, fimbrae, and/or toxins or toxoids
- infectious agents for example, bacteria, viruses, and other microorganisms.
- antigens for example, lipids and/or nucleic acids are antigenic, preferably, when combined with proteins and/or polysaccharides.
- the term “approximately” or “about, ” as applied to one or more values of interest refers to a value that is similar to a stated reference value. In certain embodiments, the term “approximately” or “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100%of a possible value) .
- association means that the moieties are physically associated or connected with one another, either directly or via one or more additional moieties that serves as a linking agent, to form a structure that is sufficiently stable so that the moieties remain physically associated under the conditions in which the structure is used, e.g., physiological conditions.
- An “association” need not be strictly through direct covalent chemical bonding. It may also suggest ionic or hydrogen bonding or a hybridization-based connectivity sufficiently stable such that the “associated” entities remain physically associated.
- Bifunctional refers to any substance, molecule or moiety which is capable of or maintains at least two functions.
- the functions may affect the same outcome or a different outcome.
- the structure that produces the function may be the same or different.
- Biocompatible As used herein, the term “biocompatible” means compatible with living cells, tissues, organs or systems posing little to no risk of injury, toxicity or rejection by the immune system.
- Biodegradable As used herein, the term “biodegradable” means capable of being broken down into innocuous products by the action of living things.
- biologically active refers to a characteristic of any substance that has activity in a biological system and/or organism. For instance, a substance that, when administered to an organism, has a biological effect on that organism, is considered to be biologically active.
- a polynucleotide described herein may be considered biologically active if even a portion of the polynucleotides is biologically active or mimics an activity considered biologically relevant.
- Chimera As used herein, “chimera” is an entity having two or more incongruous or heterogeneous parts or regions.
- Compound As used herein, the term “compound, ” is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted.
- the compounds described herein can be asymmetric (e.g., having one or more stereocenters) . All stereoisomers, such as enantiomers and diastereomers, are intended to be included unless otherwise indicated.
- Tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton.
- Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
- Compounds of the present disclosure also include all of the isotopes of the atoms occurring in the intermediate or final compounds. “Isotopes” refers to atoms having the same atomic number but different mass numbers resulting from a different number of neutrons in the nuclei. For example, isotopes of hydrogen include tritium and deuterium.
- the compounds and salts of the present disclosure can be prepared in combination with solvent or water molecules to form solvates and hydrates by routine methods.
- conserved refers to nucleotides or amino acid residues of a polynucleotide sequence or polypeptide sequence, respectively, that are those that occur unaltered in the same position of two or more sequences being compared. Nucleotides or amino acids that are relatively conserved are those that are conserved amongst more related sequences than nucleotides or amino acids appearing elsewhere in the sequences.
- two or more sequences are said to be “completely conserved” ifthey are 100%identical to one another. In some embodiments, two or more sequences are said to be “highly conserved” ifthey are at least 70%identical, at least 80%identical, at least 90%identical, or at least 95%identical to one another. In some embodiments, two or more sequences are said to be “highly conserved” if they are about 70%identical, about 80%identical, about 90%identical, about 95%, about 98%, or about 99%identical to one another.
- two or more sequences are said to be “conserved” if they are at least 30%identical, at least 40%identical, at least 50%identical, at least 60%identical, at least 70%identical, at least 80%identical, at least 90%identical, or at least 95%identical to one another. In some embodiments, two or more sequences are said to be “conserved” ifthey are about 30%identical, about 40%identical, about 50%identical, about 60%identical, about 70%identical, about 80% identical, about 90%identical, about 95%identical, about 98%identical, or about 99%identical to one another. Conservation of sequence may apply to the entire length of a polynucleotide or polypeptide or may apply to a portion, region or feature thereof.
- controlled release refers to a pharmaceutical composition or compound release profile that conforms to a particular pattern of release to effect a therapeutic outcome.
- Cytostatic refers to inhibiting, reducing, suppressing the growth, division, or multiplication of a cell (e.g., a mammalian cell (e.g., a human cell) ) , bacterium, virus, fungus, protozoan, parasite, prion, or a combination thereof.
- Cytotoxic refers to killing or causing injurious, toxic, or deadly effect on a cell (e.g., a mammalian cell (e.g., a human cell) ) , bacterium, virus, fungus, protozoan, parasite, prion, or a combination thereof.
- delivery refers to the act or manner of delivering a compound, substance, entity, moiety, cargo or payload.
- delivery agent refers to any substance which facilitates, at least in part, the in vivo delivery of a polynucleotide to targeted cells.
- Destabilized As used herein, the term “destable, ” “destabilize, ” or “destabilizing region” means a region or molecule that is less stable than a starting, wild-type or native form of the same region or molecule.
- Detectable label refers to one or more markers, signals, or moieties which are attached, incorporated or associated with another entity that is readily detected by methods known in the art including radiography, fluorescence, chemiluminescence, enzymatic activity, absorbance and the like. Detectable labels include radioisotopes, fluorophores, chromophores, enzymes, dyes, metal ions, ligands such as biotin, avidin, streptavidin and haptens, quantum dots, and the like. Detectable labels may be located at any position in the peptides or proteins disclosed herein. They may be within the amino acids, the peptides, or proteins, or located at the N-or C-termini.
- Digest means to break apart into smaller pieces or components. When referring to polypeptides or proteins, digestion results in the production of peptides.
- Dosing regimen is a schedule of administration or physician determined regimen of treatment, prophylaxis, or palliative care.
- Encapsulate As used herein, the term “encapsulate” means to enclose, surround or encase.
- Encoded protein cleavage signal refers to the nucleotide sequence which encodes a protein cleavage signal.
- nucleic acid vaccines are “engineered” when they are designed to have a feature or property, whether structural or chemical, that varies from a starting point, wild type or native molecule.
- an effective amount of an agent is that amount sufficient to effect beneficial or desired results, for example, clinical results, and, as such, an “effective amount” depends upon the context in which it is being applied.
- an effective amount of an agent is, for example, an amount sufficient to achieve treatment, as defined herein, of cancer, as compared to the response obtained without administration of the agent.
- Exosome is a vesicle secreted by mammalian cells or a complex involved in RNA degradation.
- expression of a nucleic acid sequence refers to one or more of the following events: (1) production of an RNA template from a DNA sequence (e.g., by transcription) ; (2) processing of an RNA transcript (e.g., by splicing, editing, 5' cap formation, and/or 3' end processing) ; (3) translation of an RNA into a polypeptide or protein; and (4) post-translational modification of a polypeptide or protein.
- Feature refers to a characteristic, a property, or a distinctive element.
- a “formulation” includes at least a polynucleotide of a nucleic acid vaccine and a delivery agent.
- fragment refers to a portion.
- fragments of proteins may comprise polypeptides obtained by digesting full-length protein isolated from cultured cells.
- a “functional” biological molecule is a biological molecule in a form in which it exhibits a property and/or activity by which it is characterized.
- homology refers to the overall relatedness between polymeric molecules, e.g. between nucleic acid molecules (e.g. DNA molecules and/or RNA molecules) and/or between polypeptide molecules.
- polymeric molecules are considered to be “homologous” to one another if their sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%identical or similar.
- the term “homologous” necessarily refers to a comparison between at least two sequences (polynucleotide or polypeptide sequences) .
- Two polynucleotide sequences are considered to be homologous if the polypeptides they encode are at least about 50%, 60%, 70%, 80%, 90%, 95%, or even 99%identical for at least one stretch of at least about 20 amino acids.
- homologous polynucleotide sequences are characterized by the ability to encode a stretch of at least 4-5 uniquely specified amino acids. For polynucleotide sequences less than 60 nucleotides in length, homology is determined by the ability to encode a stretch of at least 4-5 uniquely specified amino acids.
- Two protein sequences are considered to be homologous ifthe proteins are at least about 50%, 60%, 70%, 80%, or 90%identical for at least one stretch of at least about 20 amino acids.
- identity refers to the overall relatedness between polymeric molecules, e.g., between polynucleotide molecules (e.g. DNA molecules and/or RNA molecules) and/or between polypeptide molecules.
- Calculation of the percent identity of two polynucleotide sequences can be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second nucleic acid sequences for optimal alignment and nonidentical sequences can be disregarded for comparison purposes) .
- the length of a sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%of the length of the reference sequence.
- the nucleotides at corresponding nucleotide positions are then compared.
- the percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which needs to be introduced for optimal alignment of the two sequences.
- the comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm.
- the percent identity between two nucleotide sequences can be determined using methods such as those described in Computational Molecular Biology, Lesk, A.M, ed., Oxford University Press, N.Y., 1988; Biocomputing: Informatics and Genome Projects, Smith, D.W., ed., Academic Press, N.Y, 1993; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; Computer Analysis of Sequence Data, Part I, Griffin, A.M, and Griffin, H.G., eds., Humana Press, N.J., 1994; and Sequence Analysis Primer, Gribskov, M.
- the percent identity between two nucleotide sequences can be determined using the algorithm of Meyers and Miller (CABIOS, 1989, 4: 11-17) , which has been incorporated into the ALIGN program (version 2.0) using a PAM 120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.
- the percent identity between two nucleotide sequences can, alternatively, be determined using the GAP program in the GCG software package using an NWSgapdna. CMP matrix.
- Methods commonly employed to determine percent identity between sequences include, but are not limited to those disclosed in Carillo, H., and Lipman, D., SIAM J Applied Math., 48: 1073 (1988) ; incorporated herein by reference. Techniques for determining identity are codified in publicly available computer programs. Exemplary computer software to determine homology between two sequences include, but are not limited to, GCG program package. (Devereux, J., et al., Nucleic Acids Research, 12 (1) , 387 (1984) ) , BLASTP, BLASTN, and FASTA (Altschul, S.F. et al, J. Molec. Biol., 215, 403 (1990) ) .
- infectious agent means an agent capable of producing an infection in an organism, for example, in an animal.
- An infectious agent may refer to any microorganism, virus, infectious substance, or biological product that may be engineered as a result of biotechnology, or any naturally occurring or bioengineered component of any such microorganism, virus, infectious substance, or biological product, can cause emerging and contagious disease, death or other biological malfunction in a human, an animal, a plant or another living organism.
- in vitro refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, in a Petri dish, etc., rather than within an organism (e.g., animal, plant, or microbe) .
- in vivo refers to events that occur within an organism (e.g., animal, plant, or microbe or cell or tissue thereof) .
- Isolated refers to a substance or entity that has been separated from at least some of the components with which it was associated (whether in nature or in an experimental setting) . Isolated substances may have varying levels of purity in reference to the substances from which they have been associated. Isolated substances and/or entities may be separated from at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more of the other components with which they were initially associated.
- isolated agents are more than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99%pure.
- a substance is “pure” if it is substantially free of other components.
- substantially isolated By “substantially isolated” is meant that the compound is substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compound of the present disclosure.
- Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99%by weight of the compound of the present disclosure, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
- Linker refers to a group of atoms, e.g., 10-1,000 atoms, and can be comprised of the atoms or groups such as, but not limited to, carbon, amino, alkylamino, oxygen, sulfur, sulfoxide, sulfonyl, carbonyl, and imine.
- the linker can be attached to a modified nucleoside or nucleotide on the nucleobase or sugar moiety at a first end, and to a payload, e.g., a detectable or therapeutic agent, at a second end.
- the linker may be of sufficient length as to not interfere with incorporation into a nucleic acid sequence.
- Modified refers to a changed state or structure of a molecule described herein. Molecules may be modified in many ways including chemically, structurally, and functionally.
- Mucus As used herein, “mucus” refers to the natural substance that is viscous and comprises mucin glycoproteins.
- Naturally occurring means existing in nature without artificial aid.
- Neutralizing antibody refers to an antibody which binds to its antigen and defends a cell from an antigen or infectious agent by neutralizing or abolishing any biological activity it has.
- Non-human vertebrate includes all vertebrates except Homo sapiens, including wild and domesticated species.
- Examples of non-human vertebrates include, but are not limited to, mammals, such as alpaca, banteng, bison, camel, cat, cattle, deer, dog, donkey, gayal, goat, guinea pig, horse, llama, mule, pig, rabbit, reindeer, sheep, water buffalo, and yak.
- nucleic acid vaccine refers to a vaccine or vaccine composition which includes a nucleic acid or nucleic acid molecule (e.g., a polynucleotide) encoding an antigen (e.g., an antigenic protein or polypeptide. )
- a nucleic acid vaccine includes a ribonucleic ( “RNA” ) polynucleotide, ribonucleic acid ( “RNA” ) or ribonucleic acid ( “RNA” ) molecule.
- RNA ribonucleic acid
- Off-target refers to any unintended effect on any one or more target, gene, or cellular transcript.
- Open reading frame refers to a continuous polynucleotide sequence, for example, a DNA sequence or RNA sequence (e.g., an mRNA sequence) , comprising a start codon, a subsequent region comprising a plurality of amino acid-encoding codons, and a terminal stop codon, wherein the region comprising the plurality of amino acid-encoding codons contains no stop codons.
- a DNA sequence or RNA sequence e.g., an mRNA sequence
- operably linked refers to a functional connection between two or more molecules, constructs, transcripts, entities, moieties or the like.
- Part As used herein, a “part” or “region” of a polynucleotide is defined as any portion of the polynucleotide which is less than the entire length of the polynucleotide.
- Peptide As used herein, “peptide” is less than or equal to 50 amino acids long, e.g., about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 amino acids long.
- Paratope As used herein, a “paratope” refers to the antigen-binding site of an antibody.
- patient refers to a subject who may seek or be in need of treatment, requires treatment, is receiving treatment, will receive treatment, or a subject who is under care by a trained professional for a particular disease or condition.
- compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
- compositions refers any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially nontoxic and non-inflammatory in a patient.
- Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors) , emollients, emulsifiers, fillers (diluents) , film formers or coatings, flavors, fragrances, glidants (flow enhancers) , lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, and waters of hydration.
- excipients include, but are not limited to: butylated hydroxytoluene (BHT) , calcium carbonate, calcium phosphate (dibasic) , calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (com) , stearic acid, sucrose, talc, titanium dioxide, vitamin A,
- compositions described herein also includes pharmaceutically acceptable salts of the compounds described herein.
- pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form (e.g., by reacting the free base group with a suitable organic acid) .
- examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
- Representative acid addition salts include acetate, acetic acid, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzene sulfonic acid, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate
- alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
- the pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
- the pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
- such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
- nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
- Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, Pharmaceutical Salts: Properties, Selection, and Use, P. H. Stahl and C. G. Wermuth (eds. ) , Wiley-VCH, 2008, and Beige et al., Journal ofPharmaceutical Science, 66, 1-19 (1977) , each of which is incorporated herein by reference
- solvate means a compound described herein wherein molecules of a suitable solvent are incorporated in the crystal lattice.
- a suitable solvent is physiologically tolerable at the dosage administered.
- solvates may be prepared by crystallization, recrystallization, or precipitation from a solution that includes organic solvents, water, or a mixture thereof.
- solvents examples include ethanol, water (for example, mono-, di-, and tri-hydrates) , N-methylpyrrolidinone (NMP) , dimethyl sulfoxide (DMSO) , ⁇ , ⁇ '-dimethyl-formamide (DMF) , N, ⁇ '-dimethylacetamide (DMAC) , 1, 3-dimethyl-2-imidazolidinone (DMEU) , l, 3-dimethyl-3, 4, 5, 6-tetrahydro-2-(lH) -pyrimidinone (DMPU) , acetonitrile (ACN) , propylene glycol, ethyl acetate, benzyl alcohol, 2-pyrrolidone, benzyl benzoate, and the like.
- NMP N-methylpyrrolidinone
- DMSO dimethyl sulfoxide
- DMF ⁇ , ⁇ '-dimethyl-formamide
- DMAC N, ⁇ '-dimethylacetamide
- Pharmacokinetic refers to any one or more properties of a molecule or compound as it relates to the determination of the fate of substances administered to a living organism. Pharmacokinetics is divided into several areas including the extent and rate of absorption, distribution, metabolism and excretion. This is commonly referred to as ADME where: (A) Absorption is the process of a substance entering the blood circulation; (D) Distribution is the dispersion or dissemination of substances throughout the fluids and tissues of the body; (M) Metabolism (or Biotransformation) is the irreversible transformation of parent compounds into daughter metabolites; and (E) Excretion (or Elimination) refers to the elimination of the substances from the body. In rare cases, some drugs irreversibly accumulate in body tissue.
- Physicochemical means of or relating to a physical and/or chemical property.
- Polypeptide per unit drug As used herein, a PUD or product per unit drug, is defined as a subdivided portion of total daily dose, usually 1 mg, pg, kg, etc., of a product (such as a polypeptide) as measured in body fluid or tissue, usually defined in concentration such as pmol/mL, mmol/mL, etc. divided by the measure in the body fluid.
- the term “preventing” refers to partially or completely delaying onset of an infection, disease, disorder and/or condition; partially or completely delaying onset of one or more symptoms, features, or clinical manifestations of a particular infection, disease, disorder, and/or condition; partially or completely delaying onset of one or more symptoms, features, or manifestations of a particular infection, disease, disorder, and/or condition; partially or completely delaying progression from an infection, a particular disease, disorder and/or condition; and/or decreasing the risk of developing pathology associated with the infection, the disease, disorder, and/or condition.
- Proliferate As used herein, the term “proliferate” means to grow, expand or increase or cause to grow, expand or increase rapidly. “Proliferative” means having the ability to proliferate. “Anti-proliferative” means having properties counter to or inapposite to proliferative properties.
- Prophylactic refers to a therapeutic or course of action used to prevent the spread of disease.
- Prophylaxis As used herein, a “prophylaxis” refers to a measure taken to maintain health and prevent the spread of disease. An “immune prophylaxis” refers to a measure to produce active or passive immunity to prevent the spread of disease.
- Protein cleavage signal refers to at least one amino acid that flags or marks a polypeptide for cleavage.
- Protein of interest As used herein, the terms “proteins of interest” or “desired proteins” include those provided herein and fragments, mutants, variants, and alterations thereof.
- purify means to make substantially pure or clear from unwanted components, material defilement, admixture or imperfection.
- the term “repeated transfection” refers to transfection of the same cell culture with a polynucleotide a plurality of times.
- the cell culture can be transfected at least twice, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, at least 16 times, at least 17 times, at least 18 times, at least 19 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times or more.
- sample refers to a subset of its tissues, cells or component parts (e.g. body fluids, including but not limited to blood, mucus, lymphatic fluid, synovial fluid, cerebrospinal fluid, saliva, amniotic fluid, amniotic cord blood, urine, vaginal fluid and semen) .
- body fluids including but not limited to blood, mucus, lymphatic fluid, synovial fluid, cerebrospinal fluid, saliva, amniotic fluid, amniotic cord blood, urine, vaginal fluid and semen.
- Signal Sequences refers to a sequence which can direct the transport or localization of a protein.
- Single unit dose is a dose of any therapeutic administered in one dose/at one time/single route/single point of contact, i.e., single administration event.
- Similarity refers to the overall relatedness between polymeric molecules, e.g., between polynucleotide molecules (e.g., DNA molecules and/or RNA molecules) and/or between polypeptide molecules. Calculation of percent similarity of polymeric molecules to one another can be performed in the same manner as a calculation of percent identity, except that calculation of percent similarity takes into account conservative substitutions as is understood in the art.
- split dose As used herein, a “split dose” is the division of single unit dose or total daily dose into two or more doses.
- Stable refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent.
- Stabilized As used herein, the term “stabilize” , “stabilized, ” “stabilized region” means to make or become stable.
- subject refers to any organism to which a composition may be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes.
- Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans) .
- the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest.
- One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result.
- the term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.
- Substantially equal As used herein as it relates to time differences between doses, the term means plus/minus 2%.
- Substantially simultaneously As used herein and as it relates to plurality of doses, the term means within 2 seconds.
- Susceptible to An individual who is “susceptible to” a disease, disorder, and/or condition has not been diagnosed with and/or may not exhibit symptoms of the disease, disorder, and/or condition but harbors a propensity to develop a disease or its symptoms.
- an individual who is susceptible to a disease, disorder, and/or condition may be characterized by one or more of the following: (1) a genetic mutation associated with development of the disease, disorder, and/or condition; (2) a genetic polymorphism associated with development of the disease, disorder, and/or condition; (3) increased and/or decreased expression and/or activity of a protein and/or nucleic acid associated with the disease, disorder, and/or condition; (4) habits and/or lifestyles associated with development of the disease, disorder, and/or condition; (5) a family history of the disease, disorder, and/or condition; and (6) exposure to and/or infection with a microbe associated with development of the disease, disorder, and/or condition.
- an individual who is susceptible to a disease, disorder, and/or condition will develop the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition will not develop the disease, disorder, and/or condition.
- Synthetic means produced, prepared, and/or manufactured by the hand of man. Synthesis of polynucleotides or polypeptides or other molecules described herein may be chemical or enzymatic.
- a vaccine is a compound or composition which comprises at least one polynucleotide encoding at least one antigen.
- Targeted cells refers to any one or more cells of interest.
- the cells may be found in vitro, in vivo, in situ or in the tissue or organ of an organism.
- the organism may be an animal, preferably a mammal, more preferably a human and most preferably a patient.
- therapeutically effective amount means an amount of an agent to be delivered (e.g., nucleic acid, drug, therapeutic agent, diagnostic agent, prophylactic agent, etc. ) that is sufficient, when administered to a subject suffering from or susceptible to an infection, disease, disorder, and/or condition, to treat, improve symptoms of, diagnose, prevent, and/or delay the onset of the infection, disease, disorder, and/or condition.
- an agent to be delivered e.g., nucleic acid, drug, therapeutic agent, diagnostic agent, prophylactic agent, etc.
- therapeutically effective outcome means an outcome that is sufficient in a subject suffering from or susceptible to an infection, disease, disorder, and/or condition, to treat, improve symptoms of, diagnose, prevent, and/or delay the onset of the infection, disease, disorder, and/or condition.
- Total daily dose As used herein, a “total daily dose” is an amount given or prescribed in 24 hr. period. It may be administered as a single unit dose.
- transfection refers to methods to introduce exogenous nucleic acids into a cell. Methods of transfection include, but are not limited to, chemical methods, physical treatments and cationic lipids or mixtures.
- translation is the process by which a polynucleotide molecule is processed by a ribosome or ribosomal-like machinery, e.g., cellular or artificial, to produce a peptide or polypeptide.
- Unmodified refers to any substance, compound or molecule prior to being changed in any way. Unmodified may, but does not always, refer to the wild type or native form of a biomolecule. Molecules may undergo a series of modifications whereby each modified molecule may serve as the “unmodified” starting molecule for a subsequent modification.
- Vaccine refers to a biological preparation that improves immunity in the context of a particular disease, disorder or condition.
- Viral protein means any protein originating from a virus.
- Embodiment 1 A polynucleotide encoding at least one structural protein of a rabies virus (RABV) , or a fragment, an antigenic peptide or a variant thereof, wherein said at least one structural protein is the glycoprotein (G) and wherein the polynucleotide comprises a first sequence region having a nucleic acid sequence that is at least 80%identity to SEQ ID NO.: 29.
- RABV rabies virus
- G glycoprotein
- Embodiment 2 The polynucleotide of Embodiment 1, wherein said first sequence region consists of SEQ ID NO.: 29.
- Embodiment 3 A polynucleotide encoding at least one structural protein of a rabies virus (RABV) , or a fragment, an antigenic peptide or a variant thereof, wherein said at least one structural protein is the glycoprotein (G) and wherein the polynucleotide comprises a first sequence region having a nucleic acid sequence that is at least 80%identity to SEQ ID NO.: 70.
- RABV rabies virus
- G glycoprotein
- Embodiment 4 The polynucleotide of Embodiment 3, wherein the first sequence region further comprises at least one stop codon.
- Embodiment 5 The polynucleotide of Embodiment 3, wherein the first sequence region further comprises at least two stop codons.
- Embodiment 6 The polynucleotide of Embodiment 3, wherein the first sequence region further comprises one stop codon.
- Embodiment 7 The polynucleotide of Embodiment 3, wherein the first sequence region further comprises two stop codons.
- Embodiment 8 The polynucleotide of Embodiment 3, wherein said first sequence region consists of SEQ ID NO.: 70.
- Embodiment 9 The polynucleotide of Embodiment 8, wherein the polynucleotide comprises a second sequence region, wherein said second sequence region comprises at least one stop codon.
- Embodiment 10 The polynucleotide of Embodiment 8, wherein the polynucleotide comprises a second sequence region, wherein said second sequence region comprises at least two stop codons.
- Embodiment 11 The polynucleotide of Embodiment 8, wherein the polynucleotide comprises a second sequence region, wherein said second sequence region comprises one stop codon.
- Embodiment 12 polynucleotide of Embodiment 8, wherein the polynucleotide comprises a second sequence region, wherein said second sequence region comprises two stop codons.
- Embodiment 13 A polynucleotide encoding at least one structural protein of a rabies virus (RABV) , or a fragment, an antigenic peptide or a variant thereof, wherein said at least one structural protein is the glycoprotein (G) and wherein the polynucleotide comprises a first sequence region having a nucleic acid sequence that is at least 80%identity to a member of the group consisting of SEQ ID NOs.: 31, 33, 35, 37 and 39.
- RABV rabies virus
- G glycoprotein
- Embodiment 14 The polynucleotide of Embodiment 3, wherein said first sequence region consists of SEQ ID NO.: 31.
- Embodiment 15 The polynucleotide of Embodiment 3, wherein said first sequence region consists of SEQ ID NO.: 33.
- Embodiment 16 The polynucleotide of Embodiment 3, wherein said first sequence region consists of SEQ ID NO.: 35.
- Embodiment 17 The polynucleotide of Embodiment 3, wherein said first sequence region consists of SEQ ID NO.: 37.
- Embodiment 18 The polynucleotide of Embodiment 3, wherein said first sequence region consists of SEQ ID NO.: 39.
- Embodiment 19 The polynucleotide of any one of Embodiments 13-18, wherein the polynucleotide further comprises a second sequence region, said second sequence region comprising the nucleic acid sequence of SEQ ID NO.: 53.
- Embodiment 20 A polynucleotide encoding at least one structural protein of a rabies virus (RABV) , or a fragment, an antigenic peptide or a variant thereof, wherein said at least one structural protein is the glycoprotein (G) and wherein the polynucleotide comprises a first sequence region having a nucleic acid sequence that is at least 80% identity to a member of the group consisting of SEQ ID NOs.: 72, 74, 76, 78, 80, 82, 84, 86, 88 and 90.
- RABV rabies virus
- G glycoprotein
- Embodiment 21 The polynucleotide of Embodiment 20, wherein the first sequence region further comprises at least one stop codon.
- Embodiment 22 The polynucleotide of Embodiment 20, wherein the first sequence region further comprises at least two stop codons.
- Embodiment 23 The polynucleotide of Embodiment 20, wherein the first sequence region further comprises one stop codon.
- Embodiment 24 The polynucleotide of Embodiment 20, wherein the first sequence region further comprises two stop codons.
- Embodiment 25 The polynucleotide of Embodiment 20, wherein said first sequence region consists of SEQ ID NO.: 72.
- Embodiment 26 The polynucleotide of Embodiment 20, wherein said first sequence region consists of SEQ ID NO.: 74.
- Embodiment 27 The polynucleotide of Embodiment 20, wherein said first sequence region consists of SEQ ID NO.: 76.
- Embodiment 28 The polynucleotide of Embodiment 20, wherein said first sequence region consists of SEQ ID NO.: 78.
- Embodiment 29 The polynucleotide of Embodiment 20, wherein said first sequence region consists of SEQ ID NO.: 80.
- Embodiment 30 The polynucleotide of Embodiment 20, wherein said first sequence region consists of SEQ ID NO.: 82.
- Embodiment 31 The polynucleotide of Embodiment 20, wherein said first sequence region consists of SEQ ID NO.: 84.
- Embodiment 32 The polynucleotide of Embodiment 20, wherein said first sequence region consists of SEQ ID NO.: 86.
- Embodiment 33 The polynucleotide of Embodiment 20, wherein said first sequence region consists of SEQ ID NO.: 88.
- Embodiment 34 The polynucleotide of Embodiment 20, wherein said first sequence region consists of SEQ ID NO.: 90.
- Embodiment 35 The polynucleotide of any one of Embodiments 25-34, wherein the polynucleotide further comprises a second sequence region, said second sequence region comprising the nucleic acid sequence of SEQ ID NO.: 53.
- Embodiment 36 The polynucleotide of any one of Embodiments 25-34, wherein the polynucleotide comprises a second sequence region, wherein said second sequence region comprises at least one stop codon.
- Embodiment 37 The polynucleotide of any one of Embodiments 25-34, wherein the polynucleotide comprises a second sequence region, wherein said second sequence region comprises at least two stop codons.
- Embodiment 38 The polynucleotide of any one of Embodiments 25-34, wherein the polynucleotide comprises a second sequence region, wherein said second sequence region comprises one stop codon.
- Embodiment 39 The polynucleotide of any one of Embodiments 25-34, wherein the polynucleotide comprises a second sequence region, wherein said second sequence region comprises two stop codons.
Landscapes
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
La présente invention concerne des compositions et des procédés pour la préparation, la fabrication et l'utilisation thérapeutique de vaccins utilisant des acides nucléiques comprenant des séquences de polynucléotides codant pour une ou plusieurs protéines structurelles d'un virus de la rage (RABV) pour le traitement, l'atténuation, la réduction et/ou la prévention de la rage.
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
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CN2022139127 | 2022-12-14 | ||
CNPCT/CN2022/139127 | 2022-12-14 | ||
CN2023081709 | 2023-03-15 | ||
CNPCT/CN2023/081709 | 2023-03-15 | ||
CN2023136849 | 2023-12-06 | ||
CNPCT/CN2023/136849 | 2023-12-06 |
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WO2024125597A1 true WO2024125597A1 (fr) | 2024-06-20 |
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PCT/CN2023/138771 WO2024125597A1 (fr) | 2022-12-14 | 2023-12-14 | Compositions et procédés pour des maladies infectieuses |
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Country | Link |
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WO (1) | WO2024125597A1 (fr) |
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2023
- 2023-12-14 WO PCT/CN2023/138771 patent/WO2024125597A1/fr unknown
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