Novel artificial nucleic acid molecules

Abstract

The present invention provides artificial nucleic acid molecules comprising novel combinations of 5' and 3' untranslated region (UTR) elements. The nucleic acid molecules of the present invention are preferably characterized by increased expression efficiency of the coding region operably linked to the UTR elements. The artificial nucleic acids can be used to treat or prevent various diseases. The present invention further provides (pharmaceutical) compositions, vaccines, and kits comprising the artificial nucleic acid molecules. Furthermore, an in vitro method for preparing the artificial nucleic acid molecules of the present invention is provided.

Description

Detailed description of the invention

[0001] To date, therapeutic nucleic acids in the form of naked DNA, viral, or bacterial DNA vectors have been used for a variety of purposes. Gene therapy attempts to treat diseases by transferring one or more therapeutic nucleic acids into a patient's cells (gene addition therapy) or by correcting defective genes, for example, through gene editing (gene replacement therapy). This technology transfer is expected to provide sustained treatment for diseases that are incurable or only temporarily curable with conventional treatment options, and also to provide treatment for diseases that were previously classified as untreatable. Currently available gene therapy strategies are typically based on either in vivo gene delivery to terminally differentiated target cells or tissues, or ex vivo gene delivery to autologous cells followed by adoptive immunization to the patient (Kumar et al. Mol Ther Methods Clin Dev. 2016; 3: 16034). Recently, clinical gene therapy has yielded some promising results, but also some failures. Preferred methods of gene delivery utilize naked DNA provided in suitable carriers, such as synthetic particles using lipids or polymers, in terms of defined composition and reproducibility in manufacturing. However, these methods have not yet achieved efficient in vivo uptake and sustained gene expression. Thus, gene replacement therapy trials that have demonstrated some clinical benefit have relied on viral vectors for gene delivery. Among the various viral vector systems, adeno-associated virus (AAV) DNA vectors are the most commonly used for in vivo gene delivery. The use of retroviral vectors (derived from gamma-retroviruses or lentiviruses) that can be incorporated into the genome of target cells is somewhat hindered by safety and ethical issues. Concerns regarding retroviral gene therapy are based on the potential for the generation of replicable retroviruses during vector production, recruitment of the vector by endogenous retroviruses in the genome, insertional mutations leading to cancer, germline changes, and the potential for the dissemination of novel viruses from gene therapy patients.AAV vectors generally do not integrate into the patient's genome and thus avoid many of these potential risks, but remaining concerns stem from site-directed integration events that are occasionally observed, vector efflux from treated patients, and potential adverse effects caused by immune responses to viral structural proteins.

[0002] Immunotherapy is a second and significant application area for therapeutic nucleic acids. In particular, DNA vaccines encoding tumor antigens are being evaluated for cancer immunotherapy. In principle, it seems preferable to utilize the patient's own adaptive immunity to fight cancer cells. DNA-based vaccines, which are based on non-viral DNA vectors, are generally easy to manipulate and can be rapidly mass-produced. These DNA vectors are stable and can be easily stored and transported. Unlike attenuated live bacterial vaccines and viral vaccines, there is no risk of pathogenic infection or induction of an antiviral immune response. Naked DNA does not readily spread from cell to cell in vivo. APCs do not readily take up expressed antigens and activate a satisfactory immune response (Yang et al. Hum Vaccin Immunother, 2014 Nov; 10(11): 3153-3164). On the other hand, limited uptake by transfection cells and consequently limited antigen transcription are major drawbacks of non-viral DNA-based vaccines. Indeed, antitumor vaccines using DNA-coding tumor antigens have achieved some success in immunoprotective experiments, and several types of anti-cancer vaccines have been designed, manufactured, and preclinically tested. However, the effects in inducing a measurable immune response and extending overall patient survival have been minimal in clinical trials.

[0003] Electroporation or viral delivery methods address this challenge, but new problems arise. In the case of electroporation, its clinical use has been limited due to the difficulty in obtaining clinically approved devices and patient consent. In the case of viral delivery, the above problem mainly relates to the potential risks associated with administering live virus while antiviral neutralizing antibodies are present in the patient (Lollini et al. Vaccines, Jun; 3(2): 467-489, 2015).

[0004] Nucleic acid-based vaccines and gene therapy technologies have come a long way since their development began. Unfortunately, in human subjects, only limited clinical outcomes have been obtained due to insufficient intake and transcription, resulting in inadequate expression of genes and antigens. For the practical application of therapeutic DNA, insufficient delivery of therapeutic proteins (in the case of gene therapy) or immunogenicity (in the case of immunotherapy) remains the biggest challenge. Li and Petrovsky Expert Rev Vaccines, 2016; 15(3): 313-329. RNA-based therapies overcome many of the shortcomings of therapeutic DNA, but there is still room for improvement regarding the expression efficiency currently observed for available therapeutic RNAs. Therefore, there is an urgent need for effective measures to help enhance the efficacy of therapeutic nucleic acids. Meeting the above requirements is the objective of this invention.

[0005] The present invention is described in detail below, but it should be understood that the present invention is not limited to the specific methodologies, protocols, and reagents described herein, and that these may change. It should also be understood that the terms used herein are not intended to limit the scope of the present invention, which is limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0006] The components of the present invention are described below. While these components are listed in conjunction with specific embodiments, it should be understood that they can be combined in any way and in any number to create additional embodiments. The various examples and preferred embodiments should not be construed as limiting the invention to only the embodiments explicitly described. This description should be understood as supporting and encompassing embodiments that combine the explicitly described embodiments with any number of disclosed and / or preferred components. Furthermore, any rearrangement and combination of all components described herein should be considered disclosed by this description unless otherwise indicated by the context.

[0007] Throughout this specification and the subsequent claims, unless the context requires otherwise, variations of the terms “comprise,” “comprises,” and “comprising” mean to include the described components, integers, or processes, but not to exclude other undescribed components, integers, or processes. The term “consist of” is a specific embodiment of the term “comprise” and excludes other undescribed components, integers, or processes. With respect to the present invention, the term “comprise” encompasses the term “consist of.” Therefore, the term “comprising” encompasses, for example, “including” and “consisting,” and the “comprising” composition X may consist of X alone or may include some additional elements, e.g., X + Y.

[0008] The terms “a,” “an,” and “the,” and similar references used in the context describing the present invention (particularly in the context of the claims), should be construed to encompass both singular and plural unless otherwise specifically indicated herein or unless the context clearly contradicts this. The descriptions of value ranges herein are intended merely as a concise way of individually referring to each distinct value that falls within that range. Unless otherwise specifically indicated herein, each individual value is incorporated herein as if it were individually described herein. Nothing in the specification should be construed to indicate that any component not described in the claims is essential to the practice of the present invention.

[0009] The term "substantially" does not exclude, for example, the word "completely," and a composition that "substantially does not contain" Y may also mean that it does not contain Y at all. In some cases, the term "substantially" may be omitted from the definition of this invention.

[0010] The term "approximately" for a numerical value x means x ± 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%.

[0011] In this invention, unless otherwise specified, alternative forms and different features of embodiments can be combined with each other.

[0012] For clarity and readability, the following definitions are given. All technical features relating to these definitions are described in each embodiment of the present invention. Further definitions and descriptions may also be specifically described in relation to these embodiments.

[0013] [Definition] [Artificial nucleic acid molecule] Artificial nucleic acid molecules can typically be understood as nucleic acid molecules that do not exist naturally, such as DNA or RNA. In other words, artificial nucleic acid molecules may be understood as non-natural nucleic acid molecules. Such nucleic acid molecules can be non-natural due to their individual sequences (sequences that do not exist naturally) and / or due to other modifications of nucleotides that do not exist naturally, such as structural modifications. Artificial nucleic acid molecules can be DNA molecules, RNA molecules, or hybrid molecules containing DNA and RNA portions. Typically, artificial nucleic acid molecules can be designed and / or produced by genetic engineering methods to correspond to a desired artificial sequence (heterogeneous sequence) of nucleotides. In this regard, the artificial sequence is usually a sequence that does not occur naturally, i.e., at least one nucleotide differs from the wild-type sequence. The term “wild-type” can be understood as a sequence that exists naturally. Furthermore, the term “artificial nucleic acid molecule” is not limited to meaning “single molecule” and is typically understood to include a collection of identical molecules. Thus, the term “artificial nucleic acid molecule” can refer to multiple identical molecules contained in an aliquot.

[0014] [DNA] DNA is a conventional abbreviation for deoxyribonucleic acid. DNA is a nucleic acid molecule, that is, a polymer made up of nucleotides. These nucleotides are typically deoxy-adenosine-monophosphate, deoxy-thymidine-monophosphate, deoxy-guanosine-monophosphate, and deoxy-cytidine-monophosphate monomers, which themselves consist of a sugar moiety (deoxyribose), a base moiety, and a phosphate moiety, and are polymerized by a characteristic backbone structure. The backbone structure is typically formed by a phosphate diester bond between the sugar moiety of the first nucleotide, i.e., deoxyribose, and the adjacent monomer, the second phosphate moiety. The specific order of monomers (i.e., the order of bases attached to the sugar / phosphate backbone) is called the DNA sequence. DNA can be single-stranded or double-stranded. In the double-stranded form, typically, the nucleotides of the first strand hybridize with the nucleotides of the second strand, for example, by A / T base pairing and G / C base pairing.

[0015] [Heterogeneous arrangement] Two sequences are typically understood as "heterogeneous" if they cannot be derived from the same gene. In other words, heterogeneous sequences can originate from the same organism, but they do not exist in nature in the same nucleic acid molecule, such as the same mRNA.

[0016] [Cloning site] A cloning site is typically understood to be a segment of a nucleic acid molecule suitable for insertion of a nucleic acid sequence, such as an open reading frame. Insertion can be carried out by any molecular biological method known to those skilled in the art, such as restriction and ligation. A cloning site typically contains one or more restriction enzyme recognition sites (restriction sites). These one or more restriction sites can be recognized by restriction enzymes that cleave DNA at these sites. A cloning site containing two or more restriction sites may also be called a multicloning site (MCS) or polylinker.

[0017] [Nucleic acid molecule] A nucleic acid molecule is a molecule containing, preferably consisting of, nucleic acid components. The term nucleic acid molecule preferably refers to a DNA or RNA molecule. This term is preferably used as a synonym for the term "polynucleotide." Preferably, a nucleic acid molecule is a polymer containing nucleotide monomers covalently bonded to each other by phosphodiester bonds of a sugar / phosphate backbone. The term "nucleic acid molecule" also includes modified nucleic acid molecules such as DNA or RNA molecules, including base modifications, sugar modifications, or backbone modifications.

[0018] [Open Reading Frame] In relation to the present invention, an open reading frame (ORF) is typically a sequence of several nucleotide triplets that can be translated into a peptide or protein. The open reading frame preferably includes, at its 5' end, a start codon, i.e., a combination of three nucleotides that typically encodes the amino acid methionine (ATG), followed by a region, the region typically having a length that is a multiple of three nucleotides. The ORF is preferably terminated by a stop codon (e.g., TAA, TAG, TGA). Typically, this is the only stop codon in the open reading frame. Therefore, in relation to the present invention, an open reading frame is a nucleotide sequence consisting of a number of nucleotides divisible by three, preferably beginning with a start codon (e.g., ATG) and preferably ending with a stop codon (e.g., TAA, TGA, or TAG). The open reading frame may be isolated or incorporated into a longer nucleic acid sequence, e.g., a vector or mRNA. The open reading frame may also be referred to as a "(protein) coding sequence" or preferably a "coding sequence."

[0019] [peptide] A peptide, or polypeptide, is typically a polymer of amino acid monomers linked by peptide bonds. It typically contains fewer than 50 monomer units. However, the term peptide does not exclude molecules with more than 50 monomer units. Longer peptides are also called "polypeptides." Polypeptides typically have between 50 and 600 monomer units.

[0020] [protein] Proteins typically consist of one or more peptides or polypeptides. Proteins are typically folded into the three-dimensional form necessary for them to perform their biological function.

[0021] [Restricted area] A restriction site, also called a restriction enzyme recognition site, is a nucleotide sequence recognized by a restriction enzyme. Restriction sites are typically short, preferably palindromic, nucleotide sequences, for example, sequences containing 4 to 8 nucleotides. Restriction sites are preferably specifically recognized by restriction enzymes. Restriction enzymes typically cleave the nucleotide sequence containing the restriction site at this site. In double-stranded nucleotide sequences, such as double-stranded DNA sequences, restriction enzymes typically cleave both strands of the nucleotide sequence.

[0022] [RNA, mRNA] RNA is a conventional abbreviation for ribonucleic acid. RNA is a nucleic acid molecule; that is, a polymer made up of nucleotides. These nucleotides are typically adenosine monophosphate monomer, uridine monophosphate monomer, guanosine monophosphate monomer, and cytidine monophosphate monomer, and are linked together along a so-called backbone. The backbone is formed by phosphate diester bonds between the sugar (i.e., ribose) of the first monomer and the phosphate group of the adjacent second monomer. The specific sequence of monomers is called an RNA sequence. RNA can usually be obtained by the transcription of a DNA sequence (for example, within a cell). In eukaryotic cells, transcription usually takes place in the nucleus or mitochondria. In vivo, when DNA is transcribed, it usually becomes so-called immature RNA. Immature RNA must be processed into so-called messenger RNA (usually abbreviated as mRNA). The processing of immature RNA (e.g., in eukaryotes) involves various different post-transcriptional modifications (e.g., splicing, 5' capping, polyadenylation, transport out of the nucleus or mitochondria, etc.). All of these processes are also called RNA maturation. Mature messenger RNA typically provides a nucleotide sequence that can be translated into the amino acid sequence of a specific peptide or protein. Mature mRNA usually contains a 5' cap, 5'-UTR, open reading frame, 3'-UTR, and poly(A) sequence. In addition to messenger RNA, there are also several non-coding RNAs. Non-coding RNAs can be involved in the regulation of transcription and / or translation.

[0023] [Sequence of nucleic acid molecules] The sequence of a nucleic acid molecule is typically understood as a specific and individual order, that is, a sequence of its nucleotides. The sequence of a protein or peptide is typically understood as a sequence of its amino acids.

[0024] [Sequence identity] Two or more sequences are identical if they exhibit the same length and order of nucleotides or amino acids. The percentage of identity typically represents the degree to which two sequences are identical, that is, typically, the percentage of nucleotides corresponding to identical nucleotides in a reference sequence at their respective sequence positions. Sequences compared for determining the degree of identity ("identity %") are typically considered to represent the same length, i.e., the length of the longest sequence of the sequences being compared. This means that a first sequence consisting of eight nucleotides is 80% identical to a second sequence consisting of ten nucleotides containing the first sequence. In other words, with respect to the present invention, sequence identity is preferably related to the percentage of nucleotides or amino acids in two or more sequences of the same length that have the same positions. Specifically, the "identity %" of two amino acid sequences or two nucleic acid sequences can be determined by aligning the sequences for optimal comparison (for example, gaps may be inserted in one of the sequences for best alignment with the other sequence) and comparing the amino acids or nucleotides at the corresponding positions. Gaps are usually considered non-identical positions, regardless of their actual positions in the alignment. The "best alignment" is typically the alignment of two sequences that yields the highest percentage of identity. The percentage of identity is determined by the number of identical nucleotides in the sequences being compared (i.e., identity % = number of identical positions / total number of positions × 100). The determination of the percentage of identity between two sequences can be performed using mathematical algorithms known to those skilled in the art.

[0025] [Stabilized nucleic acid molecule] A stabilized nucleic acid molecule is a nucleic acid molecule (preferably a DNA or RNA molecule) that has been modified to be more stable against disintegration or degradation than an unmodified nucleic acid molecule, for example, by environmental factors or enzymatic digestion (such as by exonuclease or endonuclease degradation). Preferably, with respect to the present invention, the stabilized nucleic acid molecule is stabilized in cells such as prokaryotic or eukaryotic cells, preferably in mammalian cells such as human cells. The stabilizing effect may also extend to extracellular environments, such as buffers, in the manufacturing process of a pharmaceutical composition containing the stabilized nucleic acid molecule.

[0026] [Transfection] The term "transfection" refers to the introduction of nucleic acid molecules, such as DNA or RNA (e.g., mRNA) molecules, into cells, preferably eukaryotic cells. With respect to the present invention, the term "transfection" encompasses all methods known to those skilled in the art for introducing nucleic acid molecules into cells, preferably eukaryotic cells (such as mammalian cells). Such methods include, for example, electroporation, lipofection (e.g., lipofection based on cationic lipids and / or liposomes), calcium phosphate precipitation, nanoparticle-based transfection, virus-based transfection, or cationic polymer-based transfection (e.g., DEAE-dextran or polyethyleneimine). Preferably, the introduction is carried out nonvirally.

[0027] [vector] The term "vector" refers to a nucleic acid molecule, preferably an artificial nucleic acid molecule. In relation to the present invention, a vector is suitable for incorporating or housing a desired nucleic acid sequence (e.g., a nucleic acid sequence including an open reading frame). Examples of such vectors include memory vectors, expression vectors, cloning vectors, and transfer vectors. A memory vector is a vector that enables the convenient storage of a nucleic acid molecule, such as an mRNA molecule. Therefore, a vector may contain, for example, a sequence corresponding to a desired mRNA sequence or a portion thereof (e.g., the coding sequence of the mRNA and the sequence corresponding to the 3'-UTR). An expression vector may be used for the production of expression products such as RNA, e.g., mRNA, or peptides, polypeptides, or proteins. For example, an expression vector may contain sequences necessary for the transcription of the vector's sequence extension (promoter sequence, e.g., an RNA polymerase promoter sequence). A cloning vector is typically a vector containing a cloning site, which can be used to incorporate a nucleic acid sequence into the vector. A cloning vector may be, for example, a plasmid vector or a bacteriophage vector. An import vector may be a vector suitable for importing nucleic acid molecules into cells or organisms, such as viral vectors. In relation to the present invention, the vector may be, for example, an RNA vector or a DNA vector. Preferably, the vector is a DNA molecule. Preferably, the vector in the sense of the present application includes a cloning site, a selection marker such as an antibiotic resistance factor, and a sequence suitable for vector proliferation, such as an origin of replication.

[0028] [Vehicle] A vehicle is typically understood to be a material suitable for storing, transporting, and / or administering compounds (such as pharmaceutically active compounds). For example, a vehicle may be a physiologically acceptable liquid suitable for storing, transporting, and / or administering pharmaceutically active compounds.

[0029] Precise control of gene expression is essential for rapid adaptation to environmental stimuli that alter the physiological state of cells, such as cellular stress and infection. Gene expression programs are subject to constant regulation and are tightly controlled by multilayer regulators acting in both cis and trans directions. For such precise control, cellular mechanisms have evolved regulators at several stages, from transcription to translational fine-tuning of gene expression. These include structural and chemical modifications of chromosomal DNA, transcriptional regulation, post-transcriptional regulation of messenger RNA (mRNA), various translational efficiencies, and protein turnover. These mechanisms work together to determine the spatiotemporal control of genes. Messenger RNA consists of a protein-coding region and 5' and 3'-UTRs (UTRs). The 3'-UTR is variable in sequence and size and spans between the stop codon and the poly(A) tail. Importantly, the 3'-UTR sequence possesses several regulatory motifs that determine mRNA turnover, stability, and localization, and therefore governs many aspects of post-transcriptional gene regulation (Schwerk and Savan, J Immunol, 2015 Oct 1; 195(7): 2963-2971). In gene therapy and immunotherapy applications, precise regulation of transgene expression is paramount to therapeutic safety and efficacy. Transgenes need to be expressed at the appropriate locations and at optimal thresholds. However, the ability to control the level of transgene expression to provide a balance between therapeutic efficacy and nonspecific toxicity remains a major challenge in current gene therapy and immunotherapy applications. Surprisingly, we have discovered that specific combinations of 5' and 3'-untranslated regions (UTRs) work together to synergistically enhance the expression of manipulably linked nucleic acid sequences. The artificial nucleic acid molecules having the UTR combination of the present invention have the effect of enabling the rapid and transient expression of large amounts of (poly)peptides or proteins delivered for the purpose of gene therapy or immunotherapy.Furthermore, the novel nucleic acid-based therapeutic agents described herein offer additional advantages over currently available therapeutic options, preferably including reduced risk of insertion mutations and greater nonviral delivery and ingestion. Therefore, the artificial nucleic acids described herein are particularly useful for a variety of in vivo therapeutic applications, including, for example, gene therapy, cancer immunotherapy, or vaccination against infected organisms.

[0030] Accordingly, in a first embodiment, the present invention relates to an artificial nucleic acid molecule comprising: at least one 5'-UTR factor derived from the 5' untranslated region (5'-UTR) of a gene selected from the group consisting of HSD17B4, ASAH1, ATP5A1, MP68, NDUFA4, NOSIP, RPL31, SLC7A3, TUBB4B, and UBQLN2; at least one 3'-UTR factor derived from the 3' untranslated region (3'-UTR) of a gene selected from the group consisting of PSMB3, CASP1, COX6B1, GNAS, NDUFA1, and RPS9; and optionally, at least one coding region operably linked to the 3'-UTR and the 5'-UTR.

[0031] The term “UTR” refers to the “untranslated region” located upstream (5') and / or downstream (3') of the coding region of a nucleic acid molecule described herein, and is typically the region adjacent to that coding region. Therefore, the term “UTR” generally encompasses the 3' untranslated region (“3'-UTR”) and the 5' untranslated region (“5'-UTR”). A UTR typically contains or may consist of a nucleic acid sequence that is not translated into a protein. Typically, a UTR contains a “regulatory factor.” The term “regulatory factor” refers to a nucleic acid sequence that can influence gene regulatory activity, i.e., the expression (particularly transcription or translation) of a manipulatively (cis or trans) bound transcriptable nucleic acid sequence. The term includes promoters, enhancers, internal ribosome entry sites (IRES), introns, leaders, transcription termination signals (such as polyadenylation signals), and poly-U sequences, as well as other expression regulators. Regulatory factors may act constitutively or in a time- and / or cell-specific manner. Optionally, regulators may exert their function through interactions (e.g., supplementation and binding) with regulatory proteins that can regulate (induce, enhance, repress, eliminate, or prevent) gene expression, particularly transcription.

[0032] The UTR is preferably “operably ligated” to the coding region, that is, positioned in a functional relationship with the coding region. Preferably, it is ligated in a manner that allows control (i.e., modulation, regulation, preferably enhancement) of the expression of the coding sequence. Preferably, the “UTR” includes or consists of a nucleic acid sequence derived from the (naturally occurring, wild-type) UTR of a gene, preferably one as illustrated herein. As used herein, the term “UTR factor” typically refers to a nucleic acid sequence corresponding to a shorter subsequence of the UTR of a parental gene ("parental" UTR). In this regard, the term “corresponding” means that the UTR factor may include or consist of an RNA sequence transcribed from the gene from which the “parental” UTR is derived (i.e., equal to the RNA sequence used to define the “parental” UTR), or the respective DNA sequences corresponding to the above RNA sequence (including sense and antisense strands, mature and immature strands), or a combination thereof.

[0033] When we say a UTR factor "derived" from the UTR of a particular gene, that UTR factor may be derived from any naturally occurring homolog, variant, or fragment of the gene in question. In other words, when we say a UTR factor "derived" from the HSD17B4 gene, each UTR factor may consist of a nucleic acid sequence corresponding to a shorter subsequence of the UTR of the "parent" HSD17B4 gene, or any HSD17B4 homolog, variant, or fragment (in particular, an HSD17B4 homolog, variant, or fragment having a variant in the UTR region compared to the "parent" HSD17B4 gene).

[0034] Throughout this specification, the term “derived” as used with respect to artificial nucleic acids also means that an artificial nucleic acid “derived” from another artificial nucleic acid also shares, for example, at least 60%, 70%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the nucleic acid from which it originates. Those skilled in the art will know that sequence identity is typically calculated for nucleic acids of the same type, i.e., for DNA or RNA sequences of the same type. Therefore, when DNA is “derived from RNA” or RNA is “derived from DNA,” it is understood that in the first step, the RNA sequence is converted to the corresponding DNA sequence (in particular by replacing uracil (U) with thymidine (T) throughout the sequence), or vice versa, the DNA sequence is converted to the corresponding RNA sequence (in particular by replacing T with U throughout the sequence). Subsequently, the sequence identity of the DNA sequence or the sequence identity of the RNA sequence is determined. Preferably, nucleic acids “derived” from nucleic acids also refer to nucleic acids that have been modified compared to the nucleic acid from which they originate, for example, to further increase RNA stability and / or to extend and / or increase protein production. With respect to an amino acid sequence (e.g., an antigenic peptide or protein), the term “derived” means that an amino acid sequence derived from another amino acid sequence shares, for example, at least 60%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence from which it originates.

[0035] With respect to a gene (or nucleic acid sequences derived from or contained in that gene, such as UTRs), the term "homolog" refers to a gene (or nucleic acid sequence derived from or contained in that gene) that is related to a second gene (or such nucleic acid sequence) by descendants from a common ancestral DNA sequence. The term "homolog" includes genes separated by speciation events ("orthologs") and genes separated by genetic duplication events ("paralogs").

[0036] With respect to the nucleic acid sequence of a gene, the term “variant” refers to a nucleic acid sequence variant, that is, a nucleic acid sequence or gene in which at least one nucleic acid in the reference (or “parent”) nucleic acid or the reference (or “parent”) nucleic acid sequence of the gene has a different nucleic acid sequence. Therefore, it is preferable that a variant nucleic acid or gene has at least one mutation, substitution, insertion or deletion in its nucleic acid sequence compared to its respective reference sequence. Preferably, as used herein, the term “variant” includes naturally occurring variants and engineered variants of nucleic acid sequences or genes. Therefore, “variant” as defined herein may be derived from, isolated from, related to, based on, or homologous to a reference nucleic acid sequence. The "variant" may preferably have sequence identity of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95%, or even further 97% with respect to the respective natural (wild-type) nucleic acid sequence or gene, or its homologue, fragment, or derivative nucleic acid sequence.

[0037] Furthermore, the term “variant” as used herein with respect to proteins or peptides is intended to be recognized and understood by those skilled in the art and to refer to a variant of a protein or peptide having an amino acid sequence that differs from the original sequence in one or more mutations (such as one or more substitutions, insertions, and / or deletions of amino acids). These fragments and / or variants are preferably possessing the same biological function or specific activity (e.g., specific antigenic properties) as the natural full-length protein. “Variants” of proteins or peptides as defined herein may include conserved amino acid substitutions compared to the natural (i.e., physiologically unmutated) sequence. In particular, these amino acid sequences (and the nucleotide sequences encoding them) fall under the term “variant” as defined herein. A substitution in which amino acids of the same class are exchanged is called a conserved substitution. The above amino acids are, in particular, amino acids having aliphatic side chains, amino acids having positively or negatively charged side chains, amino acids having aromatic side chains, or amino acids whose side chains can form hydrogen bonds (e.g., amino acids having hydroxyl function side chains). This means that (1) for example, an amino acid having a polar side chain may be substituted by another amino acid having a similarly polar side chain, or (2) for example, an amino acid characterized by a hydrophobic side chain may be substituted by another amino acid having a similarly hydrophobic side chain (e.g., serine by threonine (threonine by serine), or leucine by isoleucine (isoleucine by leucine)). Insertions and substitutions may occur, in particular, at positions in the sequence that do not affect the three-dimensional structure or at positions in the sequence that do not affect the binding site. Changes in the three-dimensional structure due to insertions or deletions can be easily determined, for example, using CD spectroscopy (circular dichroism spectroscopy).A "variant" of a protein or peptide may have at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% amino acid identity with respect to at least 10, 20, 30, 50, 75, or 100 amino acid lengths of the protein or peptide. Preferably, the protein variant encompasses a functional variant of the protein. This means that the variant exhibits the same effects or functionality as the protein from which it originates, or at least 40%, 50%, 60%, 70%, 80%, 90%, or 95% of the effects or functionality.

[0038] With respect to nucleic acid sequences or genes, the term “fragment” refers to a contiguous partial sequence of a full-length reference (or “parent”) nucleic acid sequence or gene. In other words, a “fragment” can typically be a shorter portion of a full-length nucleic acid sequence or gene. Thus, a fragment typically consists of a sequence that is identical to the corresponding contiguous sequence within a full-length nucleic acid sequence or gene. The term includes naturally occurring fragments as well as manipulated fragments. With respect to the present invention, a preferred fragment of a sequence consists of a contiguous sequence of nucleic acid corresponding to the contiguous sequence of entities within the nucleic acid or gene from which the fragment originates, representing at least 20%, preferably at least 30%, more preferably at least 40%, more preferably at least 50%, even more preferably at least 60%, even more preferably at least 70%, and most preferably at least 80% of the entire (i.e., full-length) nucleic acid sequence or gene from which the fragment originates. The sequence identity expressed with respect to such a fragment preferably refers to the entire nucleic acid sequence or gene. The "fragment" may preferably contain a nucleic acid sequence having sequence identity of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95%, or even further 97% with respect to the reference nucleic acid sequence or gene from which it is derived.

[0039] UTR factors are preferably “functional,” meaning they can elicit the same desired biological effect as the parent UTR from which they originate, i.e., they can modulate, control, or regulate (induce, enhance, suppress, eliminate, or prevent, preferably induce or enhance) the expression of a operably linked coding sequence. As used herein, “expression” generally includes all steps of protein biosynthesis, particularly transcription, mRNA processing, and translation. UTR factors, particularly 3'-UTR factors and 5'-UTR factors in combinations specified herein, can, for example, modulate the polyadenylation, translation initiation, translation efficiency, localization, and / or stability of nucleic acids containing the UTR factors (typically through the action of regulatory regions contained in the UTR factors).

[0040] The artificial nucleic acid molecule of the present invention advantageously comprises at least one 5'-UTR factor and at least one 3'-UTR factor, each derived from a gene selected from the group described herein. Preferred 5'-UTR factors are preferably selected from 5'-UTR factors derived from the 5'-UTR of a gene selected from the group consisting of HSD17B4, ASAH1, ATP5A1, MP68, NDUFA4, NOSIP, RPL31, SLC7A3, TUBB4B, and UBQLN2, and are preferably 5'-UTR factors defined herein. Preferred 3'-UTR factors are preferably selected from 3'-UTR factors derived from the 3'-UTR of a gene selected from the group consisting of PSMB3, CASP1, COX6B1, GNAS, NDUFA1, and RPS9, and are preferably 3'-UTR factors defined herein. Furthermore, the artificial nucleic acid molecule of the present invention may optionally include at least one coding region operably linked to the 3'-UTR factor and the 5'-UTR factor. Therefore, preferably, the artificial nucleic acid molecule of the present invention may include a 5'-UTR factor as defined herein operably linked in the 5'→3' direction to a coding region (cds) encoding a target (poly)peptide or protein, and a 3'-UTR factor operably linked to the coding region (5'-UTR-cds-3'-UTR).

[0041] Typically, the 5'- and / or 3'-UTR factors of the artificial nucleic acid molecules of the present invention may be “heterogeneous” with respect to at least one coding sequence. As used herein, the term “heterogeneous” typically refers to a nucleic acid sequence derived from a different species than the reference nucleic acid sequence. Thus, a “heterogeneous sequence” is derived from a gene of a different origin compared to the reference sequence, and typically its nucleic acid sequence differs from the reference sequence and / or may encode a different gene product.

[0042] [UTR] <5'-UTR> The artificial nucleic acids described herein include at least one 5'-UTR factor derived from the 5'-UTR of a gene shown herein, or its homolog, variant, fragment, or derivative thereof.

[0043] The term "5'-UTR" refers to a portion of a nucleic acid molecule located at the 5' (i.e., "upstream") of the open reading frame that is not translated into a protein. In the context of this invention, the 5'-UTR begins at the transcription start site and ends at the nucleotide immediately preceding the start codon of the open reading frame. The 5'-UTR may contain factors (also called regulators) for regulating gene expression. Such regulators may, for example, be ribosome binding sites. The 5'-UTR may undergo post-transcriptional modifications (e.g., modification by adding a 5' cap). Therefore, the 5'-UTR may correspond to a nucleic acid located between the 5' cap and the start codon, particularly a sequence of mature mRNA, and more specifically, an extended sequence starting from a nucleotide located on the 3' side of the 5' cap (preferably from a nucleotide adjacent to the 3' of the 5' cap) to a nucleotide located on the 5' side of the start codon of the protein-coding sequence (transcription start site) (preferably to a nucleotide adjacent to the 5' of the start codon of the protein-coding sequence (transcription start site)). The nucleotides adjacent to the 3' end of the 5' cap of mature mRNA typically correspond to the transcription start site. The 5'-UTR typically has a length of 500, 400, 300, 250, or less than 200 nucleotides. In some embodiments, its length can range from at least 10, 20, 30, or 40 nucleotides, and preferably up to 100 or 150 nucleotides.

[0044] Preferably, at least one 5'-UTR factor comprises or consists of a nucleic acid sequence derived from the 5'-UTR of a chordate gene, preferably a vertebrate gene, more preferably a mammalian gene, most preferably a human gene, or a nucleic acid sequence derived from a variant of the 3'-UTR of a chordate gene, preferably a vertebrate gene, more preferably a mammalian gene, most preferably a human gene.

[0045] Some of the 5'-UTR factors identified herein may originate from the 5'-UTR of TOP genes, or from their homologs, variants, or fragments. “TOP genes” are typically characterized by the presence of a 5'-terminal oligopyrimidine sequence (TOP), and further typically by growth-related translational regulation. However, TOP genes with tissue-specific translational regulation are also known. mRNA containing a 5'-TOP is usually referred to as TOP mRNA. Therefore, genes that produce such messenger RNA are referred to as TOP genes. TOP sequences have been found, for example, in genes and mRNA encoding peptide elongation factors and ribosomal proteins. A 5'-terminal oligopyrimidine sequence (“5'TOP” or “TOP”) is typically a sequence of pyrimidine nucleotides located in the 5'-terminal region of a nucleic acid molecule. The 5'-terminal region of the nucleic acid molecule may be the 5'-terminal region of a particular mRNA molecule, or the 5'-terminal region of a functional unit (e.g., the transcription region of a particular gene). The 5'-UTR of the TOP gene corresponds to the 5'-UTR sequence of the mature mRNA derived from the TOP gene (preferably extending from the nucleotide located on the 3' side of the 5' cap to the nucleotide located on the 5' side of the start codon). The TOP sequence typically begins with a cytidine (usually corresponding to the transcription start site) followed by a sequence of approximately 3 to 30 pyrimidine nucleotides. The pyrimidine sequence (and therefore the 5'TOP) terminates one nucleotide 5' from the first purine nucleotide located downstream of the TOP.

[0046] The 5'-UTR of a TOP gene typically does not contain a start codon at all (preferably, it does not contain an upstream AUG (uAUG) or an upstream open reading frame (uORF)). Here, the upstream AUG and upstream open reading frame are understood to be the AUG and open reading frame that are typically located on the 5' side of the start codon (AUG) of the open reading frame to be translated. Generally, the 5'-UTR of a TOP gene is relatively short. The length of the 5'-UTR of a TOP gene can vary between 20 and 500 nucleotides. The above length is typically less than about 200 nucleotides, preferably less than about 150 nucleotides, and more preferably less than about 100 nucleotides. TOP may contain, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more nucleotides. As used herein, the term “TOP motif” refers to the nucleic acid sequence corresponding to the 5'TOP as defined above. Therefore, the “TOP motif” is preferably a continuous sequence of pyrimidine nucleotides with a length of 3 to 30 nucleotides. The TOP motif is preferably composed of at least 3 pyrimidine nucleotides, preferably at least 4 pyrimidine nucleotides, more preferably at least 6 pyrimidine nucleotides, more preferably at least 7 nucleotides, and most preferably at least 8 pyrimidine nucleotides. In this case, the continuous sequence of pyrimidine nucleotides preferably begins with a cytosine nucleotide at its 5' end. In the TOP gene and TOP mRNA, the “TOP motif” preferably begins with a transcription start site at its 5' end. Furthermore, the "TOP motif" preferably terminates one nucleotide 5' from the first purine nucleotide residue in the gene or mRNA. The "TOP motif" is preferably located at the 5' end of a sequence representing the 5'-UTR, or at the 5' end of a sequence encoding the 5'-UTR.Therefore, when a continuous sequence of three or more pyrimidine nucleotides is located at the 5'-end of each sequence (such as an artificial nucleic acid molecule, a 5'-UTR factor of an artificial nucleic acid molecule, or a nucleic acid sequence derived from the 5'-UTR of the TOP gene described herein), it is preferable to refer to such a continuous sequence as a "TOP motif". In other words, a continuous sequence of three or more pyrimidine nucleotides that is not located at the 5'-end of a 5'-UTR or 5'-UTR factor and is located somewhere within the 5'-UTR or 5'-UTR factor is preferably not referred to as a "TOP motif".

[0047] In one embodiment, the 5'-end of the mRNA is "gggaga".

[0048] The 5'-UTR factor derived from the 5'-UTR of the TOP gene exemplified herein may preferably lack the TOP motif or 5'-TOP as defined above. Therefore, the nucleic acid sequence of the 5'-UTR factor derived from the 5'-UTR of the TOP gene may terminate at the 3'-end of the nucleic acid sequence with the nucleotide located at the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th or 10th position upstream of the start codon (such as A(U / T)G) of the gene or mRNA from which the nucleic acid sequence is derived. Therefore, the 5'-UTR factor does not contain any part of the region encoding a protein. Therefore, preferably, only the part encoding the amino acid of the artificial nucleic acid is provided by the coding sequence.

[0049] Specific 5'-UTR factors contemplated in the present invention are described in detail below.

[0050] <5'-UTR factor derived from HSD17B4> The artificial nucleic acid according to the present invention may include a 5'-UTR factor derived from the 5'-UTR of a gene encoding 17-beta-hydroxysteroid dehydrogenase 4 or a homolog, variant, fragment, or derivative thereof (preferably lacking the 5'-TOP motif).

[0051] Such 5'-UTR factors preferably contain or consist of a nucleic acid sequence derived from the 5'-UTR of the 17-beta-hydroxysteroid dehydrogenase 4 (also known as peroxisome multifunctional enzyme type 2) gene, preferably from a vertebrate, more preferably mammalian, most preferably human 17-beta-hydroxysteroid dehydrogenase 4 (HSD17B4) gene, or its homolog, variant, fragment, or derivative, where preferably the 5'-UTR factor does not contain the 5'TOP of the above gene. The above gene preferably encodes the 17-beta-hydroxysteroid dehydrogenase 4 protein, or its homolog, variant, fragment, or derivative, corresponding to human 17-beta-hydroxysteroid dehydrogenase 4 (UniProt reference number Q9BPX1, entry version number 139 of August 30, 2017).

[0052] Therefore, the artificial nucleic acid according to the present invention may contain a 5'-UTR factor derived from the HSD17B4 gene, particularly a 5'-UTR factor derived from the 5'-UTR of the above HSD17B4 gene. Preferably, the above 5'-UTR factor contains, or consists of, the DNA sequence described in SEQ ID NO: 1 or its homolog, variant, fragment, or derivative. Particularly, it has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% (the higher the better), preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95% or even 97% sequence identity with the nucleic acid sequence described in SEQ ID NO: 1, and contains, or consists of, a DNA sequence having such sequence identity. Alternatively, the above 5'-UTR factor contains, or consists of, the RNA sequence described in SEQ ID NO: 2 or its homolog, variant, fragment, or derivative. Particularly, it has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% (the higher the better), preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95% or even 97% sequence identity with the nucleic acid sequence described in SEQ ID NO: 2, and contains, or consists of, an RNA sequence having such sequence identity.

[0053] <5'-UTR factor derived from ASAH1> The artificial nucleic acid according to the present invention may contain a 5'-UTR factor derived from the 5'-UTR of a gene encoding acid ceramidase (ASAH1) or its homolog, variant, fragment, or derivative.

[0054] Such 5'-UTR factors preferably contain or consist of a nucleic acid sequence derived from the 5'-UTR of the acid ceramidase (ASAH1) gene, preferably from a vertebrate, more preferably from a mammal, most preferably from the human acid ceramidase (ASAH1) gene, or its homolog, variant, fragment, or derivative. The gene preferably encodes an acid ceramidase protein corresponding to human acid ceramidase (UniProt reference number Q13510, entry version number 177 of June 7, 2017), or its homolog, variant, fragment, or derivative.

[0055] Therefore, the artificial nucleic acid according to the present invention may contain a 5'-UTR factor derived from the ASAH1 gene, particularly from the 5'-UTR of the ASAH1 gene. Preferably, the 5'-UTR factor contains, or consists of, the DNA sequence set forth in SEQ ID NO: 3 or its homolog, variant, fragment, or derivative. In particular, the DNA sequence has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% (the higher the better), preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95% or even 97% sequence identity to the nucleic acid sequence set forth in SEQ ID NO: 3, or consists of such DNA sequences. Alternatively, the 5'-UTR factor contains, or consists of, the RNA sequence set forth in SEQ ID NO: 4 or its homolog, variant, fragment, or derivative. In particular, the RNA sequence has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% (the higher the better), preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95% or even 97% sequence identity to the nucleic acid sequence set forth in SEQ ID NO: 4, or consists of such RNA sequences.

[0056] <5'-UTR factor derived from ATP5A1> The artificial nucleic acid according to the present invention may contain a 5'-UTR factor derived from the 5'-UTR of a gene encoding mitochondrial ATP synthase subunit alpha (ATP5A1) or its homolog, variant, fragment, or derivative. Here, the 5'-UTR factor preferably lacks a 5'TOP motif.

[0057] Such 5'-UTR factors preferably contain or consist of a nucleic acid sequence derived from the 5'-UTR of the mitochondrial ATP synthase subunit alpha (ATP5A1) gene, preferably from a vertebrate, more preferably mammalian, most preferably human mitochondrial ATP synthase subunit alpha (ATP5A1) gene, or its homolog, variant, fragment, or derivative, wherein the 5'-UTR factor preferably does not contain the 5'TOP of the above gene. The above gene may preferably encode the mitochondrial ATP synthase subunit alpha protein corresponding to human acidic mitochondrial ATP synthase subunit alpha (UniProt reference number P25705, entry version number 208 of August 30, 2017), or its homolog, variant, fragment, or derivative.

[0058] Therefore, the artificial nucleic acid according to the present invention may contain a 5'-UTR factor derived from the ATP5A1 gene, particularly from the 5'-UTR of the above ATP5A1 gene. Preferably, the above 5'-UTR factor contains, or consists of, the DNA sequence set forth in SEQ ID NO: 5 or its homolog, variant, fragment, or derivative. In particular, it has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% (the higher, the more preferable), preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95% or even 97% sequence identity with the nucleic acid sequence set forth in SEQ ID NO: 5, or consists of such DNA sequences. Alternatively, the above 5'-UTR factor contains, or consists of, the RNA sequence set forth in SEQ ID NO: 6 or its homolog, variant, fragment, or derivative. In particular, it has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% (the higher, the more preferable), preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95% or even 97% sequence identity with the nucleic acid sequence set forth in SEQ ID NO: 6, or consists of such RNA sequences.

[0059] <5'-UTR factor derived from MP68> The artificial nucleic acid according to the present invention may contain a 5'-UTR factor derived from the 5'-UTR of a gene encoding MP68 or its homolog, variant, fragment, or derivative.

[0060] Such 5'-UTR factors preferably contain or consist of a nucleic acid sequence derived from the 5'-UTR of a 6.8kDa mitochondrial proteolipide (MP68) gene, preferably from a vertebrate, more preferably mammalian, and most preferably human 6.8kDa mitochondrial proteolipide (MP68) gene, or its homolog, variant, fragment, or derivative. The gene may preferably encode a 6.8kDa mitochondrial proteolipide (MP68) protein, or its homolog, variant, fragment, or derivative, corresponding to human 6.8kDa mitochondrial proteolipide (MP68) (UniProt reference number P56378, entry version number 127 of February 15, 2017).

[0061] Therefore, the artificial nucleic acid according to the present invention may contain a 5'-UTR factor derived from the MP68 gene, particularly from the 5'-UTR of the MP68 gene. Preferably, the 5'-UTR factor contains, or consists of, the DNA sequence set forth in SEQ ID NO: 7 or its homolog, variant, fragment, or derivative. In particular, it has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% (the higher the better), preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95% or even 97% sequence identity with the nucleic acid sequence set forth in SEQ ID NO: 7, and contains, or consists of, a DNA sequence having such sequence identity. Alternatively, the 5'-UTR factor contains, or consists of, the RNA sequence set forth in SEQ ID NO: 8 or its homolog, variant, fragment, or derivative. In particular, it has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 7%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% (the higher the better), preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95% or even 97% sequence identity with the nucleic acid sequence set forth in SEQ ID NO: 8, and contains, or consists of, an RNA sequence having such sequence identity.

[0062] <5'-UTR factor derived from NDUFA4> The artificial nucleic acid according to the present invention may contain a 5'-UTR factor derived from the 5'-UTR of a gene encoding cytochrome c oxidase subunit (NDUFA4) or its homolog, fragment, or variant.

[0063] Such 5'-UTR factors preferably contain or consist of a nucleic acid sequence derived from the 5'-UTR of the cytochrome c oxidase subunit (NDUFA4) gene, preferably from a vertebrate, more preferably mammalian, most preferably human cytochrome c oxidase subunit (NDUFA4) gene, or its homolog, variant, fragment, or derivative. The gene may preferably encode a cytochrome c oxidase subunit (NDUFA4) protein corresponding to the human cytochrome c oxidase subunit (NDUFA4) protein (UniProt reference number O00483, entry version number 149, August 30, 2017).

[0064] Therefore, the artificial nucleic acid according to the present invention may contain a 5'-UTR factor derived from the NDUFA4 gene, and the above 5'-UTR factor includes, or consists of, the DNA sequence described in SEQ ID NO: 9 or its homolog, variant, fragment, or derivative. In particular, it has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% (the higher, the more preferable), preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95% or even 97% sequence identity with the nucleic acid sequence described in SEQ ID NO: 9, and includes, or consists of, a DNA sequence having such sequence identity. Alternatively, the above 5'-UTR factor includes, or consists of, the RNA sequence described in SEQ ID NO: 10 or its homolog, variant, fragment, or derivative. In particular, it has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% (the higher, the more preferable), preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95% or even 97% sequence identity with the nucleic acid sequence described in SEQ ID NO: 10, and includes, or consists of, an RNA sequence having such sequence identity.

[0065] <5'-UTR factor derived from NOSIP> The artificial nucleic acid according to the present invention may contain a 5'-UTR factor derived from the 5'-UTR of a gene encoding a nitric oxide synthase interacting protein (NOSIP) or its homolog, variant, fragment, or derivative.

[0066] Such 5'-UTR factors preferably contain or consist of a nucleic acid sequence derived from the 5'-UTR of a nitric oxide synthase interacting protein (NOSIP) gene, preferably from a vertebrate, more preferably mammalian, most preferably human nitric oxide synthase interacting protein (NOSIP) gene, or its homolog, variant, fragment, or derivative. The gene may preferably encode a nitric oxide synthase interacting protein (NOSIP) protein corresponding to the human nitric oxide synthase interacting protein (NOSIP) protein (UniProt reference number Q9Y314, entry version number 130, June 7, 2017).

[0067] Therefore, the artificial nucleic acid according to the present invention may contain a 5'-UTR factor derived from the NOSIP gene, and the above 5'-UTR factor includes, or consists of, the DNA sequence described in SEQ ID NO: 11 or its homolog, variant, fragment, or derivative. In particular, it has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% (the higher, the more preferable), preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95% or even 97% sequence identity with the nucleic acid sequence described in SEQ ID NO: 11, or consists of such DNA sequences. Alternatively, the above 5'-UTR factor includes, or consists of, the RNA sequence described in SEQ ID NO: 12 or its homolog, variant, fragment, or derivative. In particular, it has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% (the higher, the more preferable), preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95% or even 97% sequence identity with the nucleic acid sequence described in SEQ ID NO: 12, or consists of such RNA sequences.

[0068] <5'-UTR factor derived from RPL31> The artificial nucleic acid according to the present invention may contain a 5'-UTR factor derived from the 5'-UTR of a gene encoding 60S ribosomal protein L31 or its homolog, variant, fragment, or derivative. Here, the above 5'-UTR factor preferably lacks the 5'TOP motif.

[0069] Such 5'-UTR factors preferably contain or consist of a nucleic acid sequence derived from the 5'-UTR of the 60S ribosomal protein L31 (RPL31) gene, preferably from a vertebrate, more preferably mammalian, most preferably human 60S ribosomal protein L31 (RPL31) gene, or its homolog, variant, fragment, or derivative thereof, wherein the 5'-UTR factor preferably does not contain the 5'TOP of the above gene. The above gene may preferably encode 60S ribosomal protein L31 (RPL31) corresponding to human 60S ribosomal protein L31 (RPL31) (UniProt reference number P62899, entry version number 138 of August 30, 2017).

[0070] Therefore, the artificial nucleic acid according to the present invention may contain a 5'-UTR factor derived from the RPL31 gene, and the 5'-UTR factor contains, or consists of, the DNA sequence set forth in SEQ ID NO: 13 or its homolog, variant, fragment, or derivative. In particular, it contains, or consists of, a DNA sequence having at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% (the higher, the more preferred), preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95% or even 97% sequence identity to the nucleic acid sequence set forth in SEQ ID NO: 13. Alternatively, the 5'-UTR factor contains, or consists of, the RNA sequence set forth in SEQ ID NO: 14 or its homolog, variant, fragment, or derivative. In particular, it contains, or consists of, an RNA sequence having at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% (the higher, the more preferred), preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95% or even 97% sequence identity to the nucleic acid sequence set forth in SEQ ID NO: 14.

[0071] <5'-UTR factor derived from SLC7A3> The artificial nucleic acid according to the present invention may contain a 5'-UTR factor derived from the 5'-UTR of a gene encoding a cationic amino acid transporter 3 (solute carrier family 7 member 3 (SLC7A3)) protein or its homolog, variant, fragment, or derivative.

[0072] Such 5'-UTR factors preferably contain or consist of a nucleic acid sequence derived from the 5'-UTR of the cationic amino acid transporter 3 (SLC7A3) gene, preferably from a vertebrate, more preferably mammalian, most preferably human cationic amino acid transporter 3 (SLC7A3) gene, or its homolog, variant, fragment, or derivative. The gene may preferably encode the cationic amino acid transporter 3 (SLC7A3) protein corresponding to the human cationic amino acid transporter 3 (SLC7A3) protein (UniProt reference number Q8WY07, entry version number 139, August 30, 2017).

[0073] Therefore, the artificial nucleic acid according to the present invention may contain a 5'-UTR factor derived from the SLC7A3 gene, and the above 5'-UTR factor includes, or consists of, the DNA sequence described in SEQ ID NO: 15 or its homolog, variant, fragment, or derivative. In particular, it has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% (the higher the better), preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95% or even 97% sequence identity with the nucleic acid sequence described in SEQ ID NO: 15, and includes, or consists of, a DNA sequence having such sequence identity. Alternatively, the above 5'-UTR factor includes, or consists of, the RNA sequence described in SEQ ID NO: 16 or its homolog, variant, fragment, or derivative. In particular, it has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% (the higher the better), preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95% or even 97% sequence identity with the nucleic acid sequence described in SEQ ID NO: 16, and includes, or consists of, an RNA sequence having such sequence identity.

[0074] <5'-UTR factor derived from TUBB4B> The artificial nucleic acid according to the present invention may contain a 5'-UTR factor derived from the 5'-UTR of a gene encoding tubulin beta-4B chain (TUBB4B) protein or its homolog, variant, fragment, or derivative.

[0075] Such 5'-UTR factors preferably contain or consist of a nucleic acid sequence derived from the 5'-UTR of the tubulin beta-4B chain (TUBB4B) gene, preferably from a vertebrate, more preferably mammalian, most preferably human tubulin beta-4B chain (TUBB4B) gene, or its homolog, variant, fragment, or derivative. The gene may preferably encode the tubulin beta-4B chain (TUBB4B) protein corresponding to the human tubulin beta-4B chain (TUBB4B) protein (UniProt reference number Q8WY07, entry version number 142, August 30, 2017).

[0076] Therefore, the artificial nucleic acid according to the present invention may include a 5'-UTR factor derived from the tubulin beta-4B chain (TUBB4B) gene, the 5'-UTR factor including or consisting of the DNA sequence described in SEQ ID NO: 17 or its homolog, variant, fragment, or derivative, and in particular including or consisting of a DNA sequence having at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with respect to the nucleic acid sequence described in SEQ ID NO: 17. Alternatively, the 5'-UTR factor may include or consist of the RNA sequence described in SEQ ID NO: 18 or its homolog, variant, fragment, or derivative thereof, and in particular, may include or consist of an RNA sequence having at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with respect to the nucleic acid sequence described in SEQ ID NO: 18.

[0077] [UBQLN2-derived 5'-UTR factor] The artificial nucleic acid according to the present invention may include a 5'-UTR factor derived from the 5'-UTR of a gene encoding the ubiquilin-2 (UBQLN2) protein or its homolog, variant, fragment, or derivative.

[0078] Such 5'-UTR factors preferably contain or consist of a nucleic acid sequence derived from the 5'-UTR of the ubiquilin-2 (UBQLN2) gene, preferably from a vertebrate, more preferably mammalian, most preferably human ubiquilin-2 (UBQLN2) gene, or its homolog, variant, fragment, or derivative. The gene may preferably encode the ubiquilin-2 (UBQLN2) protein corresponding to the human ubiquilin-2 (UBQLN2) protein (UniProt reference number Q9UHD9, entry version number 151, August 30, 2017).

[0079] Therefore, the artificial nucleic acid according to the present invention may include a 5'-UTR factor derived from the ubiquilin-2 (UBQLN2) gene, the 5'-UTR factor including or consisting of the DNA sequence described in SEQ ID NO: 19 or its homolog, variant, fragment, or derivative, and in particular including or consisting of a DNA sequence having at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with respect to the nucleic acid sequence described in SEQ ID NO: 19. Alternatively, the 5'-UTR factor may include or consist of the RNA sequence described in SEQ ID NO: 20 or its homolog, variant, fragment, or derivative thereof, and in particular, it may include or consist of an RNA sequence having at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with respect to the nucleic acid sequence described in SEQ ID NO: 20.

[0080] <3'-UTR> The artificial nucleic acid described in this specification further comprises at least one 3'-UTR factor derived from the 3'-UTR of the gene defined in this specification, or a homolog, variant, or fragment of the above gene. The term "3'-UTR" refers to a part of a nucleic acid molecule that is located at the 3' (i.e., "downstream") of an open reading frame and is not translated into a protein. With respect to the present invention, the 3'-UTR corresponds to the sequence located between the stop codon of the protein-coding sequence (preferably, immediately adjacent to the 3' side of the stop codon of the protein-coding sequence) and the poly(A) sequence of the artificial nucleic acid (RNA) molecule.

[0081] Preferably, at least one 3'-UTR factor comprises a nucleic acid sequence derived from the 3'-UTR of a chordate gene, preferably a vertebrate gene, more preferably a mouse gene, even more preferably a mammalian gene, and most preferably a human gene, or comprises or consists of a nucleic acid sequence derived from a variant of the 3'-UTR of a chordate gene, preferably a vertebrate gene, more preferably a mouse gene, even more preferably a mammalian gene, and most preferably a human gene.

[0082] <3'-UTR factor derived from PSMB3> The artificial nucleic acid according to the present invention may comprise a 3'-UTR factor derived from the 3'-UTR of a gene encoding a proteasome subunit beta type 3 (PSMB3) protein or a homolog, variant, fragment, or derivative thereof.

[0083] Such 3'-UTR factors preferably contain or consist of a nucleic acid sequence derived from the 3'-UTR of the proteasome subunit beta-3 (PSMB3) gene, preferably from a vertebrate, more preferably mammalian, most preferably human proteasome subunit beta-3 (PSMB3) gene, or its homolog, variant, fragment, or derivative. The gene may preferably encode the proteasome subunit beta-3 (PSMB3) protein corresponding to the human proteasome subunit beta-3 (PSMB3) protein (UniProt reference number P49720, entry version number 183 of August 30, 2017).

[0084] Therefore, the artificial nucleic acid according to the present invention may contain a 3'-UTR factor derived from the PSMB3 gene, and the above 3'-UTR factor includes, or consists of, the DNA sequence set forth in SEQ ID NO: 23 or its homolog, variant, fragment, or derivative. In particular, it has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% (the higher, the more preferred), preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95% or even 97% sequence identity with the nucleic acid sequence set forth in SEQ ID NO: 23, or consists of such DNA sequences. Alternatively, the above 3'-UTR factor includes, or consists of, the RNA sequence set forth in SEQ ID NO: 24 or its homolog, variant, fragment, or derivative. In particular, it has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% (the higher, the more preferred), preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95% or even 97% sequence identity with the nucleic acid sequence set forth in SEQ ID NO: 24, or consists of such RNA sequences.

[0085] <3'-UTR factor derived from CASP1> The artificial nucleic acid according to the present invention may contain a 3'-UTR factor derived from the 3'-UTR of a gene encoding a caspase-1 (CASP1) protein or its homolog, variant, fragment, or derivative.

[0086] Such 3'-UTR factors preferably comprise or consist of a nucleic acid sequence derived from the 3'-UTR of the caspase-1 (CASP1) gene, preferably of vertebrates, more preferably of mammals, and most preferably of the human caspase-1 (CASP1) gene, or a homolog, variant, fragment, or derivative thereof.

[0087] Therefore, the artificial nucleic acid according to the present invention may contain a 3'-UTR factor derived from the CASP1 gene, and the above 3'-UTR factor contains or consists of the DNA sequence set forth in SEQ ID NO: 25 or a homolog, variant, fragment, or derivative thereof. In particular, it has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% (the higher the better), preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95% or even 97% sequence identity to the nucleic acid sequence set forth in SEQ ID NO: 25 and contains or consists of a DNA sequence having such sequence identity. Alternatively, the above 3'-UTR factor contains or consists of the RNA sequence set forth in SEQ ID NO: 26 or a homolog, variant, fragment, or derivative thereof. In particular, it has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% (the higher the better), preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95% or even 97% sequence identity to the nucleic acid sequence set forth in SEQ ID NO: 26 and contains or consists of an RNA sequence having such sequence identity.

[0088] <3'-UTR factor derived from COX6B1> The artificial nucleic acid according to the present invention may include a 3'-UTR factor derived from the 3'-UTR of a gene encoding the cytochrome c oxidase subunit 6B1 (COX6B1) protein or its homolog, variant, fragment, or derivative.

[0089] Such 3'-UTR factors preferably contain or consist of a nucleic acid sequence derived from the 3'-UTR of the cytochrome c oxidase subunit 6B1 (COX6B1) gene, preferably from a vertebrate, more preferably mammalian, most preferably human cytochrome c oxidase subunit 6B1 (COX6B1) gene, or its homolog, variant, fragment, or derivative thereof. The gene may preferably encode the cytochrome c oxidase subunit 6B1 (COX6B1) protein corresponding to the human cytochrome c oxidase subunit 6B1 (COX6B1) protein (UniProt reference number P14854, entry version number 166, August 30, 2017).

[0090] Therefore, the artificial nucleic acid according to the present invention may contain a 3'-UTR factor derived from the COX6B1 gene, and the above 3'-UTR factor contains, or consists of, the DNA sequence set forth in SEQ ID NO: 27 or its homolog, variant, fragment, or derivative. In particular, it has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% (the higher, the more preferable), preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95% or even 97% sequence identity with the nucleic acid sequence set forth in SEQ ID NO: 27, or consists of such DNA sequences. Alternatively, the above 3'-UTR factor contains, or consists of, the RNA sequence set forth in SEQ ID NO: 28 or its homolog, variant, fragment, or derivative. In particular, it has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% (the higher, the more preferable), preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95% or even 97% sequence identity with the nucleic acid sequence set forth in SEQ ID NO: 28, or consists of such RNA sequences.

[0091] <3'-UTR factor derived from GNAS> The artificial nucleic acid according to the present invention may contain a 3'-UTR factor derived from the 3'-UTR of a gene encoding a guanine nucleotide-binding G protein subunit alpha isoform short (GNAS) protein or its homolog, variant, fragment, or derivative.

[0092] Such 3'-UTR factors preferably contain or consist of a nucleic acid sequence derived from the 3'-UTR of a guanine nucleotide-binding G protein subunit alpha isoform short chain (GNAS) gene, preferably a vertebrate, more preferably mammalian, most preferably human guanine nucleotide-binding G protein subunit alpha isoform short chain (GNAS) gene, or its homolog, variant, fragment, or derivative. The gene may preferably encode a guanine nucleotide-binding G protein subunit alpha isoform short chain (GNAS) protein corresponding to the human guanine nucleotide-binding G protein subunit alpha isoform short chain (GNAS) protein (UniProt reference number P63092, entry version number 153 of August 30, 2017).

[0093] Therefore, the artificial nucleic acid according to the present invention may contain a 3'-UTR factor derived from the GNAS gene, and the above 3'-UTR factor includes, or consists of, the DNA sequence described in SEQ ID NO: 29 or its homolog, variant, fragment, or derivative. In particular, it includes, or consists of, a DNA sequence having at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% (the higher, the more preferred), preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95% or even 97% sequence identity to the nucleic acid sequence described in SEQ ID NO: 29. Alternatively, the above 3'-UTR factor includes, or consists of, the RNA sequence described in SEQ ID NO: 30 or its homolog, variant, fragment, or derivative. In particular, it includes, or consists of, an RNA sequence having at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% (the higher, the more preferred), preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95% or even 97% sequence identity to the nucleic acid sequence described in SEQ ID NO: 30.

[0094] <3'-UTR factor derived from NDUFA1> The artificial nucleic acid according to the present invention may contain a 3'-UTR factor derived from the 3'-UTR of a gene encoding NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1 (NDUFA1) protein or its homolog, variant, fragment, or derivative.

[0095] Such 3'-UTR factors preferably contain or consist of a nucleic acid sequence derived from the 3'-UTR of the NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1 (NDUFA1) gene, preferably a vertebrate, more preferably a mammalian, most preferably human NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1 (NDUFA1) gene, or its homolog, variant, fragment, or derivative. The gene may preferably encode the NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1 (NDUFA1) protein corresponding to the human NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1 (NDUFA1) protein (UniProt reference number O15239, entry version number 152, August 30, 2017).

[0096] Therefore, the artificial nucleic acid according to the present invention may contain a 3'-UTR factor derived from the NDUFA1 gene, and the 3'-UTR factor includes, or consists of, the DNA sequence set forth in SEQ ID NO: 31 or its homolog, variant, fragment, or derivative. In particular, it includes, or consists of, a DNA sequence having at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% (the higher the better), preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95% or even 97% sequence identity to the nucleic acid sequence set forth in SEQ ID NO: 31. Alternatively, the 3'-UTR factor includes, or consists of, the RNA sequence set forth in SEQ ID NO: 32 or its homolog, variant, fragment, or derivative. In particular, it includes, or consists of, an RNA sequence having at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% (the higher the better), preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95% or even 97% sequence identity to the nucleic acid sequence set forth in SEQ ID NO: 32.

[0097] <3'-UTR derived from RPS9> The artificial nucleic acid according to the present invention may contain, or consist of, a 3'-UTR factor including a nucleic acid sequence derived from the 3'-UTR of a gene encoding a 40S ribosomal protein S9 (RPS9) protein or its homolog, variant, fragment, or derivative.

[0098] Such 3'-UTR factors preferably contain or consist of a nucleic acid sequence derived from the 3'-UTR of the 40S ribosomal protein S9 (RPS9) gene, preferably from a vertebrate, more preferably mammalian, most preferably human 40S ribosomal protein S9 (RPS9) gene, or its homolog, variant, fragment, or derivative. The gene may preferably encode the 40S ribosomal protein S9 (RPS9) protein (UniProt reference number P46781, entry version number 179 of August 30, 2017).

[0099] Therefore, the artificial nucleic acid according to the present invention may include a 3'-UTR factor derived from the RPS9 gene, the 3'-UTR factor including or consisting of the DNA sequence described in SEQ ID NO: 33 or its homolog, variant, fragment, or derivative, and in particular including or consisting of a DNA sequence having at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with respect to the nucleic acid sequence described in SEQ ID NO: 33. Alternatively, the 5'-UTR factor may include or consist of the RNA sequence described in SEQ ID NO: 34 or its homolog, variant, fragment, or derivative thereof, and in particular, may include or consist of an RNA sequence having at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with respect to the nucleic acid sequence described in SEQ ID NO: 34.

[0100] [UTR combination] Preferably, at least one 5'-UTR factor and at least one 3'-UTR factor act synergistically to regulate, more preferably induce or enhance, the expression of at least one coding sequence operably linked to the UTR factor. Herein, it is assumed that each of the 5'- and 3'-UTR factors exemplified herein may be used in any conceivable combination.

[0101] Table 1 below lists preferred combinations of 5'- and 3'-UTR factors.

[0102] [Table 1] TIFF0007863957000002.tif211169

[0103] In particular, the following UTR combinations are preferred: 5'-UTR:ASAH1+3'-UTR:CASP1; 5'-UTR:ASAH1+3'-UTR:COX6B1; 5'-UTR:ASAH1+3'-UTR:Gnas; 5'-UTR:ASAH1+3'-UTR:Ndufa1.1; 5'-UTR:ASAH1+3'-UTR:PSMB3; 5'-UTR:ASAH1+3'-UTR:RPS9; 5'-UTR:ATP5A1+3'-UTR:CASP1; 5'-UTR:ATP5A1+3'-UTR :COX6B1;5'-UTR:ATP5A1+3'-UTR:Gnas;5'-UTR:ATP5A1+3'-UTR:Ndufa1.1;5'-UTR:ATP5A1+3'-UTR:PSMB3;5'-UTR:ATP5A1+3'-UTR:R PS9;5'-UTR:HSD17B4+3'-UTR:CASP1;5'-UTR:HSD17B4+3'-UTR:COX6B1;5'-UTR:HSD17B4+3'-UTR:Ndufa1.1;5'-UTR:HSD17B4+3'-UTR: PSMB3;5'-UTR:HSD17B4+3'-UTR:RPS9;5'-UTR:Mp68+3'-UTR:CASP1;5'-UTR:Mp68+3'-UTR:COX6B1;5'-UTR:Mp68+3'-UTR:Gnas;5'-UT R:Mp68+3'-UTR:Ndufa1.1;5'-UTR:Mp68+3'-UTR:PSMB3;5'-UTR:Mp68+3'-UTR:RPS9;5'-UTR:Ndufa4+3'-UTR:CASP1;5'-UTR:Ndufa4+3 '-UTR:COX6B1;5'-UTR:Ndufa4+3'-UTR:Gnas;5'-UTR:Ndufa4+3'-UTR:Ndufa1.1;5'-UTR:Ndufa4+3'-UTR:PSMB3;5'-UTR:Ndufa4+3'- UTR:RPS9;5'-UTR:Nosip+3'-UTR:CASP1;5'-UTR:Nosip+3'-UTR:COX6B1;5'-UTR:Nosip+3'-UTR:Gnas;5'-UTR:Nosip+3'-UTR:Ndufa1.1;5'-UTR:Nosip+3'-UTR:PSMB3;5'-UTR:Nosip+3'-UTR:RPS9;5'-UTR:Rpl31+3'-UTR:CASP1;5'-UTR:Rpl31+3'- UTR:COX6B1;5'-UTR:Rpl31+3'-UTR:Gnas;5'-UTR:Rpl31+3'-UTR:Ndufa1.1;5'-UTR:Rpl31+3'-UTR:PSMB3;5'-U TR:Rpl31+3'-UTR:RPS9;5'-UTR:Slc7a3+3'-UTR:CASP1;5'-UTR:Slc7a3+3'-UTR:COX6B1;5'-UTR:Slc7a3+3'-UT R:Ndufa1.1;5'-UTR:Slc7a3+3'-UTR:PSMB3;5'-UTR:Slc7a3+3'-UTR:RPS9;5'-UTR:TUBB4B+3'-UTR:CASP1;5'-UT R:TUBB4B+3'-UTR:COX6B1;5'-UTR:TUBB4B+3'-UTR:Gnas;5'-UTR:TUBB4B+3'-UTR:Ndufa1.1;5'-UTR:TUBB4B+3' -UTR:PSMB3;5'-UTR:TUBB4B+3'-UTR:RPS9;5'-UTR:Ubqln2+3'-UTR:CASP1;5'-UTR:Ubqln2+3'-UTR:COX6B1;5'-U TR:Ubqln2+3'-UTR:Gnas; 5'-UTR:Ubqln2+3'-UTR:Ndufa1.1; 5'-UTR:Ubqln2+3'-UTR:PSMB3; and 5'-UTR:Ubqln2+3'-UTR:RPS9, preferably the UTR combination 5'-UTR:HSD17B4+3'-UTR:Gnas, more preferably the UTR combination 5'-UTR:Slc7a3+3'-UTR:Gnas.

[0104] Each of the UTR factors defined in Table 1 by reference to a specific sequence number may include a variant or fragment of the nucleic acid sequence defined by that specific sequence number, exhibiting sequence identity of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, preferably at least 70%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, most preferably at least 95%, and even more preferably at least 97% with respect to each nucleic acid sequence defined by reference to that specific sequence number. Each of the sequences identified in Table 1 by reference to those specific sequence numbers may be defined by its corresponding DNA sequence, as shown herein. Each of the sequences identified in Table 1 by reference to those specific sequence numbers may be modified (optionally and independently of each other) as described below herein.

[0105] Preferred artificial nucleic acids according to the present invention may include the following: a-1: At least one 5'-UTR factor derived from the 5'-UTR of the HSD17B4 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the PSMB3 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or a-2: At least one 5'-UTR factor derived from the 5'-UTR of the NDUFA4 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the PSMB3 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or a-3: At least one 5'-UTR factor derived from the 5'-UTR of the SLC7A3 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the PSMB3 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or a-4: At least one 5'-UTR factor derived from the 5'-UTR of the NOSIP gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the PSMB3 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or a-5: At least one 5'-UTR factor derived from the 5'-UTR of the MP68 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the PSMB3 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or b-1: At least one 5'-UTR factor derived from the 5'-UTR of the UBQLN2 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the RPS9 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or b-2: At least one 5'-UTR factor derived from the 5'-UTR of the ASAH1 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the RPS9 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or b-3: At least one 5'-UTR factor derived from the 5'-UTR of the HSD17B4 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the RPS9 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or b-4: At least one 5'-UTR factor derived from the 5'-UTR of the HSD17B4 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the CASP1 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or b-5: At least one 5'-UTR factor derived from the 5'-UTR of the NOSIP gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the COX6B1 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or c-1: At least one 5'-UTR factor derived from the 5'-UTR of the NDUFA4 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the RPS9 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or c-2: At least one 5'-UTR factor derived from the 5'-UTR of the NOSIP gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the NDUFA1 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or c-3: At least one 5'-UTR factor derived from the 5'-UTR of the NDUFA4 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the COX6B1 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or c-4: At least one 5'-UTR factor derived from the 5'-UTR of the NDUFA4 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the NDUFA1 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or c-5: At least one 5'-UTR factor derived from the 5'-UTR of the ATP5A1 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the PSMB3 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or d-1: At least one 5'-UTR factor derived from the 5'-UTR of the RPL31 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the PSMB3 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or d-2: At least one 5'-UTR factor derived from the 5'-UTR of the ATP5A1 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the CASP1 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or d-3: At least one 5'-UTR factor derived from the 5'-UTR of the SLC7A3 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the GNAS1 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or d-4: At least one 5'-UTR factor derived from the 5'-UTR of the HSD17B4 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the NDUFA1 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or d-5: At least one 5'-UTR factor derived from the 5'-UTR of the SLC7A3 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the NDUFA1 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or e-1: At least one 5'-UTR factor derived from the 5'-UTR of the TUBB4B gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the RPS9 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or e-2: At least one 5'-UTR factor derived from the 5'-UTR of the RPL31 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the RPS9 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or e-3: At least one 5'-UTR factor derived from the 5'-UTR of the MP68 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the RPS9 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or e-4: At least one 5'-UTR factor derived from the 5'-UTR of the NOSIP gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the RPS9 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or e-5: At least one 5'-UTR factor derived from the 5'-UTR of the ATP5A1 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the RPS9 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or e-6: At least one 5'-UTR factor derived from the 5'-UTR of the ATP5A1 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the COX6B1 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or f-1: At least one 5'-UTR factor derived from the 5'-UTR of the ATP5A1 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the GNAS gene, or its corresponding RNA sequence, homolog, fragment, or variant; or f-2: At least one 5'-UTR factor derived from the 5'-UTR of the ATP5A1 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the NDUFA1 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or f-3: At least one 5'-UTR factor derived from the 5'-UTR of the HSD17B4 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the COX6B1 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or f-4: At least one 5'-UTR factor derived from the 5'-UTR of the HSD17B4 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the GNAS1 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or f-5: At least one 5'-UTR factor derived from the 5'-UTR of the MP68 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the COX6B1 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or g-1: At least one 5'-UTR factor derived from the 5'-UTR of the MP68 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the NDUFA1 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or g-2: At least one 5'-UTR factor derived from the 5'-UTR of the NDUFA4 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the CASP1 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or g-3: At least one 5'-UTR factor derived from the 5'-UTR of the NDUFA4 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the GNAS gene, or its corresponding RNA sequence, homolog, fragment, or variant; or g-4: At least one 5'-UTR factor derived from the 5'-UTR of the NOSIP gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the CASP1 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or g-5: At least one 5'-UTR factor derived from the 5'-UTR of the RPL31 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the CASP1 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or h-1: At least one 5'-UTR factor derived from the 5'-UTR of the RPL31 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the COX6B1 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or h-2: At least one 5'-UTR factor derived from the 5'-UTR of the RPL31 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the GNAS gene, or its corresponding RNA sequence, homolog, fragment, or variant; or h-3: At least one 5'-UTR factor derived from the 5'-UTR of the RPL31 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the NDUFA1 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or h-4: At least one 5'-UTR factor derived from the 5'-UTR of the SLC7A3 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the CASP1 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or h-5: At least one 5'-UTR factor derived from the 5'-UTR of the SLC7A3 gene, or its corresponding RNA sequence, homolog, fragment, or variant; and at least one 3'-UTR factor derived from the 3'-UTR of the COX6B1 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or i-1: At least one 5'-UTR factor derived from the 5'-UTR of the SLC7A3 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the RPS9 gene, or its corresponding RNA sequence, homolog, fragment, or variant; or i-2: At least one 5'-UTR factor derived from the 5'-UTR of the Ndufa4.1 gene, or its corresponding RNA sequence, homolog, fragment, or variant, and at least one 3'-UTR factor derived from the 3'-UTR of the CASP1 gene, or its corresponding RNA sequence, homolog, fragment, or variant.

[0106] Particularly preferred artificial nucleic acids may include a-1, a-2, a-3, a-4, or a-5, preferably a combination of UTRs described in a-1.

[0107] Surprisingly, we discovered that specific combinations of 5' and 3'-untranslated regions (UTRs) work together as described herein to synergistically enhance the expression of manipulably linked nucleic acid sequences. Testing for synergistic effects of UTR combinations is routine for those skilled in the art; for example, synergistic effects can be tested by luciferase expression after mRNA transfection to demonstrate the existence of a synergistic effect, i.e., an effect exceeding an additive one.

[0108] [Expression in the liver] Any combination of UTRs described herein is intended to modulate, preferably induce, and more preferably enhance the expression of operable linked coding sequences (cds). While we do not wish to be bound by any particular theory, some of the UTR combinations described herein may be particularly useful when used in relation to specific coding sequences and / or specific target cells or tissues.

[0109] In some embodiments, the artificial nucleic acid molecule according to the present invention is the UTR factor defined above, i.e., a-2(NDUFA4 / PSMB3); a-5(MP68 / PSMB3); c-1(NDUFA4 / RPS9); a-1(HSD17B4 / PSMB3); e-3(MP68 / RPS9); e-4(NOSIP / RPS9); a-4(NOSIP / PSMB3); e-2(RPL31 / RPS9); e-5(ATP5A1 / RPS9); d-4(HSD The following may be included: 17B4 / NUDFA1); b-5(NOSIP / COX6B1); a-3(SLC7A3 / PSMB3); b-1(UBQLN2 / RPS9); b-2(ASAH1 / RPS9); b-4(HSD17B4 / CASP1); e-6(ATP5A1 / COX6B1); b-3(HSD17B4 / RPS9); g-5(RPL31 / CASP1); h-1(RPL31 / COX6B1); and / or c-5(ATP5A1 / PSMB3). Such artificial nucleic acid molecules may be particularly useful for the expression of the encoded (poly)peptide or protein of interest in the liver. Therefore, such artificial nucleic acid molecules are intended to be used in particular for systemic administration, especially intravenous, intraperitoneal, intramuscular or intratracheal administration or injection, and optionally in combination with the liver targeting factors described herein (listed below). Furthermore, without intending to imply any specific limitations, the above-mentioned combinations of UTRs may be particularly useful for artificial nucleic acids that, in at least one of their coding regions, encode a therapeutic (poly)peptide or protein, an antigenic or allergic (poly)peptide or protein (e.g., a protein useful for treating diseases selected from the group consisting of, for example, genetic diseases, allergies, autoimmune diseases, infectious diseases, neoplasms, cancer and tumor-related diseases, inflammatory diseases, diseases of the blood and hematopoietic organs, endocrine, nutritional and metabolic diseases, diseases of the nervous system, diseases of the circulatory system, diseases of the respiratory system, diseases of the digestive system, diseases of the skin and subcutaneous tissue, diseases of the musculoskeletal system and connective tissue, and diseases of the genitourinary system (independently if hereditary or acquired), and combinations thereof).

[0110] [Emission from the dermis, epidermis, and subcutaneous tissue] In some embodiments, the artificial nucleic acid molecule according to the present invention is the UTR factor defined above, i.e., a-1(HSD17B4 / PSMB3); a-3(SLC7A3 / PSMB3); e-2(RPL31 / RPS9); a-5(MP68 / PSMB3); d-1(RPL31 / PSMB3); a-2(NDUFA4 / PSMB3); h-1(RPL31 / COX6B1); b-1(UBQLN2 / RPS9); a-4(NOSIP / PSMB3); c-5(AT P5A1 / PSMB3); b-5(NOSIP / COX6B1); d-4(HSD17B4 / NDUFA1); i-1(SLC7A3 / RPS9); f-3(HSD17B4 / COX6B1); b-4(HSD17B4 / CASP1); g-5(RPL31 / CASP1); c-2(NOSIP / NDUFA1); e-4(NOSIP / RPS9); c-4(NDUFA4 / NDUFA1); and / or d-5(SLC7A3 / NDUFA1). Such artificial nucleic acid molecules may be particularly useful for the expression of the encoded (poly)peptide or protein of interest in the skin. Therefore, such artificial nucleic acid molecules are particularly intended to be used in intradermal administration, especially topical, transdermal, intradermal injection, subcutaneous, or epidermal administration or injection. Furthermore, without intending to imply any specific limitations, the above-mentioned combinations of UTRs may be particularly useful for artificial nucleic acids that, in at least one of their coding regions, encode a therapeutic (poly)peptide or protein, an antigenic or allergic (poly)peptide or protein (e.g., a protein useful for treating diseases selected from the group consisting of, for example, genetic diseases, allergies, autoimmune diseases, infectious diseases, neoplasms, cancer and tumor-related diseases, inflammatory diseases, diseases of the blood and hematopoietic organs, endocrine, nutritional and metabolic diseases, diseases of the nervous system, diseases of the circulatory system, diseases of the respiratory system, diseases of the digestive system, diseases of the skin and subcutaneous tissue, diseases of the musculoskeletal system and connective tissue, and diseases of the genitourinary system (independently if hereditary or acquired), and combinations thereof).

[0111] [Expression in muscles] In some embodiments, the artificial nucleic acid molecule according to the present invention is the UTR factor defined above, i.e., a-4(NOSIP / PSMB3);a-1(HSD17B4 / PSMB3);a-5(MP68 / PSMB3);d-3(SLC7A3 / GNAS);a-2(NDUFA4 / PSMB3);a-3(SLC7A3 / PSMB3);d-5(SLC7A3 / NDUFA1);i-1(SLC7A3 / RPS9);d-1(RPL31 / PSMB3);d-4(HSD17B4 / NDUFA1);b-3(HSD17B4 / RPS9);f-3(HSD17B4 / COX6B1);f-4(HSD17B4 / GNAS);h-5(SLC7A3 / COX6B1);g-4(NOSIP / CASP1);c-3(NDUFA4 / COX6B1);b-1(UBQLN2 / RPS9);c-5(ATP5A1 / PSMB3);h-4(SLC7A3 / CASP1);h-2(RPL31 / GNAS);e-1(TUBB4B / RPS9);f-2(ATP5A1 / NDUFA1);c-2(NOSIP / NDUFA1);b-5(NOSIP / COX6B1);and / or e-4(NOSIP / RPS9). Such artificial nucleic acid molecules may be particularly useful for the expression of the encoded (poly)peptide or protein of interest in skeletal muscle, smooth muscle, or cardiac muscle. Therefore, such artificial nucleic acid molecules are particularly intended in this specification to be used for intramuscular administration, more preferably intramuscular injection or intracardiac injection.Furthermore, without intending to imply any specific limitations, the above-mentioned combinations of UTRs may be particularly useful for artificial nucleic acids that, in at least one of their coding regions, encode a therapeutic (poly)peptide or protein, an antigenic or allergic (poly)peptide or protein (e.g., a protein useful for treating diseases selected from the group consisting of, for example, genetic diseases, allergies, autoimmune diseases, infectious diseases, neoplasms, cancer and tumor-related diseases, inflammatory diseases, diseases of the blood and hematopoietic organs, endocrine, nutritional and metabolic diseases, diseases of the nervous system, diseases of the circulatory system, diseases of the respiratory system, diseases of the digestive system, diseases of the skin and subcutaneous tissue, diseases of the musculoskeletal system and connective tissue, and diseases of the genitourinary system (independently if hereditary or acquired), and combinations thereof).

[0112] [Expression in tumors and cancer cells] In some embodiments, the artificial nucleic acid molecule according to the present invention is the UTR factor defined above, namely e-1(TUBB4B / RPS9); b-2(ASAH1 / RPS9); c-3(NDUFA4 / COX6B1); a-1(HSD17B4 / PSMB3); c-4(NDUFA4 / NDUFA1); b-4(HSD17B4 / CASP1); d-2(ATP5A1 / CASP1); b-5(NOSIP / COX6B1) ;a-2(NDUFA4 / PSMB3);b-1(UBQLN / RPS9);a-3(SLC7A3 / PSMB3);f-4(HSD17B4 / GNAS);c-2(NOSIP / NDUFA1);b-3(HSD17B4 / RPS9);c-5(ATP5A1 / PSMB3);a-4(NOSIP / PSMB3);d-5(SLC7A3 / NDUFA1);or f-3(HSD17B4 / COX6B1). Such artificial nucleic acid molecules may be particularly useful for the expression of the encoded (poly)peptide or protein of interest in tumors or cancer cells, including carcinomas, sarcomas, lymphomas, leukemias, germ cell tumors, or blastoma cells. Accordingly, such artificial nucleic acid molecules are particularly intended to be used for intratumoral, intramuscular, subcutaneous, intravenous, intradermal, intraperitoneal, intrapleural, intraosseous administration or injection as described herein. Furthermore, without intending to imply any specific limitations, the above-mentioned UTR combinations may be particularly useful for artificial nucleic acids that encode, in at least one of their coding regions, a therapeutic (poly)peptide or protein, an antigenic or allergic (poly)peptide or protein as described herein (e.g., a protein useful for treating a disease selected from the group consisting of cancer and tumor diseases).

[0113] [Expression in kidney cells] In some embodiments, the artificial nucleic acid molecule according to the present invention is the UTR factor defined above, i.e., b-2(ASAH1 / RPS9); c-1(NDUFA4 / RPS9.1); e-3(MP68 / RPS9); c-4(NDUFA4 / NDUFA1); c-2(NOSIP / NDUFA1); h-2(RPL31 / CASP1); d-2(ATP5A1 / CASP1); b-3(HSD17B4 / RPS9); a-2(NDUFA4 / PSMB3); f-4(HSD1 7B4 / GNAS);d-3(SLC7A3 / GNAS);g-1(MP68 / NDUFA1);c-3(NDUFA4 / COX6B1);e-5(ATP5A1 / RPS9);h-3(RPL31 / NDUFA1);a-1(HSD17B4 / PSMB3);a-5(MP68 / PSMB3);g-4(NOSIP / CASP1);b-1(UQBLN / RPS9);d-4(HSD17B4 / NDUFA1);or e-2(RPL31 / RPS9). Such artificial nucleic acid molecules may be particularly useful for the expression of the encoded (poly)peptide or protein of interest in kidney cells. Therefore, such artificial nucleic acid molecules are intended to be used in particular for systemic administration, especially intravenous, intraperitoneal, intramuscular or intratracheal administration or injection, and optionally in combination with the kidney targeting factors described herein. Furthermore, without intending to imply any specific limitations, the above-mentioned combinations of UTRs may be particularly useful for artificial nucleic acids that, in at least one of their coding regions, encode a therapeutic (poly)peptide or protein, an antigenic or allergic (poly)peptide or protein (e.g., a protein useful for treating diseases selected from the group consisting of, for example, genetic diseases, allergies, autoimmune diseases, infectious diseases, neoplasms, cancer and tumor-related diseases, inflammatory diseases, diseases of the blood and hematopoietic organs, endocrine, nutritional and metabolic diseases, diseases of the nervous system, diseases of the circulatory system, diseases of the respiratory system, diseases of the digestive system, diseases of the skin and subcutaneous tissue, diseases of the musculoskeletal system and connective tissue, and diseases of the genitourinary system (independently if hereditary or acquired), and combinations thereof).

[0114] From the above viewpoint, the artificial nucleic acid molecule of the present invention can be defined as described above, where, - The 5'-UTR factor derived from the HSD17B4 gene described above contains or comprises a DNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the DNA sequence described in SEQ ID NO: 1, or the nucleic acid sequence described in SEQ ID NO: 1, or contains or comprises an RNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the RNA sequence described in SEQ ID NO: 2, or the nucleic acid sequence described in SEQ ID NO: 2. - The 5'-UTR factor derived from the ASAH1 gene described above contains or comprises a DNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the DNA sequence described in SEQ ID NO: 3, or the nucleic acid sequence described in SEQ ID NO: 3, or contains or comprises an RNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the RNA sequence described in SEQ ID NO: 4, or the nucleic acid sequence described in SEQ ID NO: 4. - The 5'-UTR factor derived from the ATP5A1 gene described above contains or comprises a DNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the DNA sequence described in SEQ ID NO: 5, or the nucleic acid sequence described in SEQ ID NO: 5, or contains or comprises an RNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the RNA sequence described in SEQ ID NO: 6, or the nucleic acid sequence described in SEQ ID NO: 6, - The 5'-UTR factor derived from the MP68 gene described above contains or comprises a DNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the DNA sequence described in SEQ ID NO: 7, or the nucleic acid sequence described in SEQ ID NO: 7, or contains or comprises an RNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the RNA sequence described in SEQ ID NO: 8, or the nucleic acid sequence described in SEQ ID NO: 8. - The 5'-UTR factor derived from the above NDUFA4 gene contains or comprises a DNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the DNA sequence described in SEQ ID NO: 9, or the nucleic acid sequence described in SEQ ID NO: 9, or contains or comprises an RNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the RNA sequence described in SEQ ID NO: 10, or the nucleic acid sequence described in SEQ ID NO: 10. - The 5'-UTR factor derived from the above NOSIP gene contains or comprises a DNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the DNA sequence described in SEQ ID NO: 11, or the nucleic acid sequence described in SEQ ID NO: 11, or contains or comprises an RNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the RNA sequence described in SEQ ID NO: 12, or the nucleic acid sequence described in SEQ ID NO: 12. - The 5'-UTR factor derived from the RPL31 gene described above contains or comprises a DNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the DNA sequence described in SEQ ID NO: 13, or the nucleic acid sequence described in SEQ ID NO: 13, or contains or comprises an RNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the RNA sequence described in SEQ ID NO: 14, or the nucleic acid sequence described in SEQ ID NO: 14. - The 5'-UTR factor derived from the above SLC7A3 gene contains or comprises a DNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the DNA sequence described in SEQ ID NO: 15, or the nucleic acid sequence described in SEQ ID NO: 15, or contains or comprises an RNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the RNA sequence described in SEQ ID NO: 16, or the nucleic acid sequence described in SEQ ID NO: 16. - The 5'-UTR factor derived from the TUBB4B gene described above contains or comprises a DNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the DNA sequence described in SEQ ID NO: 17, or the nucleic acid sequence described in SEQ ID NO: 17, or contains or comprises an RNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the RNA sequence described in SEQ ID NO: 18, or the nucleic acid sequence described in SEQ ID NO: 18. - The 5'-UTR factor derived from the UBQLN2 gene described above contains or comprises a DNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the DNA sequence described in SEQ ID NO: 19, or the nucleic acid sequence described in SEQ ID NO: 19, or contains or comprises an RNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the RNA sequence described in SEQ ID NO: 20, or the nucleic acid sequence described in SEQ ID NO: 20. - The 3'-UTR factor derived from the PSMB3 gene described above contains or comprises a DNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the DNA sequence described in SEQ ID NO: 23, or the nucleic acid sequence described in SEQ ID NO: 23, or contains or comprises an RNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the RNA sequence described in SEQ ID NO: 24, - The 3'-UTR factor derived from the CASP1 gene described above contains or comprises a DNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the DNA sequence described in SEQ ID NO: 25, or the nucleic acid sequence described in SEQ ID NO: 25, or contains or comprises an RNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the RNA sequence described in SEQ ID NO: 26, or the nucleic acid sequence described in SEQ ID NO: 26. - The 3'-UTR factor derived from the COX6B1 gene described above contains or comprises a DNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the DNA sequence described in SEQ ID NO: 27, or the nucleic acid sequence described in SEQ ID NO: 27, or contains or comprises an RNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the RNA sequence described in SEQ ID NO: 28, or the nucleic acid sequence described in SEQ ID NO: 28. - The 3'-UTR factor derived from the GNAS gene described above contains or comprises a DNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the DNA sequence described in SEQ ID NO: 29, or the nucleic acid sequence described in SEQ ID NO: 29, or contains or comprises an RNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the RNA sequence described in SEQ ID NO: 30, or the nucleic acid sequence described in SEQ ID NO: 30. - The 3'-UTR factor derived from the above NDUFA1 gene contains or comprises a DNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the DNA sequence described in SEQ ID NO: 31, or the nucleic acid sequence described in SEQ ID NO: 31, or contains or comprises an RNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the RNA sequence described in SEQ ID NO: 32, or the nucleic acid sequence described in SEQ ID NO: 32, and / or - The 3'-UTR factor derived from the RPS9 gene described above includes or comprises a DNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the DNA sequence described in SEQ ID NO: 33, or the nucleic acid sequence described in SEQ ID NO: 33, or includes or comprises an RNA sequence, fragment or variant thereof having at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% (higher is preferable) sequence identity with the RNA sequence described in SEQ ID NO: 34, or the nucleic acid sequence described in SEQ ID NO: 34.

[0115] [Coding Area] The artificial nucleic acid according to the present invention comprises at least one coding region or coding sequence that is operably linked (typically adjacent) to at least one 3'-UTR factor and at least one 5'-UTR factor as defined herein. The terms “coding sequence” or “cds” and “coding region” are used interchangeably herein and refer to a segment or portion of nucleic acid that codes for the (gene) product of interest. A gene product is the product of gene expression and comprises (poly)peptides and nucleic acids ((protein)coding RNA (e.g., mRNA) and non-(protein)coding RNA (e.g., tRNA, rRNA, microRNA, siRNA)). Typically, at least one coding region of the artificial nucleic acid molecule of the present invention can code for at least one (poly)peptide or protein (hereinafter referred to as the “(poly)peptide or protein of interest”). The coding region typically consists of exons delimited by a start codon at its 5' end (e.g., AUG) and a stop codon at its 3' end (e.g., UAG, UAA, UGA). In the artificial nucleic acid molecule of the present invention, the coding region is delimited by at least one 5'-UTR factor and at least one 3'-UTR factor as defined herein.

[0116] The (poly)peptide or protein of interest generally comprises any (poly)peptide or protein that can be encoded by a nucleic acid sequence of at least one coding region and can be expressed under conditions suitable for producing a functional (poly)peptide or protein product. In this context, the term “functional” means “capable of performing a desired biological function” and / or “exhibiting a desired biological property.” The (poly)peptide or protein of interest may have a variety of functions and may include, for example, antibodies, enzymes, signaling proteins, receptors, receptor ligands, peptide hormones, transport proteins, structural proteins, neurotransmitters, growth regulators, serum proteins, carriers, drugs, immunostimulants, oncogenes, tumor suppressors, toxins, tumor antigens, and others. These proteins can be post-translationally modified into proteins, glycoproteins, lipoproteins, phosphoproteins, etc. Furthermore, the present invention envisions any of the disclosed (poly)peptides or proteins in their naturally occurring (wild-type) forms, as well as their variants, fragments, and derivatives. The encoded (poly)peptides and proteins may have different effects. In this specification, coding regions encoding therapeutic, antigenic, and allergenic (poly)peptides are particularly envisioned, but are not limited to these.

[0117] [Therapeutic (poly)peptides or proteins] At least one coding region of the artificial nucleic acid molecule of the present invention may encode at least one “therapeutic (poly)peptide or protein”. The term “therapeutic (poly)peptide or protein” refers to a (poly)peptide or protein that can mediate a desired diagnostic, preventive, or therapeutic effect, preferably resulting in the detection, prevention, improvement, and / or cure of a disease.

[0118] Preferably, the artificial nucleic acid molecule according to the present invention may include at least one coding region encoding a therapeutic protein that replaces a deficient, missing, or mutated protein; a therapeutic protein advantageous for treating hereditary or acquired diseases (infectious diseases, or neoplasms, e.g., cancer or tumor diseases); an adjuvant or immunostimulant therapeutic protein; a therapeutic antibody or antibody fragment, variant, or derivative; a peptide hormone; a gene editing agent; an immune checkpoint inhibitor; a T cell receptor or fragment, variant, or induced T cell receptor; and / or an enzyme.

[0119] A therapeutic (poly)peptide or protein that “substitutes a deficient, defective, or mutated protein” can be selected from any (poly)peptide or protein that exhibits the desired biological properties and / or can exert the desired biological function of the wild-type protein whose absence, defect, or mutation causes the disease. In this specification, “deficiency” means that the expression of the protein from its coding gene is inhibited or lost to such an extent that the protein becomes undetectable, typically in its target site in the body of the affected subject (i.e., a cell compartment, cell type, tissue, or organ). Protein expression is affected at various levels, and a "deficiency" or "lack of production" of a protein in the body of an affected patient may result from mutations in coding genes, e.g., epigenetic changes or sequence mutations in either its open reading frame or its regulators (e.g., nonsense mutations or deletions leading to interference or exclusion of gene transcription), defects in mRNA processing (e.g., defects in mRNA splicing, maturation, or transport from the nucleus), defects in protein translation, or errors in protein folding, translocation (i.e., failure to enter the secretory pathway correctly), or transport (i.e., failure to enter its intended transport pathway correctly). A "deficiency" of a protein, i.e., a decrease in the amount of detectable protein at its target site (i.e., a cell compartment, cell type, tissue, or organ) within the body of the affected subject, can be caused by the same mechanisms that result in a complete lack of protein expression as exemplified above. However, defects leading to a protein "deficiency" do not necessarily completely prevent or eliminate protein expression from the affected gene; rather, they may lead to a decrease in expression levels (for example, if one allele is affected and the other allele functions normally). The term "mutation" encompasses both variants and differences in amino acid sequences in post-translational modifications of proteins. Protein "mutants" are typically non-functional or dysfunctional and may exhibit abnormal folding, translocation, or transport properties or characteristics.

[0120] "Therapeutic (poly)peptides or proteins are advantageous for treating infectious diseases or neoplasms, such as cancer or neoplastic diseases, diseases of the blood and hematopoietic organs, endocrine, nutritional intake and metabolic diseases, diseases of the nervous system, diseases of the circulatory system, diseases of the respiratory system, diseases of the digestive system, diseases of the skin and subcutaneous tissue, diseases of the musculoskeletal system and connective tissue, and diseases of the genitourinary system, whether hereditary or acquired." Therapeutic (poly)peptides or proteins include any (poly)peptides or proteins whose expression can prevent, improve or cure hereditary or acquired diseases. Such (poly)peptides or proteins may exert their therapeutic function by exerting any suitable biological action or function, in principle. In some embodiments, such (poly)peptides or proteins may not act by preferably substituting deficient, defective or mutant proteins and / or by inducing an immune or allergenic response. For example, (poly)peptides or proteins that are advantageous in treating hereditary or acquired diseases such as infections or neoplasms may include particularly favored therapeutic proteins that are especially advantageous in treating acquired or hereditary metabolic or endocrine disorders (indicated in parentheses the specific disease in which the therapeutic protein is used in treatment): acid sphingomyelinase (Niemann-Pick disease), adipotide (obesity), agalsidase-beta (human galactosidase A) (Fabry disease; prevents lipid accumulation that can lead to renal and cardiovascular complications), alglucosidase (Pompe disease (glycostored storage disease type II)), alpha-galactosidase A (alpha-GAL A, agalsidase alpha) (Fabry disease), alpha-glucosidase (glycostored storage disease (GSD), Pompe disease), alpha-L-iduronidase (mucopolysaccharidosis (MPS), Harler syndrome, Chaillet syndrome), alpha-N-acetylglucosaminidase (Sanfilippo syndrome), amphiregulin (cancer, metabolic disorders), angiopoietin (Ang1, Ang2, Ang3, Ang4, ANGPTL2, ANGPTL3, ANGPTL4, ANGPTL5, ANGPTL6, ANGPTL7) (vascular formation, vascular stabilization), betacerlin (metabolic disorders),Beta-glucuronidase (Sly syndrome), bone morphogenetic proteins (BMP1, BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8a, BMP8b, BMP10, BMP15) (regenerative effects, bone-related diseases, chronic kidney disease (CKD)), CLN6 protein (CLN6 disease - atypical late infancy type, late variant, early juvenile type, neuronal ceroid depathenia (NCL)), epidermal growth factor (EGF) (wound healing, regulation, increase, and differentiation of cell proliferation), epigen (metabolic disorders), epiregulin (metabolic disorders), fibroblasts Growth factors (FGF, FGF-1, FGF-2, FGF-3, FGF-4, FGF-5, FGF-6, FGF-7, FGF-8, FGF-9, FGF-10, FGF-11, FGF-12, FGF-13, FGF-14, FGF-16, FGF-17, FGF-17, FGF-18, FGF-19, FGF-20, FGF-21, FGF-22, FGF-23) (wound healing, vascular formation, endocrine disorders, tissue regeneration), galsulfase (mucopolysaccharidosis type VI), ghrelin (irritable bowel syndrome (IBS), obesity, Prader-Willi syndrome, type II diabetes) Glucocerebrosidase (Gaucher disease), GM-CSF (regenerative effect, leukocyte production, cancer), heparin-binding EGF-like growth factor (HB-EGF) (wound healing, cardiac hypertrophy and cardiac development and function), hepatocyte growth factor HGF (regenerative effect, wound healing), hepcidin (iron metabolism disorder, beta-thalassemia), human albumin (decreased albumin production (hypoproteinemia), increased albumin loss (nephrotic syndrome), decreased circulating blood volume, hyperbilirubinemia), idulosulfase (iduronate-2-sulfatase) (mucopolysaccharidosis type II (Hunter disease)) Syndrome), integrin alpha-V beta-3, alpha-V beta-5 and alpha-5 beta-1 (macromolecules and proteinases of the binding matrix, vascularization), iuzuronate sulfatase (Hunter syndrome), laronidase (Harler and Harler-Schaye forms of mucopolysaccharidosis type I), N-acetylgalactosamine-4-sulfatase (rhASB; galsulfase, arylsulfatase A (ARSA), arylsulfatase B (ARSB)) (arylsulfatase B deficiency, Maloto-Lamy syndrome, mucopolysaccharidosis type VI),N-acetylglucosamine-6-sulfatase (Sanfilippo syndrome), neurotrophin (NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin 4 / 5 (NT-4 / 5) (regenerative effect, cardiovascular disease, coronary artery sclerosis, obesity, type 2 diabetes, metabolic syndrome, acute coronary syndrome, dementia, depression, schizophrenia, autism, Rett syndrome, anorexia nervosa, bulimia nervosa, wound healing, skin ulcers, corneal ulcers, Alzheimer's disease), neuregulin (NRG1, NRG2, NRG3, NRG4) (metabolic disorders, schizophrenia), neuropilin (NRP-1, NRP-2) (vascular formation, axon guidance, cell survival, migration), obestatin (irritable bowel syndrome (IBS), obesity, Prader-Willi syndrome, type 2 diabetes), platelet-derived growth factor (P DGF (PDGF-A, PDGF-B, PDGF-C, PDGF-D) (regenerative effect, wound healing, vascular formation disorders, arteriosclerosis, fibrosis, cancer), TGF-beta receptor (endoglin, TGF-beta-1 receptor, TGF-beta-2 receptor, TGF-beta-3 receptor) (renal fibrosis, kidney disease, diabetes, ultimately end-stage renal disease (ESRD), vascular formation), thrombopoietin (THPO) (megakaryocyte growth factor (MGDF)) (platelet disorders, donated platelets, platelet count after myelosuppressive chemotherapy) (Recovery), Exchange Growth Factor (TGF (TGF-α, TGF-Beta (TGF-Beta 1, TGF-Beta 2, and TGF-Beta 3))) (Regenerative effect, wound healing, immunity, cancer, heart disease, diabetes, Marfan syndrome, Loeys-Dietz syndrome), VEGF (VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F, and PIGF) (Regenerative effect, vascularization, wound healing, cancer, permeability), Nesiritide (Acute decompensated congestive heart failure), Trypsin (Pressure ulcers) (varicose vein ulcers, cleaning of escalators, dehiscences, sunburn, meconium ileus), adrenocorticotropic hormone (ACTH) (Addison's disease, small cell carcinoma, adrenoleukodystrophy, congenital adrenal hyperplasia, Cushing's syndrome, Nelson syndrome, infantile seizures), atrial natriuretic peptide (ANP) (endocrine disorders), cholecystokinin (various), gastrin (hypogastrinemia), leptin (diabetes mellitus, hypertriglyceridemia, obesity), oxytocin (promotes lactation, halts labor progression),Somatostatin (symptomatic treatment for carcinoid syndrome, acute variceal bleeding, and acromegaly, polycystic disease of the liver and kidneys, symptoms of acromegaly and neuroendocrine tumors), vasopressin (antidiuretic hormone) (diabetes insipidus), calcitonin (postmenopausal osteoporosis, hypercalcemia, Paget's disease, bone metastases, phantom limb pain, spinal stenosis), exenatide (type 2 diabetes resistant to metformin and sulfonylurea treatment), growth hormone (GH), somatotropin (growth hormone) Mon deficiency or growth retardation due to chronic renal failure, Prader-Willi syndrome, Turner syndrome, AIDS wasting or cachexia due to antiviral treatment), insulin (diabetes, diabetic ketoacidosis, hyperkalemia), insulin-like growth factor 1 IGF-1 (growth retardation in children with GH gene deletion or severe primary IGF1 deficiency, neurodegenerative diseases, cardiovascular diseases, heart failure), mecasermin lymphabate IGF-1 analog (GH gene deletion or severe primary IGF1 deficiency) Growth retardation, neurodegenerative diseases, cardiovascular diseases, and heart failure in children with F1 deficiency), mecasermin, IGF-1 analogs (growth retardation, neurodegenerative diseases, cardiovascular diseases, and heart failure in children with GH gene deletion or severe primary IGF1 deficiency), pegvisomant (acromegaly), pramulintide (diabetes, used in combination with insulin), teriparatide (human parathyroid hormone residues 1-34) (severe osteoporosis), becaprelmin (a cleansing aid for diabetic ulcers), dibotermin-alf a(bone morphogenetic protein 2) (spinal fusion, bone injury repair), histrelin acetate (gonadotropin-releasing hormone; GnRH) (precocious puberty), octreotide (relief of symptoms in acromegaly, VIP secretory adenoma, and metastatic carcinoid tumors), and palifermin (keratinocyte growth factor; KGF) (severe oral mucositis in patients undergoing chemotherapy and wound healing), or isoforms, homologs, fragments, variants, or derivatives of any of these proteins.

[0121] These and other proteins are understood to be therapeutic because they treat the target by adequately replacing the incomplete endogenous production of functional proteins.

[0122] Therefore, such therapeutic proteins are typically mammalian proteins, particularly human proteins.

[0123] The following therapeutic proteins may be used to treat acquired or hereditary blood disorders, cardiovascular diseases, respiratory diseases, cancer or neoplastic diseases, infections or immunodeficiencies (the specific disease for which the therapeutic protein is used for treatment is indicated in parentheses): alteplase (tissue plasminogen activator; tPA) (pulmonary embolism, myocardial infarction, acute ischemic stroke, central venous access device occlusion), anistreplase (thrombolysis), antithrombin III (AT-III) (hereditary AT-III deficiency, thromboembolism), bivalirudin (reduces the risk of blood coagulation in coronary angioplasty and heparin-induced thrombocytopenia), darbepoetin alfa (chronic renal insufficiency and chronic renal Treatment of anemia in patients undergoing dialysis (+ / - failure), drolecogin alfa (active protein C) (severe sepsis with high mortality risk), erythropoietin, epoetin alfa, erythropoietin, ertropoetin (anemia due to chronic disease, myelodysplasia, renal failure or chemotherapy-induced anemia, preoperative preparation), factor IX (hemophilia B), factor VIIa (inhibitor of bleeding and factor VIII or factor IX in patients with type A or B hemophilia), factor VIII (hemophilia A), repiridine (heparin-induced thrombocytopenia), type C protein concentrate (venous thrombosis, fulminant purpura), leteplase (tPA deletion mutant protein) (management of acute myocardial infarction, ventricular function) (improvement of), streptokinase (acute progressive transmural myocardial infarction, pulmonary embolism, deep vein thrombosis, arterial thrombosis or embolism, arteriovenous cannula occlusion), tenecteplase (acute myocardial infarction), urokinase (pulmonary embolism), angiostatin (cancer), anti-CD22 immunotoxin (relapsed CD33+ acute myeloid leukemia), denileukin difuticotox (cutaneous T-cell lymphoma (CTCL)), immunocyanin (bladder and prostate cancer), MPS (metallopanthimulin) (cancer), aflibercept (non-small cell lung cancer (NSCLC), metastatic colorectal cancer (mCRC), hormone-refractory metastatic prostate cancer, wet macular degeneration), endostatin (cancer, inflammatory diseases such as rheumatoid arthritis and Crohn's disease, diabetic retinopathy, psoriasis,(and endometriosis), collagenase (cleaning of chronic skin ulcers and severe burns, Dupuytren's contracture, Pyronie's disease), star deoxyribonuclease I, dorunase (cystic fibrosis; reduces respiratory infections in selected patients with FVC exceeding 40% of the predicted value), hyaluronidase (used as an adjuvant to enhance the absorption and dispersion of injected drugs, especially ophthalmic surgery and certain contrast agents), papain (cleaning of necrotic tissue or liquefaction of decayed flesh in acute and chronic lesions, pressure ulcers, varicose veins and diabetic ulcers, burns, postoperative wounds, pilonidal cyst wounds, carbuncles, and other wounds), L-asparaginase (acute lymphoblastic leukemia, requires exogenous asparagine for proliferation), pegasparaginase (acute lymphoblastic leukemia, requires exogenous asparagine for proliferation), rasburicase ( Childhood leukemia patients, lymphoma, and solid tumors undergoing anticancer treatment that may cause tumor lysis syndrome), human chorionic gonadotropin (HCG) (assisted reproductive technology), human follicle-stimulating hormone (FSH) (assisted reproductive technology), luteinizing alpha (infertility with luteinizing hormone deficiency), prolactin (hypoprolactinemia, serum prolactin deficiency, ovarian dysfunction in women, anxiety, arterial erectile dysfunction, premature ejaculation, oligospermia, asthenospermia, seminal vesicle dysfunction, androgen deficiency in men), alpha-1 proteinase inhibitors (congenital antitrypsin deficiency), lactase (gas, abdominal distension, cramps and diarrhea due to lactose indigestion), pancreatic enzymes (lipase, amylase, protease) (cystic fibrosis, chronic pancreatitis, pancreatic insufficiency, post-Billroth II gastric bypass surgery) II gastric bypass surgery), pancreatic duct obstruction, steatorrhea, indigestion, gas, abdominal distension), adenosine deaminonase (bovine pegademase, PEG-ADA) (severe combined immunodeficiency disease due to adenosine deaminase deficiency), abatacept (rheumatoid arthritis (especially in cases unresponsive to TNFα suppression)), alefacept (psoriasis vulgaris), anakinra (rheumatoid arthritis), etanercept (rheumatoid arthritis, polyarticular juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, psoriasis vulgaris, ankylosing spondylitis), interleukin-1 (IL-1) receptor antagonist, anakinra (inflammation and cartilage deterioration associated with rheumatoid arthritis),Thymurin (neurodegenerative diseases, rheumatism, anorexia nervosa), TNF-alpha antagonists (autoimmune disorders such as rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, psoriasis, hidradenitis suppurativa, and refractory asthma), enfuvirtide (HIV-1 infection), and thymosin alpha-1 (hepatitis B and C), or isoforms, homologs, fragments, variants, or derivatives of any of these proteins.

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P6、FLNA、FLT4、FMO3、FMO4、FMR2、FMR1、FN、FN1 / m、FOXC1、FOXE1、FOXL2、FOXO1A、FPDMM、FPF、Fra-1、FRAXF、FRDA、FSH B、FSHMD1A、FSHR、FTH1、FTHL17、FTL、FTZF1、FUCA1、FUT2、FUT6、FUT1、FY、G250、G250 / CAIX、G6PC、G6PD、G6PT1、G6PT2、 GAA、GABRA3、GAGE-1、GAGE-2、GAGE-3、GAGE-4、GAGE-5、GAGE-6、GAGE-7b、GAGE-8、GALC、GALE、GALK1、GALNS、GALT、GAM T、GAN、GAST、GASTRIN17、GATA3、GATA、GBA、GBE、GC、GCDH、GCGR、GCH1、GCK、GCP-2、GCS1、G-CSF、GCSH、GCSL、GCY、GDEP、GDF5, GDI1, GDNF, GDXY, GFAP, GFND, GGCX, GGT1, GH2, GH1, GHR, GHRHR, GHS, GIF, GINGF, GIP, GJA3, GJA8, GJB2, GJB3, GJB6, GJB1, GK, GLA, GLB, GLB1, G LC3B, GLC1B, GLC1C, GLDC, GLI3, GLP1, GLRA1, GLUD1, GM1(fuc-GM1), GM2A, GM-CSF, G MPR、GNAI2、GNAS、GNAT1、GNB3、GNE、GNPTA、GNRH、GNRH1、GNRHR、GNS、GnT-V、gp100、GP 1BA、GP1BB、GP9、GPC3、GPD2、GPDS1、GPI、GP1BA、GPN1LW、GPNMB / m、GPSC、GPX1、GRHPR GRK1, GROα, GROβ, GROγ, GRPR, GSE, GSM1, GSN, GSR, GSS, GTD, GTS, GUCA1A, GUCY2D, GU LOP、GUSB、GUSM、GUST、GYPA、GYPC、GYS1、GYS2、H0KPP2、H0MG2、HADHA、HADHB、HAGE、H AGH、HAL、HAST-2、HB1、HBA2、HBA1、HBB、HBBP1、HBD、HBE1、HBG2、HBG1、HBHR、HBP1、HBQ 1、HBZ、HBZP、HCA、HCC-1、HCC-4、HCF2、HCG、HCL2、HCL1、HCR、HCVS、HD、HPN、HER2、HER 2 / NEU、HER3、HERV-K-MEL、HESX1、HEXA、HEXB、HF1、HFE、HF1、HGD、HHC2、HHC3、HHG、HK1 HLA-A, HLA-A*0201-R170I, HLA-A11 / m, HLA-A2 / m, HLA-DPB1 HLA-DRA, HLCS, HLXB9, HMBS, HMGA2, HMGCL, HMI, HMX2, HMO1, HMO1 HMW-MAA、HND、HNE、HNF4A、HOAC、HOMEOBOX NKX3.1、HOM-TES-14 / SCP-1、HOM-TES-85、HOXA1 HOXD13, HP, HPC1, HPD, HPE2, HPE1, HPFH, HPFH2, HPRT1, HPS1, HPT, HPV-E6 HPV-E7, HR, HRAS, HRD, HRG, HRPT2, HRPT1, HRX, HSD11B2, HSD17B3, HSD17B4 HSD3B2, HSD3B3, HSN1, HSP70-2M, HSPG2, HST-2, HTC2, HTC1, hTERT, HTN3, HT R2C, HVBS6, HVBS1, HVEC, HV1S, HYAL1, HYR, I-309, IAB, IBGC1, IBM2, ICAM1ICAM3, iCE, ICHQ, ICR5, ICR1, ICS1, IDDM2, IDDM1, IDS, IDUA, IF, IFNa / b, IFNGR1, IGAD1, IGER, IGF-1R, IGF2R, IGF1, IGH, IGHC, IGHG2, IGHG1, IGHM, IGHR, IGKC, IHG1, IHH, IKBKG, IL1, IL-1RA, IL10, IL-11, IL12, IL12RB1, IL13, IL-13R alpha2, IL-15, IL-16, IL-17, IL18, IL-1a, IL-1 alpha, IL-1b, IL-1 beta, IL1RAPL1, IL2, IL24, IL-2R, IL2RA, IL2RG, IL3, IL3RA, IL4, IL4R, IL4R, IL-5, IL6, IL-7, IL7R, IL-8, IL-9, immature laminin receptor, IMMP2L, INDX, INFGR1, INFGR2, INF alpha, IFN beta, INF gamma, INS, INSR, INVS, IP-10, IP2, IPF-1, IP1, IRF6, IRS1, ISCW, ITGA2, ITGA2B, ITGA6, ITGA7, ITGB2, ITGB3, ITGB4, ITIH1, ITM2B, IV, IVD, JAG1, JAK3, JBS, JBTS1, JMS, JPD, KAL1, KAL2, KALI, KLK2, KLK4, KCNA1, KCNE2, KCNE1, KCNH2, KCNJ1, KCNJ2, KCNJ1, KCNQ2, KCNQ3, KCNQ4, KCNQ1, KCS, KERA, KFM, KFS, KFSD, KHK, ki-67, KIAA0020, KIAA0205, KIAA0205 / m, KIF1B, KIT, KK-LC-1, KLK3, KLKB1, KM-HN-1, KMS, KNG, KNO, K-RAS / m, KRAS2, KREV1, KRT1, KRT10, KRT12, KRT13, KRT14, KRT14L1, KRT14L2, KRT14L3, KRT16, KRT16L1, KRT16L2, KRT17, KRT18, KRT2A, KRT3, KRT4, KRT5, KRT6A, KRT6B, KRT9, KRTHB1, KRTHB6, KRT1, KSA, KSS, KWE, KYNU, L0H19CR1, L1CAM, LAGE, LAGE-1, LALL, LAMA2, LAMA3, LAMB3, LAMB1, LAMC2, LAMP2, LAP, LCA5LCAT, LCCS, LCCS1, LCFS2, LCS1, LCT, LDHA, LDHB, LDHC, LDLR, LDLR / FUT, LEP, LEWISY, LGCR, LGGF-PBP, LGI1, LGMD2H, LGMD1A LGMD1B, LHB, LHCGR, LHON, LHRH, LHX3, LIF, LIG1, LIMM, LIMP2 LIPA, LIPA, LIPB, LIPC, LIVIN, L1CAM, LMAN1, LMNA, LMX1B, LO LR, LOR, LOX, LPA, LPL, LPP, LQT4, LRP5, LRS1, LSFC, LT-ベー, L TBP2, LTC4S, LYL1, XCL1, LYZ, M344, MA50, MAA, MADH4, MAFD2, M AFD1、MAGE、MAGE-A1、MAGE-A10、MAGE-A12、MAGE-A2、MAGE-A3、MAGE-A4、MAGE-A6、MAGE-A9、MAGEB1、MAGE-B10、MAGE-B16、MAG E-B17、MAGE-B2、MAGE-B3、MAGE-B4、MAGE-B5、MAGE-B6、MAGE-C1、MAGE-C2、MAGE-C3、MAGE-D1、MAGE-D2、MAGE-D4、MAGE-E1、M AGE-E2, MAGE-F1, MAGE-H1, MAGEL2, MGB1, MGB2, MAN2A1, MAN2B1, MANBA, MANBB, MAOA, MAOB, MAPK8IP1, MAPT, MART-1, MART-2 MART2 / m, MAT1A, MBL2, MBP, MBS1, MC1R, MC2R, MC4R, MCC, MCCC2, MCCC1, MCDR1, MCF2, MCKD, MCL1, MC1R, MCOLN1, MCOP, MCOR CP-1, MCP-2, MCP-3, MCP-4, MCPH2, MCPH1, MCS, M-CSF, MDB, MDC R, MDM2, MDRV, MDS1, ME1, ME1 / m, ME2, ME20, ME3, MEAX, MEB, MEC CCL-28, MECP2, MEFV, MELANA, MELAS, MEN1, MSLN, MET, MF4, MG50, MG50 / PXDN, MGAT2, MGAT5, MGC1 MGCR, MGCT, MGI, MGP, MHC2TA, MHS2, MHS4, MIC2, MIC5, MIDI, MIF, MIP, MIP-5 / HCC-2, MITF, MJD, MKI67, MKKS.MKS1, MLH1, MLL, MLLT2, MLLT3, MLLT7, MLLT1, MLS, MLYCD, MMA1a, MMP11, MMVP1, MN / CA IX-Antigen、MNG1、MN1、MOC31、MOCS2、MOCS1、MOG、MORC、MOS、MOV18、M PD1, MPE, MPFD, MPI, MPIF-1, MPL, MPO, MPS3C, MPZ, MRE11A, MROS, MRP1 MRP2, MRP3, MRSD, MRX14, MRX2, MRX20, MRX3, MRX40, MRXA, MRX1, MS, M S4A2, MSD, MSH2, MSH3, MSH6, MSS, MSSE, MSX2, MSX1, MTATP6, MTC03, MT CO1, MTCYB, MTHFR, MTM1, MTMR2, MTND2, MTND4, MTND5, MTND6, MTND1, M TP, MTR, MTRNR2, MTRNR1, MTRR, MTTE, MTTG, MTTI, MTTK, MTTL2, MTTL1 MTTN, MTTP, MTTS1, MUC1, MUC2, MUC4, MUC5AC, MUM-1, MUM-1 / m, MUM-2 MUM-2 / m, MUM-3, MUM-3 / m, MUT, mutantp21ras, MUTYH, MVK, MX2, MXI1; MY05A, MYB, MYBPC3, MYC, MYCL2, MYH6, MYH7, MYL2, MYL3, MYMY, MYO15A MYO1G, MYO5A, MYO7A, MYOC, Myosin / m, MYP2, MYP1, NA88-A, N-linkage Pyrenees Arena-V, NAGA, NAGLU, NAMSD, NAPB, NAT2, NAT, NBIA1, NBS1 NCAM, NCF2, NCF1, NDN, NDP, NDUFS4, NDUFS7, NDUFS8, NDUFV1, NDUFV2 NEB, NEFH, NEM1, Neo-PAP, neo-PAP / m, NEU1, NEUROD1, NF2, NF1, NFYC / m、NGEP、NHS、NKS1、NKX2E、NM、NME1、NMP22、NMTC、NODAL、NOG、NOS3、N OTCH3, NOTCH1, NP, NPC2, NPC1, NPHL2, NPHP1, NPHS2, NPHS1, NPM / ALK. NPPA, NQO1, NR2E3, NR3C1, NR3C2, NRAS, NRAS / m, NRL, NROB1, NRTN, NSE.NSX, NTRK1, NUMA1, NXF2, NY-CO1, NY-ESO1, NY-ESO-B, NY-LU-12, ALDOA, NYS2, N YS4, NY-SAR-35, NYS1, NYX, OA3, OA1, OAP, OASD, OAT, OCA1, OCA2, OCD1, OCRL, OC RL1、OCT、ODDD、ODT1、OFC1、OFD1、OGDH、OGT、OGT / m、OPA2、OPA1、OPD1、OPEM、OPG 、OPN、OPN1LW、OPN1MW、OPN1SW、OPPG、OPTB1、TTD、ORM1、ORP1、OS-9、OS-9 / m、OSM LIF、OTC、OTOF、OTSC1、OXCT1、OYTES1、P15、P190マイナーB CR-ABL, P2RY12, P3, P16, P40, P4HB, P-501, P53, P53 / m P97 PABPN1, PAFAH1B1, PAFAH1P1, PAGE-4, PAGE-5, PAH, PAI-1, PAI-2, PAK3, PAP, PAPPA, PARK2, PART-1, PATE. PAX2, PAX3, PAX6, PAX7, PAX8, PAX9, PBCA, PBCRA1, PBT, PBX1, PBXP1, PC, PCBD, PCCA, PCCB, PCK2, PCK1, PCLD, PC OS1, PCSK1, PDB1, PDCN, PDE6A, PDE6B, PDEF, PDGFB, PDGFR, PDGFRL, PDHA1, PDR, PDX1, PECAM1, PEE1, PEO1, PEPD PEX10, PEX12, PEX13, PEX3, PEX5, PEX6, PEX7, PEX1, PF4, PFBI, PFC, PFKFB1, PFKM, PGAM2, PGD, PGK1, PGK1P1 PGL2, PGR, PGS, PHA2A, PHB, PHEX, PHGDH, PHKA2, PHKA1, PHKB, PHKG2, PHP, PHYH, PI, PI3, PIGA, PIM1-KINASE, PI N1, PIP5K1B, PITX2, PITX3, PKD2, PKD3, PKD1, PKDTS, PKHD1, PKLR, PKP1, PKU1, PLA2G2A, PLA2G7, PLAT, PLEC1 LG, PLI, PLOD, PLP1, PMEL17, PML, PML / RAR, PMM2, PMP22, PMS2, PMS1, PNKD, PNLIP, POF1, POLA, POLH, POMC.PON2、PON1、PORC、POTE、POU1F1、POU3F4、POU4F3、POU1F1、PPAC、PPARG、PPCD、PPGB、PPH1、PPKB、PPMX、PPOX、PPP1R3A、PPP2R2B、PPT1、PRAME、PRB、PRB3、 PRCA1, PRCC, PRD, PRDX5 / m, PRF1, PRG4, PRKAR1A, PRKCA, PRKDC, PRKWNK4 PRNP, PROC, PRODH, PROM1, PROP1, PROS1, PRST, PRP8, PRPF31, PRPF8, PRPH2 PRPS2, PRPS1, PRS, PRSS7, PRSS1, PRTN3, PRX, PSA, PSAP, PSCA, PSEN2, PSE N1、PSG1、PSGR、PSM、PSMA、PSORS1、PTC、PTCH、PTCH1、PTCH2、PTEN、PTGS1、PT H、PTHR1、PTLAH、PTOS1、PTPN12、PTPNil、PTPRK、PTPRK / m、PTS、PUJO、PVR、P VRL1, PWCR, PXE, PXMP3, PXR1, PYGL, PYGM, QDPR, RAB27A, RAD54B, RAD54L, RA G2、RAGE、RAGE-1、RAG1、RAP1、RARA、RASA1、RBAF600 / m、RB1、RBP4、RBP4、RB S、RCA1、RCAS1、RCCP2、RCD1、RCV1、RDH5、RDPA、RDS、RECQL2、RECQL3、RECQL4 REG1A, REHOBE, REN, RENBP, RENS1, RET, RFX5, RFXANK, RFXAP, RGR, RHAG, R HAMM / CD168, RHD, RHO, Rip-1, RLBP1, RLN2, RLN1, RLS, RMD1, RMRP, ROM1, RO R2, RP, RP1, RP14, RP17, RP2, RP6, RP9, RPD1, RPE65, RPGR, RPGRIP1, RP1, RP 10、RPS19、RPS2、RPS4X、RPS4Y、RPS6KA3、RRAS2、RS1、RSN、RSS、RU1、RU2、RUN X2、RUNXl、RWS、RYR1、S-100、SAA1、SACS、SAG、SAGE、SALL1、SARDH、SART1、S ART2、SART3、SAS、SAX1、SCA2、SCA4、SCA5、SCA7、SCA8、SCA1、SCC、SCCD、SCF、 SCLC1, SCN1A, SCN1B, SCN4A, SCN5A, SCNN1A, SCNN1B, SCNN1G, SCO2, SCP1, S CZD2、SCZD3、SCZD4、SCZD6、SCZD1、SDF-1、SDHA、SDHD、SDYS、SEDL、SERPENA7、SERPINA3、SERPINA6、SERPINA1、SERPINC1、SERPIND1、SERPINE1、SERPINF2、SERPING1、SERPINI1、SFTPA1、SFTPB 、SFTPC、SFTPD、SGCA、SGCB、SGCD、SGCE、SGM1、SGSH、SGY-1、SH2D1A、SHBG、SHFM2、SHFM3、SHFM1、SHH、SHOX、SI、SIAL、SIALYL LEWISX、SIASD、S11、SIM1、SIRT2 / m、SIX3、SJS1、SKP2、SLC10A2、SLC12A1、SLC12A3、SLC17A5、SLC19A2、SLC22A1L、SLC22 A5、SLC25A13、SLC25A15、SLC25A20、SLC25A4、SLC25A5、SLC25A6、SLC26A2、SLC26A3、SLC26A4、SLC2A1、SLC2A2、SLC2A4、 SLC3A1, SLC4A1, SLC4A4, SLC5A1, SLC5A5, SLC6A2, SLC6A3, SLC6A4, SLC7A7, SLC7A9, SLC11A1, SLOS, SMA, SMAD1, SMAL, SMARCB1, SMAX2, SMCR, SMCY, SM1, SMN2, SMN1, SMPD1, SNCA, SNRPN, SOD2, SOD3, SOD1, SOS1, SOST, SOX9, SOX10, Sp17, SANX C、SPG23、SPG3A、SPG4、SPG5A、SPG5B、SPG6、SPG7、SPINK1、SPINK5、SPPK、SPPM、SPSMA、SPTA1、SPTB、SPTLC1、SRC、SRD5A2 、SRPX、SRS、SRY、βhCG、SSTR2、SSX1、SSX2(HOM-MEL-40 / SSX2)、SSX4、ST8、STAMP-1、STAR、STARP1、STATH、STEAP、STK2、ST SYT-SSX -2、TA-90、TAAL6、TACSTD1、TACSTD2、TAG72、TAF7L、TAF1、TAGE、TAG-72、TALI、TAM、TAP2、TAP1、TAPVR1、TARC、TARP、TAT、TAZ、TBP、TBX22、TBX3、TBX5、TBXA2R、TBXAS1、TCAP、TCF2、TCF1、TCIRG1、TCL2、TCL4、TCL1A、TCN2、TCOF1、TCR、T CRA、TDD、TDFA、TDRD1、TECK、TECTA、TEK、TEL / AML1、TEL AB1、TEX15、TF、TFAP2B、TFE3、TFR2、TG、TGFアルファ、TGFベータ、TGFベータI、TGFベータ1、TGFベータR2、TGFベータRE、TGFガンマ、TGFベータRII、TGIF、TGM-4、TGM1、TH、THAS、THBD、THC、THC2、THM 、THPO、THRA、THRB、TIMM8A、TIMP2、TIMP3、TIMP1、TITF1、TKCR、TKT、TLP、TLR1、TLR10、TLR2、TLR3、TLR4、TLR4、TL R5、TLR6、TLR7、TLR8、TLR9、TLX1、TM4SF1、TM4SF2、TMC1、TMD、TMIP、TNDM、TNF、TNFRSF11A、TNFRSF1A、TNFRSF6、T NFSF5、TNFSF6、TNFアルファ、TNFベータ、TNNI3、TNNT2、TOC、TO P2A、TOP1、TP53、TP63、TPA、TPBG、TPI、TPI / m、TPI1、TPM3 、TPM1、TPMT、TPO、TPS、TPTA、TRA、TRAG3、TRAPPC2、TRC8、TREH、TRG、TRH、TRIM32、TRIM37、TRP1、TRP2、TRP-2 / 6b、 TRP-2 / INT2、Trp-p8、TRPS1、TS、TSC2、TSC3、TSC1、TSG101、TSHB、TSHR、TSP-180、TST、TTGA2B、TTN、TTPA、TTR、TU M2-PK, TULP1, TWIST, TYH, TYR, TYROBP, TYROBP, TYRP1, TYS, UBE2A, UBE3A, UBE1, UCHL1, UFS, UGT1A, ULR, UMPK, UMPS, UOX, UPA, UQCRC1, URO5, UROD, UPK1B UROS、USH2A、USH3A、USH1A、USH1C、USP9Y、UV24、VBCH、VCF、VDI、VDR、VEGF、VE GFR-2、VEGFR-1、VEGFR-2 / FLK-1、VHL、VIM、VMD2、VMD1、VMGLOM、VNEZ、VNF、VP、VRNI, VWF, VWS, WAS, WBS2, WFS2, WFS1, WHCR, WHN, WISP3, WMS, WRN, WS2A, WS2B, WSN, WSS, WT2, WT3, WT1, WTS, WWS, XAGE, XDH, XIC, XIST, XK, XM, XPA, XPC, XRCC9, XS, ZAP70, ZFHX1B, ZFX, ZFY, ZIC2, ZIC3, ZNF145, ZNF261, ZNF35, ZNF41, ZNF6, ZNF198, and ZWS1, or any isoform, homolog, fragment, variant, or derivative of any of these proteins may be selected.

[0125] Furthermore, therapeutic (poly)peptides or proteins include AIF, Apaf, e.g., Apaf-1, Apaf-2, Apaf-3, or APO-2(L), APO-3(L), ​​apopine, Bad, Bak, Bax, Bcl-2, Bcl-x[L], Bcl-x[s], bik, CAD, calpain, caspases, e.g., caspase-1, caspase-2, caspase-3, caspase-4, caspase-5, caspase-6, caspase-7, caspase-8, caspase-9, caspase-10, caspase-11, ced-3, ced-9, c-Jun, c-Myc, crm A, and cytochromes. CCdR1, DcR1, DD, DED, DISC, DNA-PKc[S], DR3, DR4, DR5, FADD / MORT-1, FAK, Fas (Fas-ligand CD95 / fas(receptor)), FLICE / MACH, FLIP, Fodrin, Phos, G-actin, Gas-2, Gerzolin, Granzyme A / BICAD, ICE, JNK, Lamin A / B, MAP, MCL-1, Mdm-2, MEKK-1, MORT-1, NEDD, NF-[kappa]B, NuMa, p53, PAK-2, PARP, Perforin, PITSLRE, PKC The selection may include apoptotic factors or apoptosis-related proteins, such as delta, pRb, presenilin, prICE, RAIDD, Ras, RIP, sphingomyelinase, herpes simplex-derived thymidine kinase, TRADD, TRAF2, TRAIL-R1, TRAIL-R2, TRAIL-R3, transglutaminase, etc., or isoforms, homologs, fragments, variants, or derivatives of any of these proteins.

[0126] The term "adjuvant" (poly)peptide or protein generally refers to any (poly)peptide or protein that can modify the effects of other drugs (typically other activators administered concurrently). Preferably, "adjuvant or immunostimulant" (poly)peptides or proteins can enhance or modulate a desired immune response to an antigen (preferably co-administered). In particular, "adjuvant or immunostimulant" (poly)peptides or proteins, when used in combination with a specific antigen, can act to promote, prolong, or enhance the immune response. To this end, "adjuvant or immunostimulant" (poly)peptides or proteins can assist in the administration and transport of the co-administered antigen, enhance the (antigen-specific) immunostimulation of the co-administered antigen, and / or initiate or increase an immune response of the innate immune system, i.e., a non-specific immune response. The exemplary “adjuvant or immunostimulatory (poly)peptides or proteins” envisioned in the present invention include, for example, mammalian proteins, particularly human adjuvant proteins (typically any human protein or peptide), that can induce an innate immune response (in mammals) as a binding reaction of an exogenous TLR ligand to a TLR.More preferably, the human adjuvant protein is TLR, NLR and RLH including TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11; NOD1, NOD2, NOD3, NOD4, NOD5, NALP1, NALP2, NALP3, NALP4, NALP5, NALP6, NALP6, NALP7, NALP7, NALP8, NALP9, NALP10, NALP 11, components and ligands of the signaling network of pattern recognition receptors including NALP12, NALP13, NALP14, lIPAF, NAIP, CIITA, RIG-I, MDA5 and LGP2, signaling molecules of TLR signaling including adapter proteins such as Trif and Cardif; components of Small-GTPases signaling (RhoA, Ras, Rac1, Cdc42, Rab, etc.), PIP ligands Components of NAL (PI3K, Src-kinase, etc.), components of MyD88-dependent signals (MyD88, IRAK1, IRAK2, IRAK4, TIRAP, TRAF6, etc.), components of MyD88-independent signals (TICAM1, TICAM2, TRAF6, TBK1, IRF3, TAK1, IRAK1, etc.); for example, Akt, MEKK1, MKK1, MKK3, MKK4, MKK6, MKK7, ERK1, ERK2, GSK3, PKC kinase The group consists of proteins that are isoforms, homologs, fragments, variants, or derivatives of any of these proteins, such as PKD kinase, GSK3 kinase, JNK, p38MAPK, TAK1, IKK, and activating kinases including TAK1; activating transcription factors including, for example, NF-Kappa B, c-Fos, c-Jun, c-Myc, CREB, AP-1, Elk-1, ATF2, IRF-3, and IRF-7.

[0127] Adjuvants (preferably mammalian) (poly)peptides or proteins may further include heat shock proteins (HSP10, HSP60, HSP65, HSP70, HSP75 and HSP90, gp96, fibrinogen, fibronectin, and TypIII repeat extra domain A). A) etc.); or components of the complement system (C1q, MBL, C1r, C1s, C2b, Bb, D, MASP-1, MASP-2, C4b, C3b, C5a, C3a, C4a, C5b, C6, C7, C8, C9, CR1, CR2, CR3, CR4, C1qR, C1INH, C4bp, MCP, DAF, H, I, P and CD59 etc.); or induced target genes (e.g., beta-defensins, cell surface proteins etc.); or human adjuvant proteins (e.g., trif, flt-3 ligand, Gp96 or fibronectin etc.), or can be selected from the group consisting of isoforms, homologs, fragments, variants or derivatives of any of these proteins.

[0128] The adjuvant (preferably mammalian) (poly)peptide or protein may be further selected from the group consisting of cytokines that induce or enhance innate immune responses, such as IL-1 alpha, IL-1 beta, IL-2, IL-6, IL-7, IL-8, IL-9, IL-12, IL-13, IL-15, IL-16, IL-17, IL-18, IL-21, IL-23, TNF alpha, IFN alpha, IFN beta, IFN gamma, GM-CSF, G-CSF, and M-CSF; chemokines such as IL-8, IP-10, MCP-1, MIP-1 alpha, RANTES, eotaxin, and CCL21; cytokines released from macrophages, such as IL-1, IL-6, IL-8, IL-12, and TNF alpha; and isoforms, homologs, fragments, variants, or derivatives of IL-1R1 and IL-1 alpha, or any of these proteins.

[0129] As used herein, the term “antibody” (Ab) includes monoclonal antibodies, polyclonal antibodies, monospecific and multispecific antibodies (e.g., bispecific antibodies), as well as antibody fragments, variants, and derivatives, insofar as they exhibit a desired biological function, typically the ability to specifically bind to a target. As used herein, “specifically bind” means that an antibody binds more readily to its intended target than to another nonspecific target. In other words, an antibody “specifically binds” or “binding specificity” to its target if it selectively binds to or recognizes a target even in the presence of non-targets measurable by quantifiable analysis (such as radioligand binding analysis, ELISA, fluorescence-based techniques (e.g., fluorescence polarization (FP), fluorescence resonance energy transfer (FRET)), or surface plasmon resonance). An antibody that “specifically binds” to its target may or may not cross-react to targets originating from different species (homologous targets).

[0130] Basic naturally occurring antibodies are heterotetrameric glycoproteins composed of two identical light (L) chains and two identical heavy (H) chains. Some antibodies may contain additional polypeptide chains, such as the J chain in IgM and IgA antibodies. Each L chain is linked to an H chain by one covalent disulfide bond, while the two H chains are linked to each other by one or more disulfide bonds depending on the H chain isotype. Each H and L chain also contains intrachain disulfide crosslinks. Each H chain has an N-terminal variable region (V H ) and the following three constant regions for the α and γ chains respectively (C H ) and four C for μ and ε isotypes H Includes a region. Each L chain has a variable region (V) at its N-terminus. L ) has a steady region at the opposite end. L is V H They are aligned to C L This is the first steady region of the heavy chain (C H1). Specific amino acid residues are thought to form an interface between the light chain variable region and the heavy chain variable region.

[0131] The L chain of any vertebrate species can be assigned to one of two distinct types called kappa and lambda based on the amino acid sequence of its constant region. Depending on the amino acid sequence of their heavy chain constant regions (C H ), immunoglobulins can be assigned to different classes or isotypes. There are five classes of immunoglobulins: namely, IgA, IgD, IgE, IgG, and IgM, each having a heavy chain designated as α, β, ε, γ, and μ, respectively. The γ and μ classes are further divided into subclasses based on relatively small differences in the sequence and function of CH. For example, humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.

[0132] V H and V LThe pairing with the antibody forms a single antigen-binding site. The term "variable" refers to the fact that the sequence of a particular segment of the variable region differs significantly from antibody to antibody. The V region mediates antigen binding and defines the specificity of a particular antibody to a particular antigen. However, variability is not evenly distributed across the entire range of the variable region. Instead, the V region consists of relatively invariant continuous sequences called framework regions (FRs) of about 15-30 amino acid residues, separated by shorter, highly variable regions called "highly variable regions" (also called "complementarity-determining regions" (CDRs)), each approximately 9-12 amino acid residues long. The variable regions of the natural heavy and light chains each contain four FRs, which are linked by three highly variable regions that form loops, primarily in the form of β-sheet structures, linking (or sometimes forming part of) the β-sheet structures. The highly variable regions in each chain are held together in close proximity by the FRs and, together with the highly variable regions of other chains, contribute to the formation of the antibody's antigen-binding site. The constant region does not directly participate in antibody binding to the antigen, but exhibits various effector functions, such as involvement in antibody-dependent cell-mediated cytotoxicity (ADCC). The term “highly variable region” (also known as “complementarity-determining region” or CDR), as used herein, refers to amino acid residues of an antibody located within the V region of an immunoglobulin, which forms the antigen-binding site and is a major determinant of antigen-binding specificity (usually three or four short regions with extreme sequence variability). CDR residues can be identified based on interspecific sequence variability or crystallographic studies of antigen-antibody complexes.

[0133] Accordingly, as used herein, the term “antibody” preferably refers to an immunoglobulin molecule, or a variant, fragment, or derivative thereof, that can specifically bind to a target epitope via at least one complementarity-determining region. This term includes monoclonal and polyclonal antibodies, monospecific, bispecific and multispecific antibodies, antibodies of any isotype including IgM, IgD, IgG, IgA, and IgE antibodies, and antibodies obtained by any means, the antibodies being said to include naturally occurring antibodies, antibodies produced by immunization in a host organism, antibodies isolated and identified from naturally occurring antibodies or antibodies produced by immunization in a host organism and recombinantly produced by biomolecular methods known in the art, as well as chimeric antibodies, human antibodies, humanized antibodies, intrabodies (i.e., antibodies expressed in cells and possibly localized to specific cellular compartments), and variants, fragments, and derivatives of any of these antibodies.

[0134] When used herein, the term “monoclonal antibody” (mab) refers to an antibody obtained from a substantially homogeneous population of antibodies; that is, the individual antibodies constituting the population are identical except for any naturally occurring mutations that may be present in small amounts. Monoclonal antibodies are highly specific to a single antigenic site. Furthermore, in contrast to “polyclonal” antibody preparations, which contain different antibodies against different epitopes, each monoclonal antibody is specific to a single epitope on an antigen. In addition to its specificity, monoclonal antibodies are advantageous in that they can be synthesized without contamination by other antibodies. The adjective “monoclonal” should not be interpreted as requiring the production of the antibody by any particular method. For example, monoclonal antibodies useful in this invention can be prepared by the hybridoma method first described in Kohler et al., Nature 256: 495 (1975), or they can be produced using recombinant DNA methods in bacterial, eukaryotic, or plant cells (see, for example, U.S. Patent No. 4,816,567). Monoclonal antibodies can also be isolated from phage antibody libraries using techniques described, for example, Clackson et al., Nature 352: 624-628 (1991) and Marks et al., J. Mol. Biol. 222: 581-597 (1991).

[0135] Monoclonal antibodies include "chimeric" antibodies in which a portion of the heavy chain and / or light chain is identical or homologous to a corresponding sequence in an antibody belonging to a particular antibody class or subclass, derived from a particular species, while the remainder of the chain is identical or homologous to a corresponding sequence in an antibody belonging to a different antibody class or subclass, derived from a different species. Chimeric antibodies include "humanized" antibodies that include, for example, a variable region antigen-binding sequence (partially or completely) derived from a non-human animal, such as a mouse or a non-human primate (e.g., Old World monkey, ape, etc.), and a human constant region sequence that can effectively mediate Fc effector function and / or exhibit reduced immunogenicity when introduced into the human body. Humanized antibodies can be prepared by first creating a "chimeric" antibody (non-human Fab transplanted onto human Fc) and selectively mutating (non-CDR) amino acids in the Fab portion of the molecule. Alternatively, "humanized" antibodies can be directly obtained by transplanting a suitable "donor" CDR coding segment derived from a non-human animal onto a human antibody "acceptor" skeleton, and, if necessary, mutating (non-CDR) amino acids for optimized binding.

[0136] An “antibody variant” or “antibody variant” refers to an antibody that contains, or consists of, an amino acid sequence in which one or more amino acid residues are modified compared to a reference or “parent” antibody. Therefore, such an antibody variant exhibits sequence identity with respect to the reference or “parent” antibody, or its light or heavy chain, of at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, preferably at least about 70%, 80%, 85%, 86%, 87%, 88%, 89%, more preferably at least about 90%, 91%, 92%, 93%, 94%, and most preferably at least about 95%, 96%, 97%, 98%, or 99% (higher is preferable) of a reference or “parent” antibody, or its light or heavy chain. Possible amino acid mutations include deletions, insertions, or changes of one or more amino acid residues. Mutations may be located in the constant region or the antigen-binding region (e.g., the highly variable region or the variable region). In some cases, conservative amino acid mutations, which involve changing an amino acid to another amino acid with similar biochemical properties (e.g., charge, hydrophobicity, and size), are preferable.

[0137] An "antibody fragment" is a part of an intact antibody (i.e., the antigen-binding site and C L and at least the heavy chain region, C H 1, C H 2 and C H Antibodies containing 3), preferably including the antigen-binding and / or variable region of an intact antibody. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies, single-chain antibodies, and bispecific or multispecific antibodies containing such antibody fragments.

[0138] Papain digestion of the antibody produced two identical antigen-binding fragments called "Fab" (fragment, antigen-binding) fragments, and a residual "Fc" (fragment, crystallizable) fragment. The Fab fragments contained the variable region (V) of the H chain. H ) and the entire L chain, and the first steady region of a single heavy chain (C H1) consists of and . Each Fab fragment is monovalent for antigen binding, that is, it has a single antigen-binding site. Pepsin treatment of the antibody yields a single large F(ab')2 fragment and a pFc' fragment, which roughly correspond to two disulfide-bonded Fab fragments with different antigen-binding activities and can still crosslink the antigen. The F(ab')2 fragment can be split into two Fab' fragments. The Fab' fragment contains one or more cysteine ​​from the antibody hinge region. H It differs from the Fab fragment in that it has several additional residues at the carboxyl terminus of one region. Fab'-SH, as used herein, refers to Fab' in which the cysteine ​​residue in the constant region has a free thiol group. The F(ab')2 antibody fragment was originally produced as a pair of Fab' fragments having a hinged cysteine ​​between them. Other antibody fragments and their chemical fragments are also known. Fab / c or Fabc antibody fragments lack one Fab region. The Fd fragment corresponds to the heavy chain portion of Fab and has a C-terminal constant region (C H 1) and N terminal variable area (V H ) includes.

[0139] The Fc fragment contains the carboxyl-terminal portions of both H chains, held together by a disulfide. The effector function of the antibody is determined by the sequence in the Fc region, which is also recognized by an Fc receptor (FcR) found in specific cell types.

[0140] "Fv" is the minimal antibody fragment containing a complete antigen-binding site. This fragment consists of a dimer of one heavy chain and one light chain variable region that are closely non-covalently associated. The folding of these two regions gives rise to six highly variable loops (three from the H chain and three from the L chain) that contribute to the amino acid residues of antigen binding and confer antigen-binding specificity to the antibody. However, even a single variable region (or half of Fv containing only the three antigen-specific CDRs) can recognize and bind to the antigen, albeit with lower affinity than the entire binding site.

[0141] A "single-stranded Fv," also abbreviated as "sFv" or "scFv," is an antibody fragment containing VH and VL antibody regions linked to a single polypeptide chain. Preferably, the sFv polypeptide further includes a polypeptide linker between the VH and VL regions, thereby enabling the sFv to form a desired structure for antigen binding.

[0142] The term "diabody" (also called "di-scFvs" or "bi-scFvs") refers to a bivalent single-stranded variable fragment in which inter-strand pairing occurs in the V region but intra-strand pairing does not occur. Two scFv fragments (see paragraph above) are linked together, typically by a short linker (about 5-10 residues), in the V region. H Region and V L This refers to antibody fragments prepared by ligating them between regions. Another possibility is two V H and two V L The objective is to construct a single peptide chain having a region ("tandem scFv"). The resulting bivalent fragment has two antigen-binding sites. Similarly, trivalent scFv trimers (also called "tribodies") and tetravalent scFv tetramers ("tetrabodies") can be produced. The bivalent or polyvalent antibody or antibody fragment may be monospecific, meaning that each antigen-binding site may target the same target. Such monospecific bivalent or polyvalent antibodies or antibody fragments preferably exhibit high binding affinity. Alternatively, the antigen-binding sites of the bivalent or polyvalent antibody or antibody fragment may target different targets, forming a bispecific or multispecific antibody or antibody fragment.

[0143] A "bispecific or multispecific antibody or antibody fragment" contains two or more specific antigen-binding sites, each capable of specifically binding to a different target. A "bispecific antibody" is typically a combination of two antibodies. H and V LIt is a heterodimer of two “crossover” scFv fragments located on polypeptide chains in different regions. Bispecific or multispecific antibodies can act as adapter molecules between effectors and their respective targets, thereby supplementing the desired antigen, typically expressed by target cells such as cancer cells, with the effector (e.g., toxins, drugs, cytokines, or effector cells such as CTLs, NK cells, macrophages, and granulocytes). Thereafter, the “bispecific or multispecific antibody” preferably brings the effector molecule or cell and the desired target into proximity and / or mediates the interaction between the effector and the target. Bispecific tandem di-scFvs, known as bispecific T cell engagers (BiTE antibody components), are an example of a bivalent and bispecific antibody with respect to the present invention.

[0144] The structure and properties of antibodies are well known in the art, particularly in Janeway's Immunobiology, 9 th

[0145] The artificial nucleic acid molecules of the present invention encoding a preferred antibody preferably contain or may contain a coding region comprising a nucleic acid sequence described in SEQ ID NOs: 1 to 61734 or any one of Tables 3, 4, 5, 6, or 9 as described in International Patent Application PCT / EP2017 / 060226, and more particularly, may contain or may contain a coding region comprising a nucleic acid sequence that is identical to or has at least 50%, 60%, 70%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, preferably at least 80%, sequence identity with respect to any fragment or variant of these RNA sequences. In this regard, the disclosures of PCT / EP2017 / 060226 are also incorporated herein by reference. Those skilled in the art know that other (redundant) mRNA sequences may also encode proteins as shown in the above references, and therefore mRNA sequences are not limited thereto.

[0146] The artificial nucleic acid molecules of the present invention encoding preferred therapeutic proteins preferably contain or may contain a coding region comprising a nucleic acid sequence described in any one of the sequence numbers listed in SEQ ID NO. 1 to SEQ ID NO. 345916 or Table I, as described in U.S. Application No. 15 / 585,561, and more particularly, may contain or may contain a coding region comprising a nucleic acid sequence that is identical to or has at least 50%, 60%, 70%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, preferably at least 80%, sequence identity with respect to any fragment or variant of these RNA sequences. In this regard, the disclosures of U.S. Application No. 15 / 585,561 are also incorporated herein by reference. Those skilled in the art know that other (redundant) mRNA sequences may also encode proteins as shown in the above references, and therefore mRNA sequences are not limited thereto.

[0147] Further artificial nucleic acid molecules of the present invention encoding preferred therapeutic proteins may preferably include or include coding regions comprising nucleic acid sequences described in any one of the sequence numbers shown in SEQ ID NOs: 1 to 345916 or Table I, as described in International Patent Application PCT / EP2017 / 060692, and in particular may include or include coding regions comprising nucleic acid sequences that are identical to or have at least 50%, 60%, 70%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, preferably at least 80%, sequence identity with respect to any fragment or variant of these RNA sequences. In this regard, the disclosures of International Patent Application PCT / EP2017 / 060692 are also incorporated herein by reference. Those skilled in the art know that other (redundant) mRNA sequences may also encode proteins as shown in the above references, and therefore mRNA sequences are not limited thereto.

[0148] The term "peptide hormone" refers to a class of peptides or proteins that have endocrine functions in animal organisms. Typically, peptide hormones exert their function by binding to receptors on the surface of target cells and transmitting signals via intracellular second messengers. Representative examples of peptide hormones include adiponectin, or Acrp30; adrenocorticotropic hormone (or corticotropin), or ACTH; amylin (or islet amyloid polypeptide), or IAPP; angiotensinogen and angiotensin, or AGT; anti-Müllerian hormone (or Müllerian inhibitor or hormone), or AMH; antidiuretic hormone (or vasopressin, arginine vasopressin), or ADH; and atrial natriuretic peptide. (or atriopeptin), i.e., ANP; brain natriuretic peptide, i.e., BNP; calcitonin, i.e., CT; cholecystokinin, i.e., CCK; corticotropin-releasing hormone, i.e., CRH; cortistatin, i.e., CORT; endothelin, i.e.; enkephalin, i.e.; erythropoietin, i.e., EPO; follicle-stimulating hormone, i.e., FSH; galanin, i.e., GAL; gastric inhibitory polypeptide, i.e., GIP; gastrin, i.e., GAS; ghrelin, i.e., GLU GCG; Glucagon-like peptide-1, or GLP1; Gonadotropin-releasing hormone, or GnRH; Growth hormone, or GH or hGH; Growth hormone-releasing hormone, or GHRH; Guaniline, or GN; Hepcidin, or HAMP; Human chorionic gonadotropin, or hCG; Human placental lactogen, or HPL; Inhibin, or Insulin, or INS; Insulin-like growth factor (or somatomedin), or IGF; Leptin, or LEP; Lipotropin, i.e., LPH; Luteinizing hormone, i.e., LH; Melanocyte-stimulating hormone, i.e., MSH or α-MSH; Motilin, i.e., MLN; Orexin, i.e.; Osteocalcin, i.e., OCN; Oxytocin, i.e., OXT; Pancreatic polypeptide, i.e., Parathyroid hormone, i.e., PTH; Pituitary adenylate cyclase-activating peptide, i.e., PACAP; Prolactin, i.e., PRL; Prolactin-releasing hormone, i.e., PRH; Relaxin, i.e., RLN;This includes renin, i.e.; secretin, i.e., SCT; somatostatin, i.e., SRIF; thrombopoietin, i.e., TPO; thyroid-stimulating hormone (or thyrotropin), i.e., TSH; thyrotropin-releasing hormone, i.e., TRH; uroguaniline, i.e., UGN; or vasoactive intestinal peptide, i.e., VIP; or isoforms, homologs, fragments, variants, or derivatives of any of these proteins.

[0149] The term “gene editing agent” refers to a (poly)peptide or protein that can modify gene expression (i.e., alter, induce, increase, decrease, suppress, eliminate, or prevent). Gene expression can be modified at several levels. Gene editing agents typically act by: (a) introducing or removing epigenetic modifications; (b) altering the sequence of a gene by, for example, introducing, deleting, or altering nucleic acid residues in the nucleic acid sequence of a gene of interest; (c) modifying the biological function of a regulator manipulably linked to a gene of interest; (d) modifying mRNA transcription, processing, splicing, maturation, or transport into the cytoplasm; (e) modifying mRNA translation; (f) modifying post-translational modifications; or (g) modifying protein translocation or transport. In a narrower sense, the term “gene editing agent” may refer to a (poly)peptide or protein that targets the cellular genome to modify gene expression, preferably by exerting functions (a) to (d), more preferably (a) to (c). Accordingly, the term “gene editing agent” as used herein includes gene editing agents that cleave or modify target DNA to induce mutations, preferably (e.g., via homologous directed repair or non-homologous end joining), but also includes gene editing agents that can reduce expression without targeted cleavage (e.g., gene editing agents fused to or conjugated to expression modulators such as transcriptional repressors or epigenetic modifiers that can reduce gene expression). Specific gene editing agents include transcriptional activators, transcriptional repressors, recombinases, nucleases, DNA-binding proteins, or combinations thereof.

[0150] The present invention also relates to artificial nucleic acids, particularly RNA, CRISPR-related proteins, and codes for (pharmaceutical) compositions and kits of parts containing them. The above-mentioned artificial nucleic acids, particularly RNA, (pharmaceutical) compositions and kits are particularly intended for use in the treatment and / or prevention of diseases to which pharmaceuticals, such as gene therapy, particularly therapy with CRISPR-related proteins, can be applied, for example, by gene editing, knock-in, knock-out, or regulation of the expression of a target gene of interest.

[0151] The term “CRISPR-related protein” refers to RNA-induced endonucleases that are part of the CRISPR (Crystalline Repetitive Parametic Sequence) system (and its homologs, variants, fragments, or derivatives) used by prokaryotes to confer adaptive immunity to foreign DNA factors. CRISPR-related proteins include, but are not limited to, Cas9, Cpf1 (Cas12), C2c1, C2c3, C2c2, Cas13, CasX, and CasY. As used herein, the term “CRISPR-related protein” includes wild-type proteins, as well as their homologs, variants, fragments, and derivatives. Therefore, when referring to artificial nucleic acid molecules encoding Cas9, Cpf1 (Cas12), C2c1, C2c3, and C2c2, Cas13, CasX, and CasY, these artificial nucleic acid molecules may encode their respective wild-type proteins, or their homologs, variants, fragments, and derivatives.

[0152] Preferably, at least one 5'-UTR factor and at least one 3'-UTR factor act synergistically to increase the expression of at least one coding sequence operably linked to the UTR. It is assumed herein that the 5'-UTR and 3'-UTR factors described may be used in any useful combination. More specifically, preferred embodiments of the present invention include selected combinations of CDS, namely, CDS selected from the group consisting of Cas9, Cpf1, CasX, CasY, and Cas13, along with HSD17B4 / Gnas.1;Slc7a3.1 / Gnas.1;ATP5A1 / CASP.1;Ndufa4.1 / PSMB3.1;HSD17B4 / PSMB3.1;RPL32var / albumin7;32L4 / albumin7;HSD17B4 / CASP1.1;Slc7a3.1 / CAS This includes combinations of UTRs selected from the group P1.1;Slc7a3.1 / PSMB3.1;Nosip.1 / PSMB3.1;Ndufa4.1 / RPS9.1;HSD17B4 / RPS9.1;ATP5A1 / Gnas.1;Ndufa4.1 / COX6B1.1;Ndufa4.1 / Gnas.1;Ndufa4.1 / Ndufa1.1;Nosip.1 / Ndufa1.1;Rpl31.1 / Gnas.1;TUBB4B.1 / RPS9.1; and Ubqln2.1 / RPS9.1.

[0153] The term "immune checkpoint inhibitor" refers to any (poly)peptide or protein that can inhibit (i.e., interfere with, block, neutralize, reduce, suppress, eliminate, or prevent) the biological activity of immune checkpoint proteins. Immune checkpoint proteins typically modulate the activation or function of T cells and are well known in the art. Immune checkpoint proteins include CTLA-4, PD-1, VISTA, B7-H2, B7-H3, PD-L1 (B7-H1, CD274), B7-H4, B7-H6, 2B4, ICOS, HVEM, PD-L2 (B7-DC, CD273), CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137, CD160, CD226, CD276, CD160, gp49B, PIR-B, KIR family receptors, TIM- This includes, but is not limited to, 1, TIM-3, TIM-4, LAG-3, BTLA, SIRP alpha (CD47), CD48, 2B4 (CD244), B7.1, B7.2, ILT-2, ILT-4, TIGIT, A2aR, DR3, IDOL, IDO2, LAIR-2, LIGHT, MARCO (macrophage receptor with collagen structure), PS (phosphatidylserine), OX-40, SLAM, TIGHT, VISTA, and / or VTCN1. Representative examples of drugs useful for inhibiting immune checkpoint proteins include antibodies (and antibody fragments, variants, or derivatives), peptides, native ligands (and ligand fragments, variants, or derivatives), and fusion proteins that either directly bind to (and thereby inactivate or inhibit) the immune checkpoint proteins, or indirectly inactivate or inhibit them, by binding to, inactivating, and / or inhibiting the receptors or downstream signaling molecules, for example, to block the interaction between one or more immune checkpoint proteins and their native receptors, and / or to prevent inhibitory signaling mediated by the binding of the immune checkpoint proteins to their native receptors.Representative examples of immune checkpoint inhibitors include A2AR; B7-H3, i.e., cD276; B7-H4, i.e., VTCN1; BTLA; CTLA-4; IDO, i.e., indreamine 2,3-dioxygenase; KIR, i.e., killer cell immunoglobulin-like receptor; LAG3, i.e., lymphocyte activator gene-3; PD-1, i.e., programmed death 1 (PD-1) receptor; PD-L1, TIM-3, i.e., T cell immunoglobulin and mucin domain 3; VISTA (protein), i.e., V domain Ig inhibitor of T cell activation; GITR, i.e., glucocorticoid-induced TNFR family-related gene; stimulant checkpoint molecules, i.e., CD27, CD40, CD122, OX40, GITR and CD137 or stimulant checkpoint molecules belonging to the B7-CD28 superfamily, i.e., CD28 and ICOS, or isoforms, homologs, fragments, variants or derivatives of any of these proteins.

[0154] The term “T cell receptor” or “TCR” refers to a T cell-specific protein receptor consisting of a variable, disulfide-linked alpha (α) and beta (β) chain, or gamma and delta (γ / δ) chain heterodimer, which optionally forms a complex with an immutable CD3-zeta (ζ) chain and / or additional (co)stimulatory signaling domain such as FcR, CD27, CD28, 4-1BB (CD137), DAP10, and / or OX40. The term “T cell receptor” includes (engineered) variants, fragments, and derivatives of such naturally occurring TCRs, including chimeric antigen receptors (CARs). The term “chimeric antigen receptor (CAR)” generally refers to an engineered fusion protein that contains a binding domain fused to an intracellular signaling domain that can activate T cells. Typically, a CAR is a chimeric polypeptide construct comprising at least an extracellular antigen-binding domain, a transmembrane domain, and a cytoplasmic signaling domain (also referred to herein as the “intracellular signaling domain”), including a functional signaling domain derived from a (co)stimulating molecule such as a CD3-zeta chain, FcR, CD27, CD28, 4-1BB (CD137), DAP10, and / or OX40. The extracellular antigen-binding domain may typically be derived from a monoclonal antibody or a fragment, variant, or derivative thereof. In certain embodiments, the CAR comprises a fusion of a single-stranded variable fragment (scFv) derived from a monoclonal antibody, fused to the CD3-zeta transmembrane and intracellular endo domains.

[0155] The artificial nucleic acid molecules of the present invention encoding preferred sequences for treating tumors or cancerous diseases preferably include or may include nucleic acid sequences described in International Patent Application WO2016170176A1, SEQ ID NOs: 1 to 10071, preferably SEQ ID NOs: 1, 3, 5, 6, 389 or 399, or any one of Tables 1 to 12 or Tables 14 to 17, or coding regions consisting of such nucleic acid sequences, and in particular may include or may include nucleic acid sequences that are identical to or have at least 50%, 60%, 70%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, preferably at least 80%, sequence identity with respect to any fragment or variant of these RNA sequences. In this regard, the disclosure in WO2016170176A1 is also incorporated herein by reference. Those skilled in the art will know that other (redundant) mRNA sequences may also encode proteins as shown in the above reference, and therefore mRNA sequences are not limited thereto.

[0156] Further artificial nucleic acid molecules of the present invention encoding preferred sequences for treating tumors or cancerous diseases preferably contain or include the nucleic acid sequence described in any one of the sequence numbers described in international patent applications WO2009046974, WO2015024666, WO2009046739, WO2015024664, WO2003051401, WO2012089338, WO2013120627, WO2014127917, WO2016170176, or WO2015135558. The coding regions may include, in particular, nucleic acid sequences that are identical to, or have at least 50%, 60%, 70%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, preferably at least 80%, sequence identity with respect to any fragment or variant of these RNA sequences, or the coding regions comprising such nucleic acid sequences. In this regard, the disclosures WO2009046974, WO2015024666, WO2009046739, WO2015024664, WO2003051401, WO2012089338, WO2013120627, WO2014127917, WO2016170176, or WO2015135558 are also incorporated herein by reference. Those skilled in the art will know that other (redundant) mRNA sequences may also encode proteins as shown in the above references, and therefore mRNA sequences are not limited thereto.

[0157] The term "enzyme" is well known in the art and refers to (poly)peptide and protein catalysts for chemical reactions. Enzymes include fully intact enzymes or their fragments, variants, or derivatives. Representative examples of enzymes include oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases.

[0158] The aforementioned therapeutic protein fragments, variants, and derivatives are also assumed to be the (poly)peptides or proteins of interest, provided that they are preferably functional and therefore capable of mediating the desired biological effect or function.

[0159] [Antigenic (poly)peptides or proteins] At least one coding region of the artificial nucleic acid molecule of the present invention may encode at least one "antigenic (poly)peptide or protein." The term "antigenic (poly)peptide or protein," or abbreviated as "antigen," generally refers to any (poly)peptide or protein that, under appropriate conditions, can interact with or be recognized by components of the immune system (such as antibodies or immune cells via antigen receptors, e.g., B cell receptors (BCRs) or T cell receptors (TCRs)) and can preferably induce an (adaptive) immune response. The term "components of the immune system" preferably refers to immune cells, immune cell receptors, and antibodies of the adaptive immune system. The "antigenic peptide or protein" preferably interacts with or is recognized by components of the immune system via its "epitope" or "antigen determinant."

[0160] The terms “epitope” or “antigen-determinant” refer to a portion or fragment of an antigenic peptide or protein recognized by the immune system. Such fragments may typically consist of approximately 5 to 20 or more amino acids. Epitopes may be “conformational” (or “discontinuous”), meaning they may consist of discontinuous sequences of amino acids from the antigenic peptide or protein from which they originate, but may be assembled, for example, into a three-dimensional structure of an MHC complex, or they may be “linear”, meaning they consist of continuous sequences of amino acids from the antigenic peptide or protein from which they originate. The term “epitope” generally encompasses “T cell epitopes” (recognized by T cells via their T cell receptors) and “B cell epitopes” (recognized by B cells via their B cell receptors). “B cell epitopes” are typically located on the outer surface of (natural) protein or peptide antigens as defined herein and may preferably contain 5 to 15 amino acids, more preferably 5 to 12 amino acids, and even more preferably 6 to 9 amino acids, or consist of these amino acids. A “T cell epitope” is typically recognized by T cells in an MHC-I or MHC-II bound form, that is, as a complex formed by an antigenic protein or peptide fragment containing an epitope and an MHC-I or MHC-II surface molecule. A “T cell epitope” may typically have a length of about 6 to about 20 or more amino acids, and T cell epitopes presented by MHC class I molecules may preferably have a length of about 8 to about 10 amino acids, for example, 8, 9, or 10 (or 11 or 12 amino acids). T cell epitopes presented by MHC class II molecules may preferably have a length of about 13 or more amino acids, for example, 13, 14, 15, 16, 17, 18, 19, 20 or more amino acids. In relation to the present invention, the term “epitope” may particularly refer to a T cell epitope.

[0161] Therefore, the term “antigenic (poly)peptide or protein” refers to a (poly)peptide that contains, consists of, or can provide at least one (functional) epitope. The artificial nucleic acid (RNA) molecules of the present invention may encode a full-length antigenic (poly)peptide or protein, or preferably a fragment thereof. The fragment may contain, consist of, or provide a (functional) epitope of the antigenic (poly)peptide or protein. A “functional” epitope refers to an epitope that can induce a desired adaptive immune response in a subject.

[0162] An artificial nucleic acid (RNA) molecule encoding at least one antigenic (poly)peptide or protein in at least one coding region can enter a target cell (e.g., a professional antigen-presenting cell (APC)), where at least one antigenic (poly)peptide or protein is expressed, processed, and presented on an immune cell (e.g., a T cell) on an MHC molecule, preferably resulting in an antigen-specific immune response (e.g., cell-mediated immunity or antibody formation). Alternatively, an artificial nucleic acid (RNA) molecule encoding at least one antigenic (poly)peptide or protein in at least one coding region can enter a target cell (e.g., a muscle cell, a dermal cell), where at least one antigenic (poly)peptide or protein is expressed and, for example, secreted into the extracellular environment by the target cell, where it encounters immune system cells (e.g., B cells, macrophages), and preferably induces an antigen-specific immune response (e.g., antibody formation).

[0163] In this specification, when we refer to an artificial nucleic acid (RNA) molecule encoding "at least one antigenic peptide or protein," it is assumed that the artificial nucleic acid (RNA) molecule may encode one or more full-length antigenic (poly)peptides or proteins, or one or more fragments, in particular a (functional) epitope. The full-length antigenic (poly)peptides or proteins, or fragments thereof, may preferably contain, consist of, or provide at least one (functional) epitope; that is, the antigenic (poly)peptides or proteins, or fragments thereof, may preferably contain or consist of a natural epitope (preferably recognized by B cells), or may be processed and presented by an MHC-I or MHC-II molecule to provide an MHC-binding epitope (preferably recognized by T cells).

[0164] The selection of a specific antigenic (poly)peptide or protein generally depends on the disease being treated or prevented. Generally, artificial nucleic acid (RNA) molecules can encode any antigenic (poly)peptide or protein associated with a disease that is treatable by inducing an immune response to the aforementioned antigens (e.g., cancer, infection).

[0165] Preferably, the artificial nucleic acid molecule according to the present invention may include at least one coding region encoding a tumor antigen, a pathogenic antigen, an autoantigen, an alloantigen, or an allergenic antigen.

[0166] The term “tumor antigen” refers to an antigenic (poly)peptide or protein derived from or associated with a (preferably malignant) tumor or cancerous disease. The terms “cancer” and “tumor” as used herein are interchangeable and refer to a neoplasm characterized by uncontrolled and usually rapid growth of cells that invade surrounding tissues and are prone to metastasis to distant body sites. This term encompasses both benign and malignant neoplasms. Malignancy in cancer is typically characterized by anaplasia, invasiveness, and metastasis, while benign malignant tumors typically lack any of these properties. The terms “cancer” and “tumor” specifically refer not only to neoplasms characterized by tumor growth, but also to cancers of the blood and lymphatic systems. “Tumor antigens” typically originate from tumor / cancer cells, preferably mammalian tumors / cancer cells, and may be located within or on the surface of tumor cells derived from mammalian tumors, preferably human tumors, such as systemic tumors or solid tumors. “Tumor antigens” generally include tumor-specific antigens (TSAs) and tumor-associated antigens (TAAs). TSAs typically result from tumor-specific mutations and are specifically expressed in tumor cells. TAA is more common, but is usually presented by both tumor cells and "normal" (healthy, non-tumor) cells.

[0167] Proteins or polypeptides may contain, or consist of, tumor antigens, fragments of tumor antigens, variants, or derivatives. Such nucleic acid molecules are particularly useful for therapeutic purposes, especially in genetic vaccination.

[0168] Preferably, the tumor antigen can be selected from the group including melanocyte-specific antigen, carcinometris antigen or tumor-specific antigen, preferably CT-X antigen, non-X CT antigen, binding partner of CT-X antigen or binding partner of non-X CT antigen or tumor-specific antigen, more preferably CT-X antigen, non-X CT antigen or tumor-specific antigen or binding partner of fragment, variant or derivative of the above tumor antigen; where each nucleic acid sequence codes for a different peptide or protein; where at least one nucleic acid sequence is 5T4, 707-AP, 9D7, AFP, AlbZIP HPG1, alpha-5-beta-1-integrin, alpha-5-beta-6-integrin, alpha-actinin-4 / m, alpha-methylacylcoenzyme A racemase, A T-4, ARTC1 / m, B7H4, BAGE-1, BCL-2, bcr / abl, beta-catenin / m, BING-4, BRCAI / m, BRCA2 / m, CA 1 5-3 / CA 27-29, CA 19-9, CA72-4, CA125, Calreticulin, CAMEL, CASP-8 / m, Cathepsin B, Cathepsin L, CD19, CD20, CD22, CD25, CDE30, CD33, CD4, CD52, CD55, CD56, CD80, CDC27 / m, CDK4 / m, CDKN2A / m, CEA, CLCA2, CML28, CML66, COA-1 / m, Coactosin-like protein, Collage XIII, COX-2, CT-9 / BRD6, Cten, Cyclin B1, Cyclin D1, cyp-B, CYPB1, DAM-1 0, DAM-6, DEK-CAN, EFTUD2 / m, EGFR, ELF2 / m, EMMPRIN, EpCam, EphA2, EphA3, ErbB3, ETV6-AML1, EZH2, FGF-5, FN, Frau-1, G250, GAGE-1, GAGE-2, G AGE-3, GAGE-4, GAGE-5, GAGE-6, GAGE7b, GAGE-8, GDEP, GnT-V, gp100, GPC3, GPNMB / m, HAGE, HAST-2, hepsin, Her2 / neu, HERV-K-MEL, HLA-A*0201-R1 7I, HLA-A11 / m, HLA-A2 / m, HNE, Homeobox NKX3.1, HOM-TES-14 / SCP-1, HOM-TES-85, HPV-E6, HPV-E7, HSP70-2M, HST-2, hTERT, iCE, IGF-1 R, IL-13Ra2, IL-2R, IL-5, Immature laminin receptor, Kallikrein-2, Kallikrein-4, i67, KIAA0205, KIAA0205 / m, KK-LC-1, K-Ras / m, LAGE-A1, LDLR-FUT, MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-A1 0, MAGE-A12, MAGE-B1, MAGE-B2, MAGE-B3, MAGE-B4, MAGE-B5, MAGE-B6, MAGE-B10, MAGE-B16, MAGE- B17, MAGE-C1, MAGE-C2, MAGE-C3, MAGE-D1, MAGE-D2, MAGE-D4, MAGE-E1, MAGE-E2, MAGE-F1, MAGE-H I, MAGEL2, Mammaglobin A, MART-1 / Melan-A, MART-2, MART-2 / m, Matrix Protein 22, MC1 R, M-CSF, ME 1 / m, Mesothelin, MG50 / PXDN, MMP1 1, MN / CA IX Antigen, MRP-3, MUC-1, MUC-2, MUM-1 / m, MUM-2 / m, MUM-3 / m, Myosin Class I / m, NA88-A, N-Acetylglucosaminitransferase V, Neo-PAP, Neo-PAP / m, NFYC / m, NGEP, NMP22, NPM / ALK, N-Ras / m, NSE, NY-ESO-1, NY-ESO-B, OA1, OFA-iLRP, OGT, OGT / m, OS-9, OS-9 / m, Osteocalcin, Osteopontin, pi 5, p190 minor bcr-abl, p53, p53 / m, PAGE-4, PAI-1, PAI-2, PAP, PART-1, PATE, PDEF, Pim-1 kinase, Pin-1, Pml / PAR alpha, POTE, PRAME, PRDX5 / m, prostain, proteinase-3, PSA, PSCA, PSGR, PSM, PSMA, PTPRK / m, RAGE-1, RBAF600 / m, RHAMM / CD168, RU1, RU2, S-100, SAGE, SART-1, SART-2, SART-3, SCC, SIRT2 / m, Sp1 7, SSX-1, SSX-2 / HOM-MEL-40, SSX-4, STAMP-1, STEAP-1, Survivin, Survivin-2B, SYT-SSX-1, SYT-SSX-2, TA-90, TAG-72, TARP, TEL-AML1, TGF-Beta, TGF-Beta-RII, TGM-4, TPI / m, TRAG-3, TRG, TRP-1, TRP-2 / 6b, TRP / INT2, TRP-p8, tyrosinase, UPA, VEGFR1, VEGFR-2 / FLK-1, WT1, and immunoglobulin idiotypes of lymphoid hematopoiesis or T cell receptor idiotypes of lymphoid hematopoiesis, or homologs, fragments, variants or derivatives of any of these tumor antigens; preferably, encoding their Survivin or homologs, or antigens or their binding partners from the MAGE family, or fragments, variants or derivatives of the above tumor antigens.

[0169] In this regard, particularly preferably, the tumor antigen is NY-ESO-1, 5T4, MAGE-C1, MAGE-C2, Survivin, Muc-1, PSA, PSMA, PSCA, STEAP, and PAP, or a homolog, fragment, variant, or derivative of any of these tumor antigens.

[0170] The term “pathogenic antigen” refers to an antigenic (poly)peptide or protein derived from or associated with a pathogen, i.e., a virus, a microorganism, or, in addition to viruses, bacteria, protozoa, or fungi, other substances that cause infectious diseases and typically disease. In particular, such “pathogenic antigens” may be able to induce an immune response in a subject, preferably a mammalian subject, more preferably a human. Typically, a pathogenic antigen may be a surface antigen located on the surface of a pathogen (e.g., its capsid, plasma membrane, or cell wall), such as a (poly)peptide or protein (or a fragment of a protein, e.g., the outer part of a surface antigen).

[0171] Therefore, in some preferred embodiments, an artificial nucleic acid (RNA) molecule may encode at least one pathogenic antigen selected from bacterial, viral, fungal, or protozoan antigens in at least one coding region thereof. The encoded (poly)peptide or protein may consist of or contain the pathogenic antigen or a fragment, variant, or derivative thereof.

[0172] Pathogenic antigens are preferably pathogens, namely Acinetobacter baumannii, Anaplasma phagocytophilum, Ancylostoma braziliense, duodenal worm, Arcanobacterium haemolyticum, Ascaris lumbricoides, Aspergillus, Astroviridae, Babesia, Bacillus anthrax, Bacillus cereus, Bartonella henselae, BK virus, Blastocystis hominis, Blastomyces dermatitidis, Bordetella pertussis, Borrelia burgdorferi, Borrelia species, Brucella species, Brugia malayi, Bunyaviridae, Burkholderia cepacia and other Burkholderia species, Burkholderia mallei, Burkholderia pseudomallei, Caritiviridae, Campylobacter, Candida albicans, Candida species, Chlamydia trachomatis, Chlamydophila pneumoniae, Chlamydophila psittaci, CJD prion, Clonorchis sinensis, Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Clostridium species, Clostridium tetanus, Clostridium coccidioides species, coronavirus, Neisseria diphtheriae, Coxiella burnetii, Crimean-Congo hemorrhagic fever virus, Cryptococcus neoformans, Cryptosporidium genus, cytomegalovirus (CMV), dengue virus (DEN-1, DEN-2, DEN-3 and DEN-4), dinuclear amoeba, Ebola virus (EBOV), Echinococcus genus, Ehrlichia chaffeensis, Ehrlichia ewingii, Ehrlichia genus, Entamoeba histolytica, Enterococcus genus, Enterovirus genus, Enterovirus, mainly Coxsackie A virus and Enterovirus 71 (EV71), Epidermal species, EB virus (EBV), Escherichia coli O1 57:H7, O1 1 1 and O104:H4, liver flukes and giant liver flukes, FFI prions, filariasis, flaviviruses, tularemia, Fusobacterium, Geotrichum candidum, Giardia lamblia, Gnathostoma species, GSS prions, Guanarito virus, Chancroid, Haemophilus influenzae, Helicobacter pylori, Henipavirus (Hendra virus, Nipah virus), Hepatitis A virus, Hepatitis B virus (HBV), Hepatitis C virus (HCV), Hepatitis D virus, Hepatitis E virus, Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), Histoplasma mapustratum, HIV (Human Immunodeficiency Virus), Hortaea Werneckii, human bocavirus (HBoV), human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7), human metapneumovirus (hMPV), human papillomavirus (HPV), human parainfluenza virus (HPIV), Japanese encephalitis virus, JC virus, Junin virus, Kingella kinge, Klebsiella granulomatis, Couloprin, Lassa virus, Legionella, Leishmania, Leptospira, Listeria monocytogenes, lymphocytic choriomeningitis virus (LCMV), Machupovirus, Malassezia species, Marburg virus, measles virus, Yokogawa fluke, Microsporidium, Molluscum contagiosum virus (MCV), mumps virus, Mycobacterium leprae and Mycobacterium lepromatosis, Mycobacterium tuberculosis, Mycobacterium Mycoplasma pneumoniae, Naegleria fowleri, American hookworm, Neisseria gonorrhoeae, Neisseria meningitidis, Nocardia asteroides, Nocardia species, circumcised filarial worm, Orientia scrub typhus, Orthomyxoviridae (influenza), Paracoccidioidesbrasiliensis, lung fluke species, Parvovirus westermani, parvovirus B19, Pasteurella, Plasmodium, Pneumocystis irovecii, poliovirus, rabies virus, respiratory syncytial virus (RSV), rhinovirus, rhinovirus, Rickettsia akari, Rickettsia, Rickettsia prowatzekii, Rickettsia rickettii, Rickettsia ciffii, Rift Valley fever virus, rotavirus, rubella virus, Sabia virus, Salmonella, Sarcoptes scabiei, SARS coronavirus, Schistosoma, Shigella, Sin Nombre virus, Hantavirus, Sporothrix schenkyi, Staphylococcus, Staphylococcus, Streptococcus Antigens may be selected from agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, Strongyloides, Tenia species, Taenia solium, tick-borne encephalitis virus (TBEV), Ascaris canis or Ascaris feline, Toxoplasma gondii, Treponema pallidum, Trichinella, Trichomonas vaginalis, Dermatophytes species, Whipworms, Trypanosoma bruseyi, Trypanosoma cruzi, Ureaplasma urealyticum, varicella-zoster virus (VZV), varicella-zoster virus (VZV), smallpox or smallpox, vCJD prion, Venezuelan encephalitis virus, Vibrio cholerae, West Nile virus, Western equine encephalitis virus, Wuchereria bancrofti, yellow fever virus, Yersinia enteritis, Pest bacillus, and Mycobacterium pseudotuberculosis, or isoforms, homologs, fragments, variants, or derivatives of any of these proteins.

[0173] Further preferred pathogenic antigens may be derived from influenza virus, syncytial virus of the respiratory system (RSV), herpes simplex virus (HSV), human papillomavirus (HPV), human immunodeficiency virus (HIV), Plasmodium, Staphylococcus aureus, dengue virus, Chlamydia trachomatis, cytomegalovirus (CMV), hepatitis B virus (HBV), Mycobacterium tuberculosis, rabies virus, and yellow fever virus, or isoforms, homologs, fragments, variants, or derivatives of any of these proteins.

[0174] Further preferred pathogenic antigens include Agrobacterium tumefaciens, Ajeromyces dermatichidis ATCC60636, alpha papillomavirus 10, Andes orthohantavirus, Andes virus CHI-7913, Aspergillus teleus NIH2624, avian hepatitis E virus, Babesia microti, Bacillus anthrax, bacteria, beta coronavirus England type 1, German cockroach, Bordetella pertussis, Borna disease virus Giesen strain He / 80, Borrelia burgdorferi B31, Borrelia burgdorferi CA12, Borrelia burgdorferi N40, Borrelia burgdorferi ZS7, Borrelia garinii IP90, Borrelia hermsii, Borreliella afzelii, Borreliella burgdorferi, Borreliella garinii, Bos Taurus, Brucella meritensis, Brugia malayi, Bundibugyo Ebola virus, Burkholderia pseudomallei, Burkholderia pseudomallei K96243, Campylobacter jejuni, Campylobacter upsaliensis, Candida albicans, guinea pig, Chikungunya virus, Chikungunya virus MY / 08 / 065, Chikungunya virus Singapore / 11 / 2008, Chikungunya virus strain LR2006_OPY1 IMT / Reunion Island / 2006, Chikungunya virus strain S27-African prototype, Chlamydia pneumoniae, Chlamydia trachomatis, Chlamydia trachomatis serotype D, Chlamydia, Clostridioides difficile, Clostridium difficile BI / NAP1 / 027, Tetanus bacillus, Convict Creek 107 virus, diphtheria bacillus, cowpox virus (BrightonRed)White-pock, Coxsackievirus A16, Coxsackievirus A9, Coxsackievirus B1, Coxsackievirus B2, Coxsackievirus B3, Coxsackievirus B4, Crimean-Congo hemorrhagic fever orthonailovirus, Cryptosporidium parvum, Dengue virus, Dengue virus type 1, Dengue virus type 1 Nauru / Westpac / 1974, Dengue virus type 1 PVP159, Dengue virus type 1 Singapore / S275 / 1990, Dengue virus type 2, Dengue virus type 2 D2 / SG / 05K4155DK1 / 2005, Dengue virus type 2 Jamaica / 1409 / 1983, Dengue virus type 2 Puerto Rico / PR159-S1 / 1969, Dengue virus type 2 strain 43, Dengue virus type 2 Thailand / 16681 / 84, Dengue virus type 2 Thailand / NGS-C / 1944, Dengue virus type 3, Dengue virus type 4, Dengue virus type 4 Dominican Republic / 814669 / 1981, Dengue virus type 4 Thailand / 0348 / 1991, Dengue virus type 1 Hawaii, Ebola virus - Mayinga, Zaire, 1976, Ebola virus, Echinococcus granulosus, Echinococcus multilocularis, Echovirus E11, Echovirus E9, Ehrlichia canis str. Jake, Ehrlichia chaffeensis, Ehrlichia chaffeensis str. Arkansas, Entamoeba histolytica, Entamoeba histolytica YS-27, Enterococcus faecium, Enterovirus A, Enterovirus A71, Enterovirus C, Escherichia coli, Giant liver fluke, Liver fluke, Four Corners Hantavirus, Tularemia bacillus, Tularemia bacillus subspecies holarctica LVS, Tularemia subspecies tularensis SCHU S4, Gambierdiscus toxicus, GB virus C, Glossina morsitans morsitans, Gnathostoma binucleatum, Gp160, H1N1 subtype, H5N1 subtype, Haemophilus influenzae NTHi1128, Haemophilus influenzae serotype B, Haemophilus influenzae subtype 1H, Hunter's orthohantavirus, Hunter's virus 76-118, HBV genotype D, Helicobacter pylori, Helicobacter pylori 26695, Heligmosomoides polygyrus, hepatitis B virus, hepatitis B virus adr4, hepatitis B virus ayw / France / Tiollais / 1979, hepatitis B virus genotype D, hepatitis B virus subtype adr, hepatitis B virus subtype adw, hepatitis B virus subtype adw2, hepatitis B virus subtype adyw, hepatitis B virus subtype AYR, hepatitis B virus subtype ayw, hepatitis C virus, hepatitis C virus (isolated group 1), hepatitis C virus (isolated group BK), hepatitis C virus (isolated group Con1), hepatitis C virus (isolated group Glasgow), hepatitis C virus (isolated group H), hepatitis C virus (isolated group H77), hepatitis C virus (isolated group HC- G9), Hepatitis C virus (Isolated group HCV-K3a / 650), Hepatitis C virus (Isolated group Japan), Hepatitis C virus (Isolated group JK049), Hepatitis C virus (Isolated group NZL1), Hepatitis C virus (Isolated group Taiwan), Hepatitis C virus genotype 1, Hepatitis C virus genotype 2, Hepatitis C virus genotype 3, Hepatitis C virus genotype 4, Hepatitis C virus genotype 5, Hepatitis C virus genotype 6, Hepatitis C virus HCT18, Hepatitis C virus HCV-KF, Hepatitis C virus isolated group HC-J1, Hepatitis C virus isolated group HC-J6, Hepatitis C virus isolated group HC-J8, Hepatitis C virus JFH-1, Hepatitis C virus subtype 1a, Hepatitis C virus subtype 1a Chiron Corp., Hepatitis C virus subtype 1b, Hepatitis C virus subtype 1b AD78, Hepatitis C virus subtype 1b isolated group BE-11, Hepatitis C virus subtype 1bJK1, Hepatitis C virus subtype 2a, Hepatitis C virus subtype 2b, Hepatitis C virus subtype 3a, Hepatitis C virus subtype 5a, Hepatitis C virus subtype 6a, Hepatitis delta virus, Hepatitis delta virus TW2667, Hepatitis E virus, Hepatitis E virus (Burma strain), Hepatitis E virus (Mexico strain), Hepatitis E virus SAR-55, Hepatitis E virus type 3 Kernow-C1, Hepatitis E virus type 4 JAK-Sai, Hepatitis A virus, Herpes simplex virus (type 1 / 17 strains), Herpesviridae, HIV-1 CRF01_AE, HIV-1 group O, HIV-1 M:A, HIV-1 M:B, HIV-1 M:B_89.6, HIV-1 M:B_HXB2R, HIV-1 M:B_MN, HIV-1 M:C, HIV-1 M:CRF01_AE, HIV-1 M:G, HIV-1 O_ANT70, Human Adenovirus 11, Human Adenovirus 2, Human Adenovirus 40, Human Adenovirus 5, Human Alpha Herpesvirus 1, Human Alpha Herpesvirus 2, Human Alpha Herpesvirus 3, Human Beta Herpesvirus 5, Human Beta Herpesvirus 6B, Human Bocavirus 1, Human Bocavirus 2, Human Bocavirus 3, Human Coronavirus 229E, Human Coronavirus OC43, Human Endogenous Retrovirus, Human Endogenous Retrovirus H, Human Endogenous Retrovirus K, Human Enterovirus 71 Subgenogroup C4, Human Gamma Herpesvirus 4, Human Gamma Herpesvirus 8, Human Hepatitis A Virus Hu / Australia / HM175 / 1976, Human Herpesvirus 1 KOS strain, Human Herpesvirus 2 333 strain, Human Herpesvirus 2 HG52 strain, Human Herpesvirus 3 H-551, Human Herpesvirus 3 Oka strain vaccine (strain Oka vaccine), Human Herpesvirus 4 B95-8 strain, Human Herpesvirus 4 type 1, Human Herpesvirus 4 type 2, Human Herpesvirus 5 AD169 strain, Human Herpesvirus 5Towne strain, Human Herpesvirus 6 (Uganda-1102 strain), Human Herpesvirus 7JI strain, Human Immunodeficiency Virus 1, Human Immunodeficiency Virus 2, Human Immunodeficiency Virus type 1 (Isolated Group YU2), Human Immunodeficiency Virus type 1 (JRCSF Isolated Group), Human Immunodeficiency Virus type 1 (NEW YORK-5 isolation group), human immunodeficiency virus type 1 (SF162 isolation group), human immunodeficiency virus type 1 (SF33 isolation group), human immunodeficiency virus type 1 BH10, human metapneumovirus, human orthopneumovirus, human papillomavirus, human papillomavirus type 11, human papillomavirus type 16, human papillomavirus type 18, human papillomavirus type 29, human papillomavirus type 31, human papillomavirus type 33, human papillomavirus type 35, human papillomavirus type 39, human papillomavirus type 44, human papillomavirus type 45, human papillomavirus type 51, human papillomavirus type 52, human papillomavirus type 58, human papillomavirus type 59, human papillomavirus type 6, human papillomavirus type 68, human papillomavirus type 6b, human papillomavirus type 73, human parainfluenza 3 virus (NIH Human parechovirus 1, human parvovirus 4, human parvovirus B19, human poliovirus 1, human poliovirus 1 Mahoney, human poliovirus 3, human polyomavirus 1, human respiratory syncytial virus (RSB1734), human respiratory syncytial virus (RSB6190), human respiratory syncytial virus (RSB6256), human respiratory syncytial virus (RSB642), human respiratory syncytial virus (subgroup B / 18537), human respiratory syncytial virus ALong strain, Human Respiratory Syncytial Virus A2, Human Respiratory Syncytial Virus S2, Human Respirovirus 3, Human Rhinovirus A89, Human Rotavirus A, Human T-cell Leukocyte Virus type 1 (Caribbean Isolation Group), Human T-cell Leukocyte Virus type 1 (MT-2 Isolation Group), Human T-cell Leukocyte Virus type 1 (ATK strain), Human T-cell Leukocyte Virus type 1 (African Isolation Group), Human T-cell Leukocyte Virus 1, Human T-cell Leukocyte Virus 2, Influenza A virus, Influenza A virus (A / Anhui / 1 / 2005(H5N1)), Influenza A virus (A / Anhui / PA-1 / 2013(H7N9)), Influenza A virus (A / Argentina / 3779 / 94(H3N2)), Influenza A virus (A / Auckland / 1 / 2009(H1N1)), Influenza A virus (A / Bar-headed Goose / Aomi / 61 / 05(H5N1)), Influenza A virus (A / Brevig Mission / 1 / 1918(H1N1)), Influenza A virus (A / California / 04 / 2009(H1N1)), Influenza A virus (A / California / 07 / 2009(H1N1)), Influenza A virus (A / California / 08 / 2009(H1N1)), Influenza A virus (A / California / 10 / 1978(H1N1)), Influenza A virus (A / Christchurch / 2 / 1988(H3N2)), Influenza A virus (A / Cordoba / 3278 / 96(H3N2)), Influenza A virus (A / France / 75 / 97(H3N2)), Influenza A virus (A / Fujian / 411 / 2002(H3N2)), Influenza A virus (A / Hong Kong / 01 / 2009(H1N1)), Influenza A virus (A / Hong Kong / 1 / 1968(H3N2) Influenza A virus (A / Indonesia / CDC699 / 2006(H5N1)), Influenza A virus (A / Iran / 1 / 1957(H2N2)), Influenza A virus (A / Memphis / 13 / 1978(H1N1)), Influenza A virus (A / Memphis / 4 / 1980(H3N2)), Influenza A virus (A / Nanchang / 58 / 1993(H3N2)), Influenza A virus (A / New York / 232 / 2004(H3N2)), Influenza Influenza A virus (A / New York / 15 / 94(H3N2)), Influenza A virus (A / New York / 17 / 94(H3N2)), Influenza A virus (A / Ohio / 3 / 95(H3N2)), Influenza A virus (A / Otago / 5 / 2005(H1N1)), Influenza A virus (A / Puerto Rico / 8 / 1934(H1N1)), Influenza A virus (A / Shandong / 5 / 94(H3N2)), Influenza A virus (A / Solomon Islands / 3 / 2006(Egg)Influenza A virus (H1N1), Influenza A virus (A / South Carolina / 1 / 1918(H1N1)), Influenza A virus (A / Swedish / Hong Kong / 126 / 1982(H3N2)), Influenza A virus (A / Swedish / Iowa / 15 / 1930(H1N1)), Influenza A virus (A / Sydney / 05 / 97-like(H3N2)), Influenza A virus (A / Texas / 1 / 1977(H3N2)), Influenza A virus (A / Udorn / 307 / 1972(H3N2)), Influenza A virus (A / Uruguay / 716 / 2007(H3N2)), Influenza A virus (A / USSR / 26 / 1985(H3N2)), Influenza A virus (A / Vietnam / 1203 / 2004(H5N1)), Influenza A virus (A / Vietnam / 1194 / 2004(H5N1)), Influenza A virus (A / Wellington / 75 / 2006(H1N1)), Influenza A virus (A / Wilson-Smith / 1933(H1N1)), Influenza A virus (A / Wuhan / 359 / 1995(H3N2)), Influenza A virus (A strain / Uma / Newmarket / 76), Influenza B virus, Japanese encephalitis virus, Japanese encephalitis virus Nakayama strain, Japanese encephalitis virus Vellore P20778, JC polyomavirus, Junimum arenavirus, Klebsiella pneumoniae, Cumulinge virus, Lake Victoria Marburg virus-Popp Lassa arenavirus, Lassa virus Josiah, Leishmania, Leishmania aethiopica, Leishmania braziliensis, Leishmania braziliensis MHOM / BR / 75 / M2904, Leishmania chagasi, Leishmania donovani, Leishmania infantum, Leishmania major, Leishmania major Friedlin strain, Leishmania panamensis, Leishmania pifanoi, Leptospira interrogans, Leptospira interrogans Australis serotype, Leptospira interrogansCopenhageni serotype, Leptospira interrogans Copenhageni serotype Fiocruz L1-130 strain, Leptospira interrogans Lai serotype, Leptospira interrogans Lai serotype HY-1 strain, Leptospira interrogans Pomona serotype, Little Cherry Virus 1, Lymphocytic Choriomeningitis Mum Arenavirus, Measles Virus, Measles Virus Edmonston strain, Merkel Cell Polyomavirus, Mobara Mum Arenavirus, Modified Vaccinia Ankara Virus, Moraxella Catarrhalis O35E, Mpapillomavirus 1, Mus musculus, Mycobacterium, Mycobacterium abscessus, Mycobacterium avium, Mycobacterium avium 8 serotype, Mycobacterium avium subspecies paratuberculosi, Mycobacterium bovis AN5, Mycobacterium bovis BCG, Mycobacterium bovis BCG Pasteur 1173P2 strain, Mycobacterium fortuitum subspecies fortuitum, Mycobacterium gilvum, Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium leprae, Mycobacterium leprae TN, Mycobacterium marinam, Mycobacterium neoaurum, Mycobacterium phlei, Mycobacterium smegma, Mycobacterium tuberculosis, Mycobacterium tuberculosis CDC1551, Mycobacterium tuberculosis H37Ra, Mycobacterium tuberculosis H37Rv, Mycobacterium ulcerans, Mycoplasma pneumoniae, Mycoplasma pneumoniae FH, Mycoplasma pneumoniae M129, American hookworm, Neisseria gonorrhoeae, Neisseria meningitidis B H44 / 76 serotypes, Nipahenipa virus, Norovirus Genoglobulin 2 Camberwell 1890, Orientia scrub typhus, Orientia troglodytes, Pan troglodytes, Paracoccidioides brasiliensis, Paracoccidioides brasiliensisB339, Plasmodium falciparum, Plasmodium falciparum 3D7, Plasmodium falciparum 7G8, Plasmodium falciparum FC27 / Papua New Guinea, Plasmodium falciparum FCR-3 / Gambia, Plasmodium falciparum WELLCOME isolation group, Plasmodium falciparum K1, Plasmodium falciparum LE5, Plasmodium falciparum Mad20 / Papua New Guinea, Plasmodium falciparum NF54, Plasmodium falciparum Palo Alto / Uganda, Plasmodium falciparum RO-33, Plasmodium falciparum chimpanzee, Plasmodium vivax, Plasmodium vivax NK, Plasmodium vivax Sal-1, Plasmodium vivax Belem strain, Plasmodium vivax-like species, Porphyromonas gingivalis, Porphyromonas gingivalis 381, Porphyromonas gingivalis OMZ 409, Prevotella oral taxon 472 F0295 strain, Pseudomonas aeruginosa, Pumara orthohantavirus, Pumara virus (Umea strain / hu), Pumara virus sotkamo / v-2969 / 81, Pythium insidiosum, Ravn virus - Ravn, Kenya, 1987, Respiratory syncytial virus, Rhodococcus fascians, Rhodococcus hoagii, Rubella virus, Rubella virus strain M33, Rubella virus strain Therien, Rubella virus vaccine strain RA27 / 3, Saccharomyces Cerevisiae, Cymiri gamma herpesvirus 2, Salmonella enterica subspecies enterica serotype cphii, Salmonella group A, Salmonella group D, Salmonella species group B, Sapporo rat virus, SARS coronavirus, SARS coronavirus BJ01, SARS coronavirus TJF, SARS coronavirus Tor2, SARS coronavirus Urbani, Schistosoma, Schistosoma japonicum, Schistosoma mansoni, Schistosoma mansoni puerto rico, Sinnombre orthohantavirus, Sindobis virus, Staphylococcus aureus, Staphylococcus aureus subspecies aureus COL, Staphylococcus aureus subspecies aureus MRSA252, Streptococcus, Streptococcus mutans, Streptococcus mutans MT8148, Streptococcus olaris, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus pyogenes serotype M24, Streptococcus pyogenes serotype M3 D58, Streptococcus pyogenes serotype M5, Streptococcus pyogenes serotype M6, Streptococcus species / group A, Taenia crassiceps, Taenia saginata, Taenia solium, Tick-borne encephalitis virus, Ascaris canis, Toxoplasma gondii, Toxoplasma gondii ME49, Toxoplasma gondii RH, Toxoplasma gondii type I, Toxoplasma gondii type II, Toxoplasma gondii type III, Toxoplasma gondii VEG, Treponema pallidum, Treponema pallidum subspecies pallidum Nichols strain, Trichomonas vaginalis, Triticum It may be derived from aestivum, Trypanosoma bruseyi bruseyi, Trypanosoma gambia, Trypanosoma cruzi, Trypanosoma cruzi Dm28c, Trypanosoma cruzi CL Brener strain, Vaccinia virus, Vesicular stomatitis virus, Vibrio cholerae, West Nile virus, West Nile virus NY-99, Wuchereria bancrofti, Yellow fever virus 17D / Tiantan, Yersinia enteritis, Zaire Ebola virus, Zika virus, or any isoform, homolog, fragment, variant or derivative of any of these proteins.

[0175] The artificial nucleic acid molecules of the present invention encoding a preferred influenza-derived pathogenic antigen preferably include a nucleic acid sequence described in any one of the sequence numbers shown in Figure 1, Figure 2, Figure 3, or Figure 4 or in Table 1, Table 2, Table 3, or Table 4 of International Patent Application No. PCT / EP2017 / 060663, or a fragment or variant of any of these sequences, in particular a nucleic acid sequence having at least 50%, 60%, 70%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, preferably at least 80%, sequence identity with any of these sequences, or a coding region consisting of such nucleic acid sequence. In this regard, the disclosures of PCT / EP2017 / 060663 are incorporated herein by reference.

[0176] A more preferable artificial nucleic acid molecule of the present invention encoding an influenza-derived pathogenic antigen may preferably include a nucleic acid sequence described in any one of the sequence numbers shown in Figure 20, Figure 21, Figure 22, or Figure 23 or in Table 1, Table 2, Table 3, or Table 4 of International Patent Application No. PCT / EP2017 / 064066, or a fragment or variant of any of these sequences, in particular a nucleic acid sequence having at least 50%, 60%, 70%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, preferably at least 80%, sequence identity with any of these sequences, or a coding region consisting of such nucleic acid sequence. In this regard, the disclosures of PCT / EP2017 / 064066 are incorporated herein by reference.

[0177] The artificial nucleic acid molecules of the present invention encoding a preferred rabies virus-derived pathogenic antigen preferably include the nucleic acid sequence described in SEQ ID NO. 24 or SEQ ID NO. 25 of International Patent Application No. WO2015 / 024665A1, or a fragment or variant of any of these sequences, in particular, a nucleic acid sequence having at least 50%, 60%, 70%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, preferably at least 80%, sequence identity to any of these sequences, or a coding region comprising such nucleic acid sequence. In this regard, the disclosure of WO2015 / 024665A1 is incorporated herein by reference.

[0178] A more preferable artificial nucleic acid molecule of the present invention encoding a rabies virus-derived pathogenic antigen may preferably include a nucleic acid sequence having at least 50%, 60%, 70%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, preferably at least 80%, sequence identity with any of these sequences, or a coding region comprising such nucleic acid sequence. In this regard, the disclosure of PCT / EP2017 / 064066 is incorporated herein by reference.

[0179] The artificial nucleic acid molecules of the present invention encoding a preferred RSV-derived pathogenic antigen preferably include a nucleic acid sequence described in any one of sequence numbers 31-35 of International Patent Application No. WO2015 / 024668A2, or a fragment or variant of any of these sequences, in particular a nucleic acid sequence having at least 50%, 60%, 70%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, preferably at least 80%, sequence identity to any of these sequences, or a coding region comprising such nucleic acid sequence. In this regard, the disclosure of WO2015 / 024668A2 is incorporated herein by reference.

[0180] The artificial nucleic acid molecules of the present invention encoding a preferred Ebola or Marburg virus-derived pathogenic antigen preferably include a nucleic acid sequence described in any one of Sequence IDs 20-233 of International Patent Application No. WO2016 / 097065A1, or a fragment or variant of any of these sequences, in particular a nucleic acid sequence having at least 50%, 60%, 70%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, preferably at least 80%, sequence identity to any of these sequences, or a coding region comprising such nucleic acid sequence. In this regard, the disclosure of WO2016 / 097065A1 is incorporated herein by reference.

[0181] The artificial nucleic acid molecules of the present invention encoding a preferred Zika virus-derived pathogenic antigen preferably include nucleic acid sequences described in SEQ ID NO. 1 to 11759 of International Patent Application No. WO2017 / 140905A1 or any one of Tables 1, 1A, 2, 2A, 3, 3A, 4, 4A, 5, 5A, 6, 6A, 7, 8, or 14, or fragments or variants of any of these sequences, in particular, nucleic acid sequences having at least 50%, 60%, 70%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, preferably at least 80%, sequence identity with any of these sequences, or may include coding regions consisting of such nucleic acid sequences. In this regard, the disclosure in WO2017 / 140905A1 is incorporated herein by reference.

[0182] The artificial nucleic acid molecules of the present invention encoding a preferred norovirus-derived pathogenic antigen preferably include nucleic acid sequences described in any one of Sequence IDs 1 to 39746 of International Patent Application No. PCT / EP2017 / 060673 or Table 1, or fragments or variants of any of these sequences, in particular, nucleic acid sequences having at least 50%, 60%, 70%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, preferably at least 80%, sequence identity to any of these sequences, or may include coding regions consisting of such nucleic acid sequences. In this regard, the disclosures of PCT / EP2017 / 060673 are incorporated herein by reference.

[0183] The artificial nucleic acid molecules of the present invention encoding a preferred rotavirus-derived pathogenic antigen preferably include a nucleic acid sequence described in any one of Sequence IDs 1 to 3593 or Tables 1 to 20 of International Patent Application No. WO2017 / 081110A1, or a fragment or variant of any of these sequences, in particular a nucleic acid sequence having at least 50%, 60%, 70%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, preferably at least 80%, sequence identity to any of these sequences, or a coding region comprising such nucleic acid sequence. In this regard, the disclosure of WO2017 / 081110A1 is incorporated herein by reference.

[0184] The term "autoantigen" refers to an endogenous "self" antigen that, despite being a normal bodily component, induces an autoimmune response in the host. In relation to the present invention, autoantigens are preferably derived from humans. The provision of artificial nucleic acid (RNA) molecules encoding antigenic (poly)peptides or proteins derived from autoantigens can be used, for example, to induce immune resistance to the above-mentioned autoantigens. In relation to the present invention, examples of autoantigens include 60kDa chaperonin 2, lipoprotein LpqH, melanoma antigen recognized by T cell 1, MHC class I polypeptide-associated sequence A, parental protein, structural polyprotein, tyrosinase, myelin proteolipide protein, Epstein-Barr nuclear antigen 1, envelope glycoprotein GP350, genomic polyprotein, collagen alpha-1(II) chain, agrecan core protein, melanocyte-stimulating hormone receptor, acetylcholine receptor subunit alpha, 60kDa heat shock protein, mitochondria, histone H4, myosin-11, glutamate decarboxylase 2, 60kDa chaperonin, PqqC-like protein, thymosin beta-10, myelin basic protein, Epstein-Barr nuclear antigen 4, melanocyte protein PMEL, HLA class II histocompatibility antigen, DQ beta-1 chain, latent membrane protein 2, integrin beta-3, nuclear protein Protein, 60S ribosomal protein L10, protein BOLF1, 60S acidic ribosomal protein P2, latent membrane protein 1, collagen alpha-2(VI) chain, exodeoxyribonuclease V, gamma, trans-activated protein BZLF1, S-arrestin, HLA class I histocompatibility antigen, A-3 alpha chain, protein CT_579, matrin-3, envelope glycoprotein B, ATP-dependent zinc metalloproteinase FtsH, U1 nuclear small ribonucleoprotein 70kDa, CD48 antigen, tubulin beta chain, actin, cytoplasm 1, Epstein-Barr nuclear antigen 3, NEDD4 family interacting protein 1, 60S ribosomal protein L28, pre-initial protein 2, insulin, isoform 2, keratin, type II cytoskeleton 3, matrix protein 1, histone H2A, Z, mRNA transport factor ICP27 homolog, nuclear small ribonucleoprotein-related proteins B and B',Large cysteine-rich periplasm protein OmcB, smootherin, nuclear small ribonucleoprotein SmD1, acetylcholine receptor subunit epsilon, invasine repeat family phosphatase, alpha-crystallin B chain, HLA class II histocompatibility antigen, DRB1-13 beta chain, HLA class II histocompatibility antigen, DRB1-4 beta chain, dihydrolipoyllysine residual acetyltransferase component of pyruvate dehydrogenase complex, mitochondria, keratin, type I cytoskeleton 18, Epstein-Barr nuclear antigen 6, protein Protein Tax-1, vimentin, keratin, type I cytoskeleton 16, keratin, type I cytoskeleton 10, HLA class I histocompatibility antigen, B-27 alpha chain, thyroglobulin, acetylcholine receptor subunit gamma, chaperone protein DnaK, protein U24, Na(+)-translocating NADH-quinone reductase subunit A, 65kDa phosphoprotein, putative ATP-dependent Clp protease ATP-binding subunit, putative outer membrane protein PmpC, heat shock 70kDa protein 1B, hemagglutinin, tetanus toxin, enolar Protein 1 containing Ras-related and plextorin homology domains, keratin, type II cytoskeleton, myosin-9, histone H1-like protein Hc1, envelope glycoprotein gp160, urease subunit beta, vasoactive intestinal polypeptide receptor 1, viral interleukin-10 homolog, histone H3.3, replication protein A32kDa subunit, putative outer membrane protein PmpD, insulin-2, L-dopachrome tautomerase, keratin, type I cytoskeleton, envelope glycoprotein H, DNA polymerase catalyst B unit, beta-2-glycoprotein 1, envelope glycoprotein gp62, serum albumin, main DNA-binding protein, HLA class I histocompatibility antigen, A-2 alpha chain, myeloblastin, POTE ankyrin domain family member I, protein E7, predictive efflux protein, replication / transcription activator, Gag-Pro-Pol polyprotein, capsid protein VP26, main capsid protein, apoptosis regulator BHRF1, Epstein-Barr nuclear antigen 2, HLA class I histocompatibility antigen, B-7 alpha chain, calreticulin,Gamma secretase C-terminal fragment 59, insulin, glucose-6-phosphatase 2, islet amyloid polypeptide, receptor tyrosine protein phosphatase N2, receptor tyrosine protein phosphatase-like N, islet cell autoantigen 1, Bos d 6, glutamate decarboxylase 1, 60S ribosomal protein L29, 28S ribosomal protein S31, mitochondria, HLA class II histocompatibility antigen, DRB1-16 beta chain, collagen alpha-3(IV) chain, glucose-6-phosphatase, glucose-6-phosphatase 3, collagen alpha-5(IV) chain, protein Nef, glial fiber acidic protein, fibrillin-1, tenacin, stromericin-1, interstitial collagenase, calpain-2 Catalytic subunit, chondroitin sulfate proteoglycan 4, fibrinogen beta chain, chaperone protein DnaJ, chitinase-3-like protein 1, matrix metalloproteinase-16, DNA topoisomerase 1, follistatin-related protein 1, Ig gamma-1 chain C region, Ig gamma-3 chain C region, collagen alpha-2(XI) chain, desmoglein-3, fibrinogen alpha chain, filaggrin, T cell receptor beta chain V region CTL-L17, T cell receptor beta T-1 chain C region, Ig heavy chain VI region EU, collagen alpha-1(IV) chain, HLA class I histocompatibility antigen, Cw-7 alpha chain, HLA class I histocompatibility antigen, B-35 alpha chain, HLA class I histocompatibility antigen, B-38 alpha chain, highly mobile protein B2, Ig ​​heavy chain V-II region ARH-77, HLA class II histocompatibility antigen, DR beta-4 chain, Ig kappa chain C region, alpha-enolase, lysosome-associated transmembrane protein 5, HLA class I histocompatibility antigen, B- 52-alpha chain, heterogeneous ribonucleoprotein A2 / B1, T cell receptor beta chain V region YT35, Ig gamma-4 chain C region, T cell receptor beta-2 chain C region, DnaJ homolog subfamily B member 2, DnaJ homolog subfamily A member 1, Ig kappa chain V-IV region Len, Ig heavy chain V-II region OU, Ig kappa chain V-IV region B17, 2',3'-cyclic nucleotide 3'-phosphodiesterase, Ig heavy chain V-II region MCE, Ig kappa chain V-III region HIC,Ig heavy chain V-II region COR, myelin-oligodendritic glycoprotein, Ig kappa chain V-II region RPMI 6410, Ig kappa chain V-II region GM607, immunoglobulin lambda-like polypeptide 5, Ig heavy chain V-II region WAH, biotin protein ligase, oligodendritic myelin glycoprotein, transaldolase, DNA helicase / primase complex-related protein, interferon beta, myelin-related oligodendritic basic protein, myelin-related glycoprotein, fusion glycoprotein F0, myelin protein P0, Ig lambda chain V-II region MGC, DNA primase, minor capsid protein L2, myelin P2 protein, peripheral myelin protein 22, retinol-binding protein 3, butyrophyllin subfamily 1 member A1, alkaline nuclease, claudin-11, N-acetylmuramoyl-L-alanine amidase CwlH, GTPase Der, possible transposese, BAC transporter, ATP-binding protein, putative, collagen alpha-2(IV) chain, calpastatin, Ig kappa chain V-III region SIE, E3 ubiquitin-protein ligase TRIM68, ion channel glutamate receptor, NMDA 2A, spectrin alpha chain, non-erythrocyte 1, lupus La protein, complement C1q subcomponent subunit A, U1 nuclear small ribonucleoprotein A, 60kDa SS-A / Ro ribonucleoprotein, DNA repair protein XRCC4, histone H3-like kinetochore protein A, histone H1.4, putative HTLV-1-related endogenous sequence, HLA class II histocompatibility antigen, DRB1-3 chain, HLA class II histocompatibility antigen, DRB1-1 beta chain, nuclear small ribonucleoprotein SmD3, tumor necrosis factor receptor supermember 6, phosphomannomutase / phosphoglucomutase, tripartite terminase subunit UL15, proteasome subunit beta-3, proliferative cell nuclear antigen, internal capsid protein Sigma-2, histone H2B-1, E3 ubiquitin-protein ligase TRIM21, DNA-directed RNA polymerase II subunit RPB1, X-ray repair complement protein 6, U1 nuclear small ribonucleoprotein C, caspase-8, 60S ribosomal protein L7, 5-hydroxytryptamine receptor 4,Nuclear small molecule ribonucleoprotein-associated protein N, expotin-1, 60S acidic ribosomal protein P0, nerve fiber heavy polypeptide, putative envelope, T cell receptor alpha chain C region, T cell receptor alpha chain V region CTL-L17, RNA polymerase sigma factor SigA, nuclear small molecule ribonucleoprotein SmD2, immunoglobulin iota chain, Ig kappa chain V-III region WOL, histone H2B 1-F / J / L type, highly mobile protein B1, X-ray repair complement protein 5, muscarinic acetylcholine receptor M3, major viral transcription factor ICP4, voltage-dependent P / Q type calcium channel subunit alpha-1A, heat shock protein HSP90-beta, DNA topoisomerase 2-beta, histone H3.1, tumor necrosis factor ligand superfamily member 6, phosphate-N-acetylmuramoyl pentapeptide-transferase, hemoglobin subunit alpha, apolipoprotein E, CD99 antigen, ATP synthase subunit beta, mitochondria, acetylcholine receptor subunit delta, acyl-CoA dehydrogenase family member 10, KN motif and ankyrin repeat domain-containing protein 3, SAM and SH3 domain-containing proteins Protein 1, Extension factor 1-alpha 1, GTP-binding nucleoprotein Ran, Myosin-7, Sal-like protein 1, IgGFc-binding protein, E3 ubiquitin-protein ligase SIAH1, Muscleblind-like protein 2, Annexin A1, Protein PET117 homolog, Mitochondria, Nuclear-ubiquitous casein and cyclin-dependent kinase substrate 1, Pleistocrine expression regulator 1, NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 3, Guanine nucleotide-binding G protein (o) subunit alpha, Microtubule-associated protein 1B, L-serine dehydratase / L-threonine deaminase, Centromere protein J, SH3 and Ankyrin multiple repeat domain protein 3, Fumarate hydratase, Mitochondria, Cofilin-1, Rho GTPase-activated protein 9, phosphatidic acid cytidylyltransferase 1, nerve fibril light polypeptide, calcinthenin-1, GPI transamidase component PIG-T, perilipin-3, protein unc-13 homolog D,WD40 repeat-containing protein SMU1, nerve fibril intermediate polypeptide, protein S100-B, carboxypeptidase E, neurexin-2-beta, NAD-dependent protein deacetylase sirtuin-2, tripartite motif-containing protein 40, neurexin-1-beta, annexin A11, hemoglobin, Robin subunit beta, glyceraldehyde-3-phosphate dehydrogenase, histidine triad nucleotide-binding protein 3, ATP synthase subunit e, mitochondria, 10kDa heat shock protein, mitochondria, cell tumor antigen p53, leukocyte-associated immunoglobulin-like receptor 1, tubulin alpha-1B chain, splicing factor, proline-rich and glutamine-rich, olfactory receptor 10A4, histone H2B 2-F type, calmodulin, RNA-binding protein Raly, phosphoinositide-3-kinase interacting protein 1, alpha-2-macroglobulin, glycogen phosphorylase, brain type, THO complex subunit 4, neuroblast differentiation-related protein AHNAK, phosphoserine aminotransferase, mitochondrial folate transporter / carrier, centrin-specific protease 3, cytoplasmic Fe-S cluster assembly factor NUBP2, histone deacetylase 7, serine / threonine-protein phosphatase 2A 55kDa regulatory subunit B alpha isoform, serine / threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha, gelzolin, insulin-like growth factor II, tight-binding protein ZO-1, Hsc70 interacting protein, FXYD domain-containing ion transport regulator 6, AP-1 complex subunit mu-1, syntenin-1, NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondria, low-density lipoprotein receptor, LIM domain transcription factor LMO4, spectrin beta chain, non-erythrocyte 1, ATP-binding cassette subfamily A member 2, NADH dehydrogenase [ubiquinone] 1 subunit C2, SPARC-like protein 1, electron transport flavin protein subunit alpha, mitochondria, glutamate dehydrogenase 1, mitochondria, complexin-2, protein-serine O-palmitre oil transferase porcupine, plexin domain-containing protein 2, threonine synthase-like 2, testican-2, CXC chemokine receptor type 1, arachidonic acid 5-lipoxygenase activating protein, neuroguidin, fatty acid 2-hydroxylase, nuclear factor 1X, LanC-like protein 1, glutamine synthetase,Lysosome-associated membrane glycoprotein 1, apolipoprotein AI, alpha-adusine, guanine nucleotide-binding protein G(I) / G(S) / G(T) subunit beta-3, endogenous membrane protein GPR137B, ubiquilin-1, aldose reductase, clathrin light chain B, V-type proton ATPase subunit F, apolipoprotein D, 40S ribosomal protein SA, Bcl-2-related transcription factor 1, phosphatidic acid cytidylyltransferase 2, ATP synthase-binding factor 6, mitochondria, receptor tyrosine protein quinine -ase erbB-2, echinoderm microtubule-associated protein-like protein 5, phosphatidylethanolamine-binding protein 1, Myc box-dependent interaction protein 1, membrane-associated phosphatidylinositol transport protein 1, 40S ribosomal protein S29, small acidic protein, galectin-3 binding protein, fatty acid synthase, baculovirus IAP repeat-containing protein 5, septin-2, cAMP-dependent protein kinase type II alpha regulatory subunit, reelin, apoptosis-promoting factor Bcl-2-like protein 14, staphylococcal nucleazide Main component protein 1, methyl-CpG binding domain protein 2, transformation / transcription domain-related protein, transcription factor HES-1, protein transporter protein Sec23B, pararemin-2, CC motif chemokine 15, sodium / potassium transporter ATPase subunit alpha-1, stasmin, heterogeneous ribonuclear protein L-like, segmental modulator 3, interferon-induced GTP-binding protein Mx2, integrin alpha-D, low-density lipoprotein receptor-related protein 5-like protein, macrophage migration inhibitor, fe Lithin light chain, dihydropyrimidinase-related protein 2, neuronal membrane glycoprotein M6-b, ATP-binding cassette subfamily A member 5, synaptosome-related protein 25, insulin-like growth factor I, ankyrin repeat domain-containing protein 29, protein spinster homolog 3, pefrin, contactin-1, microfibrillary-related glycoprotein 3, von Willebrand factor, nuclear small ribonucleoprotein G, interleukin-12 receptor subunit beta-1, epoxide hydrolase 1, cytochrome b-c1 complex subunit 10,Monoglyceride lipase, serotransferrin, alpha-synuclein, cytoplasmic nonspecific dipeptidase, transgerin-2, testisin, Fms-related tyrosine kinase 3 ligand, noerin-2, serine / threonine protein kinase DCLK1, interferon alpha-2, acetylcholine receptor subunit beta, histone H2A type 1, beta-2 adrenergic receptor, putrescine aminotransferase, interferon alpha-1 / 13, protein NEDD1, DNAJ homolog subfamily B member 1, tubulin beta 6 chain, non-histone chromosome protein HMG-17, polyprotein, exosome component 10, native cytotoxicity attractant receptor 3 ligand 1, Gag polyprotein, band 3 anion carrier protein, protease, histidine-tRNA ligase, cytoplasm, collagen alpha-1 (XVII) chain, emboplakin, histone H2B 1-C / E / F / G / I type, diaminopimelic acid decarboxylase, histone H2B 2-E type, cytochrome P450 2D6, dihydrolipoyllysine residual succinyltransferase component of 2-oxoglutarate dehydrogenase complex, histone H2B 1-H type, thyroid peroxidase, proline-rich transmembrane protein 2, periplakin, integrin alpha-6, distonin, desmoplakin, histone H2B 1-J type, histone H2B 1-B type, 6,7-dimethyl-8-ribitylrumazine synthase, thyrotropin receptor, integrin alpha-IIb, pore membrane glycoprotein 210, protein U2, DST protein, plectin, Sll0397 protein, Bos d 10, outer capsid protein VP4, 5,6-dihydroxyindole-2-carboxylate oxidase, O-phosphoseryl-tRNA(Sec) selenatetransferase, ATP-dependent Clp protease protein degradation subunit, lymphocyte activation gene 3 protein, phosphoprotein 85, L1 protein, actin, alpha skeletal muscle, dihydrolipoyl dehydrogenase, dihydrolipoyllysine residual succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondria, liver carboxylesterase 1,Dihydrolipoyllysine residual acetyltransferase component of pyruvate dehydrogenase complex, acetyltransferase component of pyruvate dehydrogenase complex, pyruvate dehydrogenase protein X component, mitochondria, dihydrolipoamide acetyltransferase, protein disulfide-isomerase A3, flotirin-2, beta-galactosidase, TSHR protein, lipoamide acyltransferase component of branched-chain alpha-keto acid dehydrogenase complex, mitochondria Doria, nuclear autoantigen Sp-100, desmoglein-1, glucagon receptor, membrane glycoprotein US8, sodium / iodide cotransporter, ORF2, capsid protein, unidentified protein LF3, formimidoyltransferase-cyclodeaminase, core-capsid crosslinking protein, neurotoxic factor ICP34.5, putative RNA-binding protein, cholesterol side-chain cleavage enzyme, mitochondria, histone H1.0, non-histone chromosome protein HMG-14, histone H5, 60S acidic ribosomal protein P1, pyruvate dehydrogenase E1 component subunit alpha, somatic cell morphology, mitochondria, rayomodin-1, unidentified protein RP382, unidentified protein U95, (type IV) pyriciliary assembly protein PilB, 2-succinylbenzoate-CoA ligase, TAZ protein, tafadin, putative lactose-specific phosphotransferase system (PTS), IIBC component, claudin-17, centrosome pericellular substance 1 protein, Yop protein translocation protein L, laminin subunit a Rufa-1, disintegrin and metalloproteinase with thrombospondin motif 13, keratin, type I cytoskeleton 14, coagulation factor VIII, keratin, type I cytoskeleton 17, neutrophil defensin 1, Ig alpha-1 chain C region, BRCA1-related RING domain protein 1, trinucleotide repeat-containing gene 6A protein, thrombopoietin, plasminogen-binding protein PgbA, steroid 17-alpha-hydroxylase / 17,20-lyase, hirsut RNA helicase 2, histone H2B type 1-N, steroid 21-hydroxylase, UreB, melanin-concentrating hormone receptor 1, blood group Rh(CE) polypeptide,HLA class II histocompatibility antigen, DP beta 1 chain, platelet glycoprotein Ib alpha chain, muscarinic acetylcholine receptor M1, outer capsid glycoprotein VP7, fibronectin, HLA class I histocompatibility antigen, B-8 alpha chain, AhpC, cytoskeleton-related protein 5, sucrase-isomaltase, intestinal tract, leukotriene B4 receptor 2, glutathione peroxidase 2, collagen alpha-1(VII) chain, nucleosome assembly protein 1-like 4, alanine-tRNA ligase, cytoplasm, extracellular calcium-sensing receptor, major centrol Mea autoantigen B, macrocosal protein deneddylase, blood group Rh(D) polypeptide, kininogen-1, peroxiredoxin-2, ezrin, DNA replication and repair protein RecF, keratin, type II cytoskeleton 6C, trigger factor, serpin B5, heat shock protein beta-1, protein-arginine deiminase type 4, potassium transport ATPase alpha chain 1, potassium transport ATPase subunit beta, forkhead box protein E3, condensin-2 complex subunit D3, myotonin-protein kinase, zinc Transporter 8, ABC transporter, substrate-binding protein, putative, aquaporin-4, cartilage intermediate protein 1, HLA class II histocompatibility antigen, DR beta 5 chain, nuclear small ribonuclear protein F, nuclear small ribonuclear protein E, Ig kappa chain VV region L7, Ig heavy chain Mem5, Ig heavy chain V-III region J606, hemoglobin subunit delta, collagen alpha-1(XV) chain, 78kDa glucose regulatory protein, 60S ribosomal protein L22, alpha-1-glycoprotein 1, malate dehydrogenase, mitochondrion Doria, 60S ribosomal protein L8, serine protease HTRA2, mitochondria, 60S ribosomal protein L23a, complement C3, collagen alpha-1 (XII) chain, angiotensinogen, protein S100-A9, annexin A2, alpha-actinin-4, HLA class II histocompatibility antigen, DQ alpha-1 chain, apolipoprotein A-IV, actin, aortic smooth muscle, HLA class II histocompatibility antigen, DP alpha-1 chain, creatine kinase type B, HLA class II histocompatibility antigen, DR beta-3 chain, histone H1x,Heterogeneous ribosomal protein U-like protein 2, basement membrane-specific heparan sulfate proteoglycan core protein, cadherin-5, 40S ribosomal protein S13, alpha-1-antitrypsin, multimelin-2, centromere protein F, 40S ribosomal protein S18, 40S ribosomal protein S25, Na(+) / H(+) exchange regulatory cofactor NHE-RF1, acti, N, cytoplasm 2, hemoglobin subunit gamma-1, hemoglobin subunit gamma-2, protein NipSnap homolog 3A, cathepsin D, 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1, 40S ribosomal protein S17, apolipoprotein B-100, histone H2B type 1-K, collagen alpha-1(I) chain, collagen alpha-2(I) chain, 3-hydroxyacyl-CoA dehydrogenase type 2, 60S ribosomal protein L27, histone H1.2, nidogen-2, cadherin-1, 60S ribosomal protein L27a, HLA class II histocompatibility antigen, DR alpha chain, dipeptidyl peptidase 1, ubiquitin-40S ribosomal protein S27a, citrate synthase, mitochondria, Tax1-bound tannin Protein 1, Myeloperoxidase, Plexin Domain-containing Protein 1, Glycogen Synthase, [Pyruvate Dehydrogenase [Acetyl Transfer]-Phosphatase 1, Mitochondria, Phorbol-12-Myristart-13-Acetate Induced Protein 1, Peroxiredoxin-5, Mitochondria, 14-3-3 Protein Zeta / Delta, ATP Synthase Subunit d, Mitochondria, Vitronectin, Lipopolysaccharide-binding Protein, Ig Heavy Chain V-III Region GAL, Protein CREG1, 60S Ribosomal Protein L6, Stabilin-1, Plasma Protease C1 Inhibitor, Ig Kappa Chain V-III Region VG, Inter-Alpha-Trypsin Inhibitor Heavy Chain H4, Alpha-1B-Glycoprotein, Tartrate-Resistant Acid Phosphatase Type 5, Sulfhydryl Oxidase 1, Complement Component C6, Glycogen Phosphorylase, Muscle Morphology, SH3 Domain-binding Glutamate-Rich Protein 3, Transformed Protein RhoA Albumin, isoform CRA_k, V-type proton ATPase subunit G1, flavin reductase (NADPH), heat shock homologous 71kDa protein, lipoprotein lipase, plasminogen, annexin, syntaxin-7, transmembrane glycoprotein NMB, coagulation factor XIIIA chain, apolipoprotein A-II, N-acetylglucosamine-6-sulfatase, complement C1q subcomponent subunit B, protein S100-A10,Fibrellis-associated glycoprotein 4, 72kDa type IV collagenase, collagen alpha-1(XI) chain, cathepsin B, palmitoyl-protein thioesterase 1, macrocyalin, histone H1.1, histone H1.5, fibromodulin, thrombospondin-1, Rho GDP-dissociation inhibitor 2, alpha-galactosidase A, superoxide dismutase [Cu-Zn], HLA class I histocompatibility antigen, alpha chain E, phosphatidylcholine-sterol acyltransferase, regmaine, low affinity immunoglobulin gamma Fc region receptor II-c, fructose-bisphosphate aldolase A, cytochrome c oxidase subunit 8A, mitochondria, pyruvate kinase PKM, endoglin, target of Nesh-SH3, cytochrome c oxidase subunit 5A, mitochondria, EGF-containing fibrin-like extracellular matrix protein 2, epididymal secretory protein E1, cathepsin S, annexin A5, allograft inflammatory factor 1, decorin, complement C1s subcomponent, low affinity immunoglobulin gamma Fc region receptor II-b, leucine-rich alpha-2 glycoprotein, lysosomal alpha-glucosidase, disintegrin and metalloproteinase domain-containing protein 9, transthyretin, malate dehydrogenase, cytoplasm, filamin-A, retinoic acid receptor response protein 1, T cell surface glycoprotein CD4, procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1, fibrinogen gamma chain, collagen alpha-2(V) chain, cystatin-B, lysosomal protective protein, granulin, collagen alpha-1(XIV) chain, C-reactive protein, beta-1,4-galactosyltransferase 1, pro low-density lipoprotein receptor Related protein 1, Ig heavy chain V-III region 23, phosphoglycerate kinase 1, alpha-2-antiplasmin, V set and immunoglobulin domain-containing protein 4, putative serine carboxypeptidase CPVL, NEDD8, ganglioside GM2 activator, clatherin, alpha-2-HS-glycoprotein, HLA class I histocompatibility antigen, B-37 alpha chain, adenosine deaminose CECR1, HLA class II histocompatibility antigen, DRB1-11 beta chain,Monocyte differentiation antigen CD14, erythrocyte band 7 intrinsic membrane protein, profilin-1, E3 ubiquitin-protein ligase TRIM9, tripartite motif-containing protein 67, TNF receptor-related factor 1, alpha-crystallin A chain, mitotic checkpoint serine / threonine-protein kinase BUB1, TATA-binding protein-related factor 2N, cyclin-F, centromere protein C, apoptosis regulator Bcl-2, 2-oxovalerate dehydrogenase subunit beta, mitochondria, koilin, nucleoplasmin-3, homeobox protein Hox-A1, serine / threonine-protein kinase Chk1, mitotic checkpoint protein BUB3, deoxyribonuclease-1, rRNA2'- O-methyltransferase fibrillarin, histone H1.3, DNA-directed RNA polymerase III subunit RPC1, DNA-directed RNA polymerase III subunit RPC2, centromere-associated protein E, kinesin-like protein KIF11, histone H4-like G-type protein, tyrosine 3-monooxygenase, ABC transporter, permease / ATP-binding protein, translation initiation factor IF-1, protein FAN, reticulon-4 receptor, myeloid cell nuclear differentiation antigen, glucose-6-phosphate isomerase, high-affinity immunoglobulin gamma Fc receptor I, tryptophan 5-hydroxylase 1, tryptophan 5-hydroxylase 2, secretory phospholipase A2 receptor, aquaporin TIP4-1, histone H2B FS-type histone H2AX, histone H2A 1-C type, ATP-sensitive inward rectifying potassium channel 10, pVII, virtual protein TTV27_gp4, virtual protein TTV25_gp2, alpha-1D adrenergic receptor, alpha-1B adrenergic receptor, packaging protein 3, virtual protein TTV14_gp2, KRR1 small subunit prosesome component homolog, bethrofin-4, alpha-2C adrenergic receptor, unidentified ORF3 protein, retinoic acid receptor beta, retinoic acid receptor alpha, B-cell lymphoma 3 protein, carbohydrate sulfotransferase 8, harmoninin, prolactin-releasing peptide receptor, sphingosine 1-phosphate receptor 1,Acyl-CoA binding domain-containing protein 5, ORF1, virtual protein TTMV3_gp2, mitochondrial afferent inner membrane translocase subunit Tim17-B, virtual protein TTV2_gp2, deficiency in melanoma 1 protein, virtual protein TTV28_gp1, virtual protein TTV26_gp2, virtual protein TTV4_gp2, virtual protein TTV28_gp4, midbrain astrocytic cell-derived neurotrophic factor, virtual protein TTMV7_gp2, virtual protein TTV19_gp2, pORF1, prehistone-like nucleoprotein, virtual protein TTV8_gp4, virtual protein TTV16_gp2, virtual protein TTV15_gp2, ORF2 / 4 protein, P2X purine receptor 2, membrane glycoprotein E3 CR1-beta, D(2) dopamine receptor, Toll-like receptor 9, phosphatidylcholine transport protein, transcription factor HIVEP2, putative peptidylarginine deiminase, 60S ribosomal protein L9, integrin beta-4, keratin, type II cytoskeleton 1, chromogranin-A, histone H3.1t, voltage-dependent L-type calcium channel subunit alpha-1D, heat shock 70kDa protein 1-like, ABC transporter-related, UDP-N-acetylglucosamine pyrophosphorylase, protein GREB1, Aldo / keto reductase, component of TOM (outer membrane translocase) complex, exinuclease ABC C subunit domain protein, phosphoenolpyruvate carboxylase, arylacetamide deacetylase-like 4, dynein heavy chain 10, axoneme, putative uracil-DNA glycosylase, spore germination protein PE, teneurine-1, putative dehydrogenase, polysaccharide biosynthesis protein, VCBS, glutamate / aspartate transporter permease protein GltK, noggin, sclerostin, HLA class I histocompatibility antigen, A-30 alpha chain, HLA class I histocompatibility antigen, A-69 alpha chain, HLA class I histocompatibility antigen, B-15 alpha chain, ion channel type glutamate receptor, NMDA1, NarH, 40S ribosomal protein S21, ceruloplasmin, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, 60S ribosomal protein L30, HLA class II histocompatibility antigen gamma chain,HLA class I histocompatibility antigen, Cw-6 alpha chain, HLA class I histocompatibility antigen, Cw-16 alpha chain, lysosomal alpha-mannosidase, heat shock protein HSP90-alpha, histone H3.2, histone H2A.J, voltage-dependent T-type calcium channel subunit alpha-1G, syncytin-1, cathelicidin antimicrobial peptide, tubulin beta-3 chain, stress-70 protein, mitochondria, putative 1,4-alpha-glucan branching enzyme Rv3031, nuclease-sensitive element-binding protein 1, complement factor H linkage Linked protein 1, glutaredoxin-1, gamma-enolase, platelet-derived growth factor receptor alpha, collagen alpha-1(VIII) chain, matrix metalloproteinase-25, interferon regulator 5, cytochrome c oxidase subunit 7c, mitochondria, heat shock-related 70kDa protein 2, cysteine-rich protein 1, NADH dehydrogenase [ubiquinone]flavin protein 2, mitochondria, glutathione S-transferase P, HLA class I histocompatibility antigen, A-68 alpha chain, HLA class I I. Histocompatibility antigen, DM beta chain, fructose-bisphosphate aldolase C, beta-2-microglobulin, cytochrome c oxidase subunit 5B, mitochondria, heat shock 70kDa protein 13, ATP synthase protein 8, 60S ribosomal protein L13a, TRNA nucleotidyltransferase family enzymes, ferredoxin-dependent glutamate synthase 2, alkaline phosphatase, tissue-nonspecific isozymes, SLAM family member 5, Slit homolog 3 protein, exchange growth factor-beta induction Protein ig-h3, mannose-binding protein C, calpain-1 catalytic subunit, actin, gamma-intestinal smooth muscle, creatine kinase type M, protein THEM6, histone-lysine N-methyltransferase ASH1L, C2 calcium-dependent domain-containing protein 4A, Ras-association domain-containing protein 10, hepatocyte adhesion molecule, ADAMTS-like protein 5, HLA class II histocompatibility antigen, DRB1-15 beta chain, anoctamin-2, phosphoglycerate mutase 1, Por secretory protein porV (Pg27, lptO),Beta-enolase, receptor antigen A, 3-oxoacyl-[acyl-carrier-protein] synthase 2, putative heat shock protein HSP90-beta 2, radixin, tubulin beta-1 chain, vacuolar protein sorting-related protein 26A, serine / threonine-protein phosphatase 5, catalase, transketolase, ta, Protein S100-A1, alpha-centractin, tubulin beta-4A chain, beta-centractin, putative phosphoglycerate mutase 4, beta-actin-like protein 2, tubulin beta-4B chain, phosphoglycerate mutase 2, alpha-internexin, tubulin beta-2A chain, dihydropyrimidinase-related protein 3, putative heat shock protein HSP90-beta-3, fructose-bisphosphate aldolase B, protein P, endoplasmin, ATP synthase subunit O, mitochondria, heat shock 70kDa protein 6, glyceraldehyde-3-phosphate Drogenase, testis-specific, nascent polypeptide-associated complex subunit alpha-2, carbonate anhydrase 2, annexin A6, E3 ubiquitin-protein ligase RNF13, bone marrow-derived growth factor, tyrosine-protein phosphatase non-receptor substrate 1, laminin subunit gamma-1, trichohyalin, thrombospondin-2, sialoadhesin, GTPase IMAP family member 1, C4b-binding protein alpha chain, voltage-dependent anion-selective channel protein 1, hemopexin, complement C5, FYVE, RhoGEF and PH domain-containing protein 2, haptoglobin, cytochrome P450 1B1, Titin, Myeloma overexpression gene 2 protein, Adipocyte enhancer binding protein 1, Protein-glutamine gamma-glutamyltransferase 2, Protein Trim21, ADAMTS-like protein 3, N-alpha-acetyltransferase 16, NatA accessory subunit, Exchange growth factor beta-1, Elastin, Protein disulfide-isomerase A5, Plastin-2, Leukocyte immunoglobulin-like receptor subfamily B member 1, Histamine H2 receptor, Prolongation factor 2, Caveolin-1, Ig gamma-2 chain C region, Immunoglobulin superfamily including leucine-rich repeat proteins, 40S ribosomal protein S9, Prolyl 4-hydroxylase subunit alpha-1, Endoplasmic reticulum-Golgi intermediate compartment protein 1, Tetranectin, Serine protease HTRA1, Heterogeneous ribonuclear protein A1, Phosducin-like protein 3, Ig lambda chain V-VI region EB4, Fibronectin type III domain-containing protein 1, Keratin,Type II cytoskeleton 2 epidermis, ferritin heavy chain, Y-box binding protein 3, complement C4-B, HLA class I histocompatibility antigen, Cw-15 alpha chain, HLA class I histocompatibility antigen, B-42 alpha chain, collagen alpha-1(V) chain, HLA class I histocompatibility antigen, B-73 alpha chain, intrinsic membrane protein 2B, lysosome-associated membrane glycoprotein 3, proteoglycan 4, ribosomal protein S6 kinase alpha-6, metalloproteinase inhibitor 2, HLA class II histocompatibility antigen, DRB1-12 beta chain, ATP-sensitive Directional rectifying potassium channel 15, vitamin D binding protein, osteopontin, deoxynucleotidyltransferase terminal interacting protein 2, olfactory receptor 5K4, myosin light chain kinase 2, skeletal / cardiac octamer-binding protein containing non-POU domain, ubiquilin-2, HLA class I histocompatibility antigen, B-51 alpha chain, minor histocompatibility antigen H13, glycophorin-C, eosinophil cationic protein, SWI / SNF complex subunit SMARCC2, macrophage mannose receptor 1, tRNA splicing protein Gauze RtcB homolog, reticlocarbin-2, heterogeneous ribosomal protein L, 40S ribosomal protein S30, collagen alpha-3(VI) chain, matrix metalloproteinase-14, antithrombin-III, 60S ribosomal protein L10a, retinol-binding protein 4, heterogeneous ribosomal protein R, lithostatin-1-alpha, Ret finger protein-like 2, zinc alpha-2-glycoprotein, carboxypeptidase Q, HLA class I histocompatibility antigen, B-56 ​​alpha chain, chondroadherin, This includes, but is not limited to, autoantigens derived from or selected from isoforms, homologs, fragments, variants, or derivatives of any of the following proteins: cysteine-rich protein 2, prosaposin, complement component C9, apolipoprotein C-II, protocadherin-16, leukocyte immunoglobulin-like receptor subfamily B member 4, galactokinase, complement factor H, unidentified protein YEL014C, glycerophosphocholine phosphodiesterase GPCPD1, echinoderm microtubule-associated protein-like 6, or any isoform, homolog, fragment, variant, or derivative of any of these proteins.

[0185] The term "alloantigen" (also called "allogeneic antigen" or "isoantigen") refers to an antigen that exists in a selective (allelegenic) form within a species and can therefore induce alloimmunity (or isoimmunity) in members of the same species, for example, during blood transfusion, tissue or organ transplantation, or sometimes during pregnancy. Typical allogeneic antigens include histocompatibility antigens and blood group antigens. In relation to the present invention, alloantigens are preferably derived from humans. Using artificial nucleic acid (RNA) molecules encoding antigenic (poly)peptides or proteins derived from alloantigens, immune resistance to the above alloantigens can be induced, for example.

[0186] In relation to the present invention, examples of allogeneic antigens include UDP-glucuronosyltransferase 2B17 precursor, MHC class I antigen HLA-A2, coagulation factor VIII precursor, coagulation factor VIII, thrombopoietin precursor (megakaryocyte colony-stimulating factor) (myeloproliferative leukemia virus oncogenic gene ligand) (C-mpl ligand) (ML) (megakaryocyte growth and development factor) (MGDF), integrin beta-3, histocompatibility (minor) HA-1, SMCY, thymosin beta-4, Y chromosome, histone demethylase UTY, HLA class II histocompatibility antigen, DP(W2) beta chain, lysine-specific demethylase 5D isoform 1, myosin-Ig, putative ubiquitin carboxyl-terminal hydrolase FAF-Y, procathepsin H, DRB1, and MHC DR beta-DRw13 variant, HLA class II histocompatibility antigen, DRB1-15 beta chain, HLA class II histocompatibility antigen, DRB1-1 beta chain precursor, minor histocompatibility protein HMSD variant form, HLA-DR3, B chain, human class II histocompatibility protein (extracellular domain) complexed with Hla-Dr1 (Dra, Drb1 0101) endogenous peptide, MHC class II HLA-DRB1, MHC class I HLA-A, human leukocyte antigen B, RAS protein activator-like 3, anoctamin-9, ATP-dependent RNA helicase DDX3Y, protocadherin-11 Y-linking, KIAA0020, platelet glycoprotein IIIa leucine-33 specific antibody light chain variable region, dead box, Y-isoform, ATP-dependent RNA helicase DDX3X isoform 2, HLA-DRB1 protein, cleaved integrin beta 3, glycoprotein IIIa, platelet membrane glycoprotein IIb, carbonate anhydrase 1, HLA class I histocompatibility antigen, A-11 alpha chain precursor, HLA-A11 antigen-A11.2. HLA class I histocompatibility antigen, A-68 alpha chain, MHC HLA-B51, MHC class I antigen HLA-A30, HLA class I histocompatibility antigen, A-1 alpha chain precursor variant, HLA class I histocompatibility antigen B-57, MHC class I antigen, MHC class II antigen, MHC HLA-DR-beta cell surface glycoprotein, DR7 beta chain glycoprotein, MHC DR-beta, lymphocyte antigen, type V collagen alpha-1, collagen alpha-2(V) chain preproprotein, sp110 nucleolar protein isoform d, integrin, alpha-2b (platelet glycoprotein IIb of IIb / IIIa complex, antigen CD41), isoform CRA_c, 40S ribosomal protein S4, Y isoform 1, unidentified protein KIAA1551, factor VIII, UDP-glucuronosyltransferase 2B17, HLA class I histocompatibility antigen, A-2 alpha chain, thrombopoietin, minor histocompatibility protein HA-1, lysine-specific demethylase 5D, HLA class II histocompatibility antigen, DP-beta-1 chain, atypical myosin-Ig HLA class II histocompatibility antigen, DRB1-13 beta chain, HLA class II histocompatibility antigen, DRB1-1 beta chain, HLA class II histocompatibility antigen, DRB1-3 chain, HLA class I histocompatibility antigen This includes, but is not limited to, allogeneic antigens derived from or selected from isoforms, homologs, fragments, variants, or derivatives of any of these proteins, including, B-46 alpha chain, Pumilio homolog 3, ATP-dependent RNA helicase DDX3X, integrin alpha-IIb, HLA class I histocompatibility antigen, A-11 alpha chain, HLA class I histocompatibility antigen, B-51 alpha chain, HLA class I histocompatibility antigen, A-30 alpha chain, HLA class I histocompatibility antigen, A-1 alpha chain, HLA class I histocompatibility antigen, B-57 alpha chain, HLA class I histocompatibility antigen, B-40 alpha chain, HLA class II histocompatibility antigen, DRB1-7 beta chain, HLA class II histocompatibility antigen, DRB1-12 beta chain, collagen alpha-1(V) chain, collagen alpha-2(V) chain, Sp110 nucleolar protein, or isoforms, homologs, fragments, variants, or derivatives of any of these proteins.

[0187] [Allergenic (poly)peptides or proteins] At least one coding region of the artificial nucleic acid molecule of the present invention may encode at least one “allergenic (poly)peptide or protein.” The term “allergenic (poly)peptide or protein” or “allergen” refers to a (poly)peptide or protein that, when exposed to a subject, can induce an allergic reaction, i.e., a pathological immune response characterized by altered bodily responsiveness (such as hypersensitivity). Typically, “allergen” is involved in “atopy,” i.e., an adverse immune response associated with immunoglobulin E (IgE). Thus, the term “allergen” typically means a substance (here, a (poly)peptide or protein) that is involved in atopy and induces IgE antibodies. Typical allergens assumed herein include proteinaceous crustacean allergens, insect allergens, mammalian allergens, mollusk allergens, plant allergens, and fungal allergens.

[0188] In relation to the present invention, examples of allergens include allergen Pen n 18, antigen name, Ara h 2.01 allergen, melanoma antigen recognized by T cell 1, nonspecific lipid transport protein precursor (LTP) (allergen Mal d 3), ovalbumin, parvalbumin beta, pollen allergen Lol p VA precursor, pollen allergen Phl p 5b precursor, pru p 1, pollen allergen Phl p 5a, Der p 1 allergen precursor, pollen allergen KBG 60 precursor, major allergen Tur c1-Turbo cornutus, mite group 2 allergen Lep d 2 precursor, Lep D 2 precursor, major latex allergen Hev b 5, major allergen Cor a 1.0401, major pollen allergen Art v 1 precursor, major pollen allergen Bet v 1-A, beta-lactoglobulin precursor, alpha-amylase inhibitor 0.28 precursor (CIII) (WMAI-1), group V allergen Phl p 5.0203 precursor, polygalacturonase precursor, pollen allergen Phl p I, Der f 2 allergen, putative nonspecific lipid transport protein 2 precursor, toxin allergen 5 precursor, pollen allergen Phl p 1 precursor, group V allergen, A chain, calcium-bound pollen allergen Phl P7 (polcarcin) crystal structure at 1.75 angstroms, Tri r 2 allergen, pathogenicity-related protein precursor, globin CTT-III precursor, major allergen Alt a 1, 13S globulin seed storage protein 3 precursor (regumin-like protein 3) (allergen Fag e 1), Lit v 1 tropomyosin, rubber extension factor protein, ovomucoid precursor, rubber particle protein, Mag3, allergen Ara h 1. Clone P41B precursor, 13S globulin seed storage protein 1 precursor (regmin-like protein 1), pollen allergen Lol p 1 precursor, major pollen allergen Jun a 1 precursor, cedar basic protein precursor, profilin, globin CTT-IV precursor, alkaline serine protease, glycinin, conglutin-7 precursor, 2S protein 1, globin CTT-VI precursor, ribonuclease mitoglyline precursor, major pollen allergen Cyn d1. Melanocyte-stimulating hormone receptor, P34 putative thiol protease precursor, bicillin-like protein, major allergen Equ c 1 precursor, major allergen Bet v 1, major allergen Can f 1 precursor, Bd 30K (34kDa mature seed protein), major pollen allergen, major pollen allergen Hol l 1 precursor, kappa casein precursor, major allergen Dau c 1 / 1, stress-inducing protein SAM22, major allergen Api g 1, glycinin G2 precursor, allergen Arah 3 / Arah 4, Der f 1 allergen, peptidase 1 precursor (mite group 1 allergen Eur m 1) (allergen Eur m I), origin precursor, alpha S1 casein, major pollen allergen Cha o 1 precursor, nonspecific lipid transport protein 1, collagen, type I, alpha 2, Der P 1. Peptidase 1 precursor (major dust mite fecal allergen Der p 1) (allergen Der p I), pollen allergen Bet v 1, phospholipase A2 precursor, dust mite group 2 allergen Der p 2, allergen Mag, major urinary protein precursor, major allergen I polypeptide chain 2 precursor, Pen a 1 allergen, Fag e 1, serum albumin precursor, pollen allergen Amb a 3, putative alpha-amylase inhibitor 0.28, albumin seed storage protein, 2S sulfur-rich seed storage protein precursor (allergen Ber e 1), seed storage protein SSP2, prohebein precursor, pollen allergen, Der p 2 allergen precursor, 2S seed storage protein 1 precursor, prohebein, 2s albumin, major allergen I, polypeptide chain 1, major allergen I polypeptide chain 1 precursor, Cry j IB precursor, dust mite group 2 allergen Der f 2 precursor, beta-casein precursor, Lep D 2 allergen precursor, allergen Cry j 2 (pollen allergen), KIAA1224 protein, hydrophobic seed protein, allergen Bos d 2 precursor, allergen II, mite group 2 allergen Der p 2 precursor, mite allergen Blo t 5, peptidase 1 precursor (major mite feces allergen Der f 1) (allergen Der f I), Par j, Can f I, pollen allergen Lol p 2-A (Lol pII-A), paramyosin, alpha-S2-casein precursor, P34 putative thiol protease, beta-lactoglobulin, major allergen Phl p 5, A chain, structure of erythrocruorin in different ligand states purified at 1.4 angstrom resolution, globin CTT-VIII, major allergen Asp f 2 precursor, tropomyosin, core protein [hepatitis B virus], omegagliadin storage protein, alpha / beta-gliadin AV, group 14 allergen protein, pollen allergen Amb a 1.1 precursor, glycinin G1 precursor, pollen allergen Amb a 2 precursor, Cry j 1 precursor, allergen Ziz m 1, glycine-rich cell wall structure protein 1.8 precursor, putative pectinate lyase 17 precursor, pectinate lyase, pectinate lyase precursor, putative pectinate lyase 18 precursor, major allergen beta-lactoglobulin, major allergen Mal d 1, alpha-S1-casein precursor, 2S seed storage protein 1, Plectrovirus spv1-r8a2b orf 14 transmembrane protein, allergen I / a, allergen Cr-PI, putative nonspecific lipid transport protein 1, Cr-PII allergen, melanoma antigen gp100, alpha-lactalbumin precursor, A chain, abnormal substructure of alpha-lactalbumin, pyrosrin-1 precursor (major allergen Myr p 1) (Myr p I), pollen allergen Lol p 3 (Lol p III), lipocalin 1 (tear prealbumin), major pollen allergen Cup a 1, melanocyte protein Pmel 17 precursor, major house dust allergen, nonspecific lipid transport protein 1 (LTP 1) (major allergen Pru d 3), nonspecific lipid transport protein 1 (LTP 1) (major allergen Pru ar 3), pollen allergen Lol p 1, alpha-gliadin, Cr-PII, albumin, alpha-S1-casein, major allergen I, ribonuclease mitoglyline, beta-casein, UA3-recognized allergen, 2S sulfur-rich seed storage protein 1, unidentified protein product, polygalacturonase, major allergen Pru av 1, Der p 1 allergen, lyase allergen, major pollen allergen Bet v1-F / I, gamma-gliadin precursor, 5-hydroxytryptamine receptor 2C (5-HT-2C) (serotonin receptor 2C) (5-HT2C) (5-HTR2C) (5HT-1C), omega-5 gliadin, enolase 1 (2-phosphoglycerate dehydratase) (2-phospho-D-glycerate hydrolyase), putative nonspecific lipid transport protein, allergen Sin a 1, glutenin, low molecular weight subunit precursor, major peanut allergen Ara H 1, mal d 3, Eukaryotic translation initiation factor 3 subunit D, tyrosinase-related protein-2, PC4 and SFRS1 interacting protein, RAD51-like 1 isoform 1, antimicrobial peptide 2, proteasome subunit alpha 3, nerve fibril heavy polypeptide (NF-H) (nerve fibril triplet H protein) (200kDa nerve fibril protein), superoxide dismutase, major pollen allergen Cor a 1 isoforms 5, 6, 11 and 16, cherry allergen PRUA1, allergen Asp f 4 precursor, A chain, major house dust mite allergen Der P 2 tertiary structure, Nmr, 10 structure, RNA-binding protein NOB1, dermatan sulfate epimerase precursor, squamous cell carcinoma antigen recognized by T cell 3, peptidyl-prolyl cis-trans isomerase B precursor, putative glycosidase crf1, A chain, hippo pollen profilin, profilin-1, avenin precursor (clone pAv122)-oat, gamma-3 avenin, celiac immunoreactive protein 2, CIP-2, prolamin 2{N-terminus}, avenin gamma-3-small naked oat (fragment), major pollen allergen Ole e 1, cytochrome P450 3A1, Ole e 1 protein, Ole e 1.0102 protein, Der f 2, GroEL-like chaperonin, major allergen Arah 1, manganese superoxide dismutase, beta-1,3-glucanase-like protein, Arah h 1 Allergen, Major Allergen Alt a 1 Precursor, Bla g 4 Allergen, Per a 4 Allergen Variant 1, Lyc e 2.0101, Pectinate Lyase 2, Allergen, Virtual Protein, Presumptive Pectinate Lyase P59, Pollen Allergen Amb a 1.4, Patatin-2-Kuras1. Calcium-binding protein, bicillin seed storage protein, major allergenic protein Mal f4, pel protein, maturation-related pectinate lyase, pectinate lyase / Amb allergen, Bet v 4, polcarcin Bet v 4, dust mite allergen Der f 6, allergen Alt a 2. Extracellular elastin-degrading metalloproteinase, pectinate lyase-like protein, pectinate lyase E, profilin-2, toxic allergen 5, cucumisin, putative peroxiredoxin, putative pectinate lyase precursor, serum albumin, pollen allergen Phl p 11. Serine (or cysteine) proteinase inhibitor, branch group B (ovalbumin), member 3, allergen Bla g 4 precursor (Bla g IV), allergen Pen n 13. Hyaluronidase A, pectinate lyase homolog, putative allergen Cup a 1. Major pollen allergen Jun v 1. Estimated allergen jun o 1. Pollen allergen Amb a 1.2, Presumed pectin lyase 13, P8 protein, Cytochrome c, Glucan endo-1,3-beta-glucosidase, Basic vacuolar isoform, 13S globulin, Beta-1,3-glucanase, Beta-1,3-glucanase, Glutenin, High molecular weight subunit DX5 precursor, X-type HMW glutenin, Glutenin, High molecular weight subunit DX5, High molecular weight glutenin subunit 1Dx2.1, High molecular weight glutenin subunit, 11S globulin-like protein, Seed storage protein, Alpha-L-Fucp-(1->3)-[Alpha-D-Manp-(1->6)-[Beta-D-Xylp-(1->2)]-Beta-D-Manp-(1->4)-Beta-D-GlcpNAc-(1->4)]-D-GlcpNAc, Beta-casein B, Type 1 nonspecific lipid transport protein precursor, Fas AMA, caspase-8 precursor, H antigen glycoprotein, H antigen gl, heat shock protein HSP90-beta, dihydrolipoamide S-acetyltransferase (E2 component of pyruvate dehydrogenase complex), isoform CRA_a, group V allergen Phl p 5.0103 precursor, Phl p 6 allergen precursor, group V allergen Phl p 5, major pollen allergen Phl p4 precursors, pollen allergen Phl p V, Phl p 3 allergen, pollen allergen Phl p I precursor, A chain, crystal structure of Phl P 1, major timothy grass pollen allergen, pollen allergen Phl p 4, profilin-3, profilin-2 / 4, pollen allergen Phl p 2, Phl p 6 IgE binding fragment, Phl p 5, N chain, crystal structure of Phl P 6, major timothy grass pollen allergen cocrystallized with zinc, group V allergen Phl p 5.0206 precursor, allergenic protein, major allergen Ani s 1, allergen Ana o 2, ENSP-like protein, BW 16kDa allergen, alpha-2(I) collagen, collagen a2(I), type 1 collagen alpha-2, Cyn d 1, major pollen allergen Aln g 1 (allergen Aln g I), allergen Len c 1.0101, galactomannan, aspartic acid protease Bla g 2, alcohol dehydrogenase, lipid transport protein precursor, alpha / beta gliadin precursor, Der f 7 allergen, Der p 7 allergen polypeptide, nonspecific lipid transport protein, major allergen I polypeptide chain 1, prunin 1 precursor, prunin 2 precursor, 11S regumin protein, Ara h 7 allergen precursors, bicillin-like protein precursors, allergen Arah6, parvalbumin-like 2, parvalbumin-like 1, casein kappa, ribosomal biodevelopmental protein LAS1L, Pen c 1, SchS21 protein, inactive hyaluronidase B, Mup1 protein, macrophage migration inhibitor, eukaryotic translation initiation factor 2 subunit 3, CR2 / CD21 / C3d / Epstein-Barr virus receptor precursor, DNA topoisomerase 2-alpha, pollen allergen Cyn d 23, major allergen Bla g 1.02, pectin methylesterase allergenic protein, major allergen Pha a 5 isoform, 2S albumin seed storage protein, aldehyde dehydrogenase (NAD+), pollen allergen Poa p 5, Bla g 1.02 variant allergen, partial, major pollen allergen Lol p 5b, Allergen Bla g 6.0301, Protein disulfide isomerase, Presumed mannitol dehydrogenase, Pollen allergen Lol p 4, Aspartate protease pep 1, Enolase, IgE-binding protein, Minor allergen Alt a 5, HDM allergen, A chain, Crystal structure of Mbp-Der P 7 fusion protein, Allergen Bla g 6.0201, Major allergen Bla g 1.0101, alpha-amylase, minor allergen, ribosomal protein P2, metalloproteinase (MEP), autophagy serine protease Alp2, allergenic isoflavone reductase-like protein Bet v 6.0102, A chain, crystal structure of complex of antibody and allergen Bla G 2, minor allergen, thioredoxin TrxA, enolase, allergen Cla h 6, glutathione-S-transferase, molecular chaperone and allergen Mod-E / Hsp90 / Hsp1, major allergen Asp F2, mite allergen Der p 3, B chain, crystal structure of Aspergillus fumigatus Mnsod, glutathione-S-transferase (GST class-sigma) (major allergen Bla g 5), minor allergen Cla h 7, unknown protein, allergenic ceratoplatin Asp F13, art v 2 allergen, polcarcin Aln g 4, major allergen and cytotoxin AspF1, pollen allergen Que a 1 isoform, trypsin-like serine protease, mite group 6 allergen Der p 6, allergen Asp F7, cell wall protein PhiA, 60kDa allergen Der f 18p, hsp70, Sal k 3 pollen allergen, acid ribosomal protein P2, B chain, crystal structure of Nadp-dependent mannitol dehydrogenase from Cladosporium Herbarum, Art v 3.0301 allergen precursor, 60S ribosomal protein L3, Der p 20 allergen, pollen allergen Sal k 1, Per a 6 allergen, gelzolin-like allergen Der f 16, A chain, major cat allergen Fel D Structural characterization of the tetramer form of 1, glutathione S-transferase, Fel d 4 allergen, major pollen allergen Dac g 4, group I allergen Ant o I (type 1), pollen, allergen Bla g 6.0101, cystatin, dust mite allergen Der p 5, allergen Fra e 1, allergen Asp F4, major antigen-like protein, PR5 allergen Cup s 3.1 Precursor, Heat Shock Protein, Allergen Precursor, Arginine Esterase Precursor, Sal k 4 Pollen Allergen, 60S Acid Ribosomal Protein P1, Pollen Allergen Jun o 4, Polcarcin Cyn d 7, Group I Pollen Allergen, Peptidyl-Prolyl Cistrans Isomerase / Cyclophyllin, Presumed, Prophyllin 2, Pollen Allergen Cyn d 15, Der f 13 Allergen, Can f 2, Peroxisome-like Protein, Peptidyl Prolyl Isomerase (Cyclophyllin), MHC Class II Antigen, BETV4 Protein, Major Pollen Allergen Pla l 1, Peptidase, MPA3 Allergen, Major Plantain Pollen Allergen, Pla l 1.0103, Major Allergen Bla g 1.0101, partial, pollen allergen Amb p 5a, Der f 16 allergen, pollen allergen Dac g 2, IgE-binding protein C-terminal fragment (148 AA), pollen allergen Dac g 3, PPIase, rAsp f 9, dust mite allergen Der p 7, thioredoxin, hydrolase, major pollen allergen Pha a 1, Der p 13 allergen, B chain, X-ray structure of Der P 2, major house dust mite allergen, oleosin 3, peptidyl-prolyl cis-trans isomerase, A chain, crystal structure of major house dust mite allergen, Der f 2, A chain, crystal structure of major allergen, cockroach-derived Bla G 4, Amb a 1-like protein, D-type LMW glutenin subunit, glutathione S-transferase 2, acid Cyn d 1 isoallergen isoform 4 precursor, albumin seed storage protein precursor, tyrosine 3-monooxygenase isoform b, N-glycoprotein, FAD-binding oxidoreductase BG60, Blo t 21 allergen, ubiquitin D, nucleoporin Nup37, non-POU domain-containing octamer-binding protein, transcription extension factor SPT5, major allergen Mal d 1 (Ypr10 protein), serpine-Z2B, Pas n 1 allergen precursor, arginine kinase, Lit v 3 allergen myosin light chain, sarcoplasmic calcium-binding protein, alpha subunit of beta-conglycinin, prunin, allergen Cry j 2, plexin-A4, nonspecific lipid transport protein, low molecular weight glutenin subunit precursor, gamma-gliadin, GATA-1 related proteins, Wilms tumor protein, ubiquitin-conjugating enzyme E2 C, fatty acid synthase, histone H4, fructose-bisphosphate aldolase A, oxidoreductase, lactoglobulin beta, immunoglobulin gamma triple chain constant region, Phlp5 precursor, dust mite allergen precursor, heat shock protein 70, major allergen I polypeptide chain 2, alpha-lactalbumin precursor protein, 30kDa pollen allergen, group 5 allergen precursor, group 1 allergen Dac g 1.01 precursor, unidentified protein, unknown timothy grass protein, kappa-casein, alpha-S1 casein, SXP / RAL-2 family protein, lipocalin-1 precursor, alpha-prothionine, major allergen Bet v 1.01A, P2 protein, osmotin, major peanut allergen Ara H 2, Der f 3 allergen, conglutin, Ara h 6 allergen, cathelicidine antimicrobial peptide, cholinesterase, Per a 2 allergen, submandibular gland androgen regulatory protein 3B, chitinase, partial, allergen Can f 4 precursor, Can f 4 variant allergen precursor, nascent polypeptide association complex subunit alpha-2, polcarcin Phl p 7 (calcium-bound pollen allergen Phl p 7) (P7), Der p II allergen, major allergen Ara h1, allergen Ara h 2.02, fatty acid binding protein, glutamate receptor, glycinin A3B4 subunit, prophylline isoallergen 2, pollen allergen Amb p 5b, calcium binding protein isoallergen 2, calcium binding protein isoallergen 1, cysteine ​​protease, prophylline isoallergen 1, ragweed homolog of Art v 1 precursor, Amb p 5, ragweed homolog of Art v 1 (isoform 1), partial, antigen E, putative pectinate lyase precursor, partial, pollen allergen Amb a 5, Amb p V allergen, hemocyanin subunit 6, major pollen allergen Cha o 2, trichohyalin, aspartyl endopeptidase, NCRA10, allergen bla g 8, vitellogenin, NCRA3, NCRA4, allergen Bla g 3 isoform 2 precursors, partially, NCRA2, NCRA13, NCRA8, NCRA1, Bla g 11, activated protein kinase C-like receptor, NCRA5, NCRA14, triose phosphate isomerase, NCRA12, NCRA7, NCRA11, trypsin, triose phosphate isomerase, partially, NCRA6, structural protein, NCRA15, NCRA9, NCRA16, Der f 4 allergen, Der f 5 allergen, Phl p 6 allergen, Der f Gal d 2 allergen, Derp_19830, glucosylceramidase, carboxypeptidase, Der f 8 allergen, partially, fructose bisphosphate aldolase, ATP synthase, Der f Alt a 10 allergen, glutamine synthetase, Derp_c23425, myosin, Der f 8 allergens, LytFM, Der f 11 allergens, serine protease, glutathione transferase mu, triose-phosphate isomerase, ubiquinol-cytochrome c reductase-binding protein-like protein, ferritin, isomerase, filamin C, Der p 5, Mag44, partial, toxic, muscle-specific protein, Der f 5.This list includes, but is not limited to, allergens derived from or selected from homologs, fragments, variants, or derivatives of any of these allergens, including: 02 allergen, Mag44, Derp_c21462, Group 18 allergen protein, Derp_c9409, napin-type 2S albumin 1 precursor, napin-type 2S albumin 3, isoflavone reductase-like protein CJP-6, pectin acid lyase 1, allergen Cry j 2, partial, major allergen Dau c 1, filamin-C, putative, Pis v 5, 0101 allergen 11S globulin precursor, Pis v 5, 48kDa glycoprotein precursor, bicillin, or homologs, fragments, variants, or derivatives of any of these allergens.

[0189] [Reporter protein] At least one coding region of the artificial nucleic acid (RNA) molecule of the present invention may encode at least one "reporter (poly)peptide or protein".

[0190] The term "reporter (poly)peptide or protein" refers to a (poly)peptide or protein expressed from a reporter gene. Reporter (poly)peptides or proteins are typically heterogeneous to the expression system used. Their presence and / or functionality can preferably be readily detected, visualized, and / or measured (e.g., by fluorescence, spectroscopy, luminometry, etc.).

[0191] Examples of reporter (poly)peptides or proteins include beta-galactosidase (encoded by the bacterial gene IacZ); luciferase; chloramphenylacetyltransferase (CAT); GUS (beta-glucuronidase); alkaline phosphatase; green fluorescent protein (GFP) and its variants and derivatives (enhanced green fluorescent protein (eGFP), CFP, YFP, GFP+, etc.); alkaline phosphatase or secretory alkaline phosphatase; peroxidase, beta-xylosidase; xyl E (catechol dioxygenase); TreA (trehalase); Discosoma species red fluorescent protein (dsRED) and its variants and derivatives (mCherry, etc.); HcRed; AmCyan; ZsGreen; ZsYellow; AsRed; and other bioluminescent proteins and fluorescent proteins. The term "luciferase" refers to a class of oxidases that can produce bioluminescence. Many luciferases, such as firefly luciferase (e.g., from the firefly Photinus pyralis), sea slug luciferase (Renilla reniformis), Metridial luciferase (MetLuc, from the marine copepod Metridia longa), equiole luciferase, dinoflagellate luciferase, or Gausian luciferase (Gluc), or isoforms, homologs, fragments, variants, or derivatives of any of these proteins are known in the art.

[0192] [Additional domains, tags, linkers, sequences, or factors] At least one coding region of the artificial nucleic acid molecule of the present invention may preferably encode an additional (poly)peptide domain, tag, linker, sequence, or factor in addition to at least one (poly)peptide or protein of interest. The nucleic acid sequence encoding the additional domain, tag, linker, sequence, or factor is operably bound in a frame to the region encoding the (poly)peptide or protein of interest, thereby allowing expression of the coding sequence to preferably produce a fusion product (or derivative) of the (poly)peptide or protein of interest linked to the additional domain, tag, linker, sequence, or factor.

[0193] For example, nucleic acid sequences encoding further (poly)peptide domains, tags, linkers, sequences, or factors are preferably in-frame with respect to the nucleic acid sequence encoding the desired (poly)peptide or protein. The codon usage frequency can be adapted to the host intended for expressing the artificial nucleic acid (RNA) molecule of the present invention.

[0194] Preferably, at least one coding region of the artificial nucleic acid molecule of the present invention may further encode at least one of the following: (a) effector domain; (b) peptide or protein tag; (c) localization signal or sequence; (d) nuclear localization signal (NLS); (e) signal peptide; (f) peptide linker; (g) secretory signal peptide (SSP); (h) multimerizing factor including dimerizing factor, trimerizing factor, tetramerizing factor, or oligomerizing factor; (i) virus-like particle (VLP) forming factor; (j) transmembrane factor; (k) dendritic cell targeting factor; (l) immunological adjuvant factor; (m) antigen presentation promoting factor; (n) 2A peptide; (o) factor that prolongs protein half-life; and / or (p) post-translational modification factor (e.g., glycosylation).

[0195] <Effector Domain> The term "effector domain" typically refers to a (poly)peptide or protein domain that confers biological effector function by interacting with a target, such as through enzyme activity, target (e.g., ligands, receptors, proteins, nucleic acids, hormones, neurotransmitter small organic molecules) binding, signal transduction, or immunostimulation.

[0196] Effector domains can be suitably (additionally) encoded by artificial nucleic acid (RNA) molecules encoding any desired (poly)peptide or protein as described herein. Effector domains fused to or inserted into the desired (poly)peptide or protein can advantageously confer further biological function or activity to the said (poly)peptide or protein. When encoded in combination with the desired (poly)peptide or protein, the effector domain can be located at the N-terminus, C-terminus, and / or within the desired (poly)peptide or protein, or in combination thereof. Another effector domain may be combined. At the nucleic acid level, the coding sequence of such an effector domain is typically located within a frame (i.e., within the same reading frame), within the coding sequence of the desired (poly)peptide or protein, from 3' to the coding sequence, or from 5' to the coding sequence, or in combination thereof.

[0197] <Peptide or protein tag> A "peptide or protein tag" is a short amino acid sequence introduced into a target (poly)peptide or protein to confer a desired biological functionality or property. Typically, "peptide tags" can be used for the detection, purification, fractionation, or addition of specific desired biological properties or functionalities.

[0198] Therefore, peptide or protein tags can be used for a variety of purposes. Almost all peptide tags can be used to detect the (poly)peptide or protein of interest using Western blotting, ELISA, ChIP, immunocytochemistry, immunohistochemistry, and fluorescence assays. Most protein or peptide tags can be used for the purification of the (poly)peptide or protein of interest. Some tags may be explored to extend the half-life of biological proteins, increase the solubility of the (poly)peptide and protein of interest, or help localize the (poly)peptide or protein into cellular compartments.

[0199] Protein or peptide tags may be appropriately (additionally) encoded by an artificial nucleic acid (RNA) molecule encoding any desired (poly)peptide or protein as described herein. A protein or peptide tag fused to or inserted into a desired (poly)peptide or protein may, for example, advantageously enable detection, purification, or fractionation of the above (poly)peptide or protein. When encoded in combination with a desired (poly)peptide or protein, the protein or peptide tag may be located at the N-terminus, C-terminus, and / or internally of the desired (poly)peptide or protein, or a combination thereof. Another protein or peptide tag may be combined. Protein or peptide tags may be repeatable and may be expressed, for example, in tandem or triplet configurations. At the nucleic acid level, the coding sequence of such a protein or peptide tag is typically located within a frame (i.e., within the same reading frame), within the coding sequence of the desired (poly)peptide or protein, from 3' to the coding sequence, or from 5' to the coding sequence, or a combination thereof.

[0200] Protein and peptide tags can be classified based on their (primary) function. Examples of protein and peptide tags envisioned in relation to the present invention include, but are not limited to, tags selected from the following groups: Affinity tags enable the purification of the (poly)peptide or protein of interest and include, but are not limited to, chitin-binding protein (CBP), maltose-binding protein (MBP), Strep tags, glutathione-S-transferase (GST), and poly(His) tags, which typically contain six tandem histidine residues forming a nickel-binding structure. Solubilization tags assist in proper folding and prevent precipitation of the (poly)peptide or protein of interest and include thioredoxin (TRX) and poly(NANP). MBP tags and GST tags may also be used as solubilization tags. Chromatography tags alter the chromatographic properties of the protein or (poly)peptide of interest, enabling their differentiation by chromatographic techniques. Typically, chromatographic tags consist of polyanionic amino acids, such as FLAG tags (which may typically include the amino acid sequence N-DYKDDDDK-C (SEQ ID NO: 378)). Epitope tags are short peptide sequences that can bind to high-affinity antibodies, for example, in Western blotting, immunofluorescence, or immunoprecipitation, but can also be used to purify the (poly)peptide or protein of interest. Epitope tags may be derived from pathogenic antigens such as viruses and include, but are not limited to, V5 tags (which may typically include the short amino acid sequence GKPIPNPLLGLDST derived from the P / V protein of paramyxovirus SV5), Myc tags (which may typically include the 10-amino acid segment of the human proto-oncogene Myc (EQKLISEEDL (SEQ ID NO: 379)), HA tags (which may typically include the short segment YPYDVPDYA (SEQ ID NO: 380) derived from human influenza hemagglutinin protein), and NE tags.Fluorescent tags such as GFP and its variants and derivatives (e.g., mfGFP, EGFP) can be used for the detection of (poly)peptides or proteins (by direct visual readout or by binding to an anti-GFP antibody) or as reporters. Protein tags may enable certain enzymatic modifications (such as biotinylation by biotin ligase) or chemical modifications (such as reaction with FlAsH-EDT2 for fluorescence imaging). Tags such as thioredoxin, poly(NANP) can increase protein solubility, while others can help localize target proteins to desired cellular compartments. Further tags include ABDz1 tag, adenylate kinase (AK tag), calmodulin-binding peptide, CusF, Fh8, HaloTag, heparin-binding peptide (HB tag), ketosteroid isomerase (KSI), Inntag, PA(NZ-1), polyarginine tag, polylysine tag, S tag, and SUMO. Peptide or protein tags may be combined or repeated. After purification, protein or peptide tags may be removed by specific proteolytic degradation (e.g., by TEV protease, thrombin, factor Xa, or enteropeptidase).

[0201] <Nuclear localization signal or sequence (NLS)> A "nuclear localization signal" or "nuclear localization sequence" (NLS) is an amino acid sequence that can target a desired (poly)peptide or protein to the nucleus; in other words, a nuclear localization signal "labels" the desired (poly)peptide or protein for nuclear translocation. Generally, proteins enter the nucleus through the outer nuclear membrane. The outer nuclear membrane consists of the concentric, outer, and inner membranes. The inner and outer membranes are linked at multiple sites, forming channels between the cytoplasm and nucleoplasm. These channels are occupied by the nuclear pore complex (NPC), a complex of multiprotein structures that mediates transport across the nuclear membrane.

[0202] Nuclear localization signals may be appropriately (additionally) encoded by artificial nucleic acid (RNA) molecules encoding any (poly)peptide or protein of interest as described herein. Nuclear localization signals fused or inserted into the (poly)peptide or protein of interest may advantageously facilitate importin (also known as caryopherin) binding and / or nuclear translocation of the above (poly)peptide or protein. While not bound by any particular theory, NLS may be particularly useful when fused or inserted into therapeutic (poly)peptides or proteins intended for nuclear targeting, e.g., gene editing agents, transcription inducers or repressors. However, NLS may also be encoded using any other (poly)peptide or protein described herein. When encoded in combination with the (poly)peptide or protein of interest, such nuclear localization signals may be located at the N-terminus, C-terminus and / or within the (poly)peptide or protein of interest, or in combination thereof. It is also conceivable that an artificial nucleic acid (RNA) molecule may encode two or more NLSs fused / inserted into the encoded (poly)peptide or protein of interest. At the nucleic acid level, such coding sequences for nuclear localization signals are typically located within a frame (i.e., within the same reading frame) within the coding sequence of the (poly)peptide or protein of interest, either starting from 3' or 5', or a combination thereof.

[0203] Typically, an "NLS" may or may consist of one or more short sequences of positively charged lysine or arginine, which are preferably exposed on the protein surface. Various NLS sequences are known in the art. Representative NLS sequences that can be selected for use in the present invention include, but are not limited to, the following: The most well-characterized transport signal is the classical NLS for nuclear protein translocation (cNLS), which consists of either a single (monosegmental) or double (biosegmental) sequence of basic amino acids. Typically, a monosegmental motif features a cluster of basic residues preceded by a helix-breaking residue. Similarly, a biosegmental motif consists of two clusters of basic residues separated by 9-12 residues. An example of a monosegmental cNLS is the SV40 giant T antigen NLS. 126 PKKKRRV 132 (Sequence ID 381)) is an example, and an example of binocular cNLS is nucleoplasmin NLS ( 155 KRPAATKKAGQAKKKK 170 (Sequence ID 382) is one example. The consecutive residues from the N-terminal lysine of monosegmental NLS are referred to as P1, P2, etc. Monosegmental cNLS typically require lysine at position P1, followed by basic residues at positions P2 and P4, which results in a loose consensus sequence of K(K / R)X(K / R) (Sequence ID 384) (Lange et al. J Biol Chem. 2007 Feb 23; 282(8): 5101-5105).

[0204] <Signal peptide> The term "signal peptide" (sometimes called secretory signal peptide or SSP, signal sequence, leader sequence, or leader peptide) refers to a short peptide (typically 16-30 amino acids long) usually found at the N-terminus of newly synthesized proteins directed towards secretory pathways. These proteins may reside within certain organelles (endoplasmic reticulum, Golgi vesicles, endosomes), be secreted from the cell, or be inserted into most cell membranes. In eukaryotic cells, signal peptides are typically cleaved from their developing polypeptide chains immediately after translocation to the endoplasmic reticulum membrane. Translocation occurs concurrently with translation and depends on cytoplasmic protein-RNA complexes (signal recognition particles, SRPs). Protein folding and certain post-translational modifications (e.g., glycosylation) typically occur within the endoplasmic reticulum (ER). The protein is then typically transported to Golgi vesicles and secreted.

[0205] The signal peptide may be appropriately (additionally) encoded by an artificial nucleic acid (RNA) molecule encoding any desired (poly)peptide or protein as described herein. The signal peptide, fused to or inserted into the desired (poly)peptide or protein, may favorably mediate the transport of the desired (poly)peptide or protein to a defined cellular compartment (e.g., the cell surface, endoplasmic reticulum (ER), or endosomal-lysosome compartment). Preferably, the signal peptide can be introduced into the desired (poly)peptide or protein to promote its secretion. In particular, when an artificial nucleic acid encoding an antigenic (poly)peptide o...

Claims

1. a. 5'-UTR factors derived from the 5' untranslated region (5'-UTR) of the HSD17B4 gene or its corresponding RNA sequence; b. 3'-UTR factors derived from the 3' untranslated region (3'-UTR) of the PSMB3 gene or its corresponding RNA sequence; and, c. At least one coding region operably linked to the 5'-UTR factor and the 3'-UTR factor, An artificial nucleic acid molecule comprising, Here, the 5'-UTR factor and / or the 3'-UTR factor are heterogeneous with respect to the coding region. The above HSD17B4 gene and the above PSMB3 gene are of human origin. - The 5'-UTR factor derived from the HSD17B4 gene contains or comprises a DNA sequence having at least 90% sequence identity with the DNA sequence described in Sequence ID No. 1, or an RNA sequence having at least 90% sequence identity with the RNA sequence described in Sequence ID No. 2, - The 3'-UTR factor derived from the PSMB3 gene contains or comprises a DNA sequence having at least 90% sequence identity with the DNA sequence described in SEQ ID NO: 23, or an RNA sequence having at least 90% sequence identity with the RNA sequence described in SEQ ID NO: 24, The above coding region does not encode CRISPR-related proteins. Compared to a reference construct containing a combination in which the 5'-UTR factor is the 5'-UTR factor of the RPL32 gene and the 3'-UTR factor is the 3'-UTR factor of the ALB7 gene, this shows increased polypeptide expression. Artificial nucleic acid molecule.

2. The artificial nucleic acid molecule according to claim 1, wherein the coding region is located between the 5'-UTR factor and the 3'-UTR factor.

3. The artificial nucleic acid molecule according to claim 2, wherein the coding region is located downstream of the 5'-UTR factor and upstream of the 3'-UTR factor.

4. The artificial nucleic acid molecule according to any one of claims 1 to 3, wherein the at least one coding region encodes at least one target (poly)peptide or protein selected from antigenic (poly)peptides or proteins, allergenic (poly)peptides or proteins, therapeutic (poly)peptides or proteins, and antibodies.

5. The above at least one antigenic (poly)peptide or protein is selected from tumor antigens, pathogenic antigens, autoantigens, alloantigens, or allergenic antigens. The artificial nucleic acid molecule according to claim 4.

6. The artificial nucleic acid molecule according to claim 5, wherein the at least one pathogenic antigen is selected from bacterial, viral, fungal, or protozoan antigens.

7. The above therapeutic (poly)peptides or proteins are - Therapeutic (poly)peptides or proteins that replace deficient, defective, or mutated proteins; - Therapeutic (poly)peptides or proteins that are beneficial for treating hereditary or acquired diseases, infections, or neoplasms (e.g., cancer or tumor diseases); - Adjuvants or immunostimulant therapeutic (poly)peptides or proteins; - therapeutic antibodies; - Peptide hormones; - Gene editing agents; - Immune checkpoint inhibitors; - T cell receptor; and / or -enzyme; An artificial nucleic acid molecule according to claim 4, selected from the above.

8. The above at least one coding area is further, (a) at least one effects domain; (b) at least one peptide or protein tag; (c) at least one localization signal or sequence; (d) at least one nuclear localization signal (NLS); (e) at least one signal peptide; and / or (f) at least one peptide linker; (g) Secretory signaling peptide (SSP), (h) Multimerizing factors including dimerizing factors, trimerizing factors, tetramerizing factors, or oligomerizing factors; (i) Factors that form virus-like particles (VLPs); (j) transmembrane factor; (k) Dendritic cell targeting factors; (l) Immunological adjuvant factors; (m) antigen presentation promoting factor; (n) 2A peptide; (o) Factors that prolong the half-life of proteins; and / or (p) Factors for post-translational modification (e.g., glycosylation), Code, The artificial nucleic acid molecule according to any one of claims 2 to 7, further comprising at least one internal ribosome entry site (IRES) and / or at least one miRNA binding site.

9. The artificial nucleic acid molecule according to any one of claims 1 to 8, wherein the artificial nucleic acid molecule is RNA.

10. The artificial nucleic acid molecule according to claim 9, wherein the RNA is mRNA, viral RNA, self-replicating RNA, or replicon RNA.

11. The artificial nucleic acid described above is a modified nucleic acid, or the artificial nucleic acid described above comprises at least one modification or non-natural nucleotide, backbone modification, sugar modification, or base modification, according to any one of claims 1 to 10.

12. The artificial nucleic acid according to claim 11, wherein the modified nucleic acid is a stabilized nucleic acid.

13. The artificial nucleic acid according to claim 11 or 12, wherein the artificial nucleic acid is RNA.

14. - The G / C content of the above artificial nucleic acid is increased compared to the G / C content of the corresponding coding sequence of the corresponding wild-type artificial nucleic acid, and / or - The C content of the above-mentioned artificial nucleic acid is increased compared to the C content of the above-mentioned corresponding coding sequence of the above-mentioned wild-type artificial nucleic acid, and / or - The codon in at least one coding region of the above artificial nucleic acid corresponds to the frequency of use of human codons. The artificial nucleic acid according to any one of claims 1 to 13.

15. The artificial nucleic acid according to claim 14, wherein the codon adaptation index (CAI) is increased or maximized in the at least one coding sequence of the artificial nucleic acid.

16. The artificial nucleic acid according to claim 14 or 15, wherein the amino acid sequence encoded by the artificial nucleic acid is unmodified compared to the amino acid sequence encoded by the corresponding wild-type artificial nucleic acid.

17. The artificial nucleic acid according to any one of claims 14 to 16, wherein the artificial nucleic acid is RNA.

18. An artificial nucleic acid according to any one of claims 1 to 17, comprising a 5' cap structure.

19. The artificial nucleic acid according to claim 18, wherein the 5' cap structure is m7GpppN or Cap1 and / or at least one histone stem loop.

20. The artificial nucleic acid according to claim 18 or 19, wherein the artificial nucleic acid is RNA.

21. An artificial nucleic acid according to any one of claims 1 to 20, comprising a poly(A) sequence.

22. The artificial nucleic acid according to claim 21, wherein the poly(A) sequence is 10 to 200, 10 to 100, 40 to 80, or 50 to 70 adenosine nucleotides.

23. The artificial nucleic acid according to claim 21 or 22, wherein the artificial nucleic acid is RNA.

24. In the direction from 5' to 3', the following factors apply: a) 5' cap structure; b) A 5'-UTR factor comprising or consisting of a nucleic acid sequence derived from the 5'-UTR as defined in claim 1; c) at least one coding sequence as defined in any one of claims 2 to 8; d) A 3'-UTR factor comprising or consisting of a nucleic acid sequence derived from the 3'-UTR as defined in claim 1; e) Poly(A) tail, f) Poly(C) tail, and g) Histone stem loop, An artificial nucleic acid according to any one of claims 1 to 23, including the above.

25. The artificial nucleic acid according to claim 24, wherein the 5' cap structure is m7GpppN or Cap1.

26. The artificial nucleic acid according to claim 24 or 25, wherein the poly(A) tail is a poly(A) tail consisting of 10 to 1000, 10 to 500, 10 to 300, 10 to 200, 10 to 100, 40 to 80, or 50 to 70 adenosine nucleotides.

27. The artificial nucleic acid according to any one of claims 24 to 26, wherein the poly(C) tail is a poly(C) tail consisting of 10 to 200, 10 to 100, 20 to 70, 20 to 60, or 10 to 40 cytosine nucleotides.

28. The artificial nucleic acid according to any one of claims 24 to 27, wherein the artificial nucleic acid is RNA.

29. A (pharmaceutical) composition or vaccine comprising at least one artificial nucleic acid molecule according to any one of claims 1 to 28 and a pharmaceutically acceptable carrier and / or excipient.

30. The (pharmaceutical) composition or vaccine according to claim 29, wherein the artificial nucleic acid molecule forms a complex with one or more cationic or polycationic compounds.

31. The (pharmaceutical) composition or vaccine according to claim 29 or 30, wherein the artificial nucleic acid molecule is RNA.

32. The (pharmaceutical) composition or vaccine according to claim 30 or 31, wherein the one or more cationic or polycationic compounds are cationic or polycationic polymers, cationic or polycationic peptides or proteins, such as protamines, cationic or polycationic polysaccharides, and / or cationic or polycationic lipids, or polymer carriers.

33. The (pharmaceutical) composition or vaccine according to any one of claims 29 to 32, wherein the artificial nucleic acid molecule forms a complex with one or more lipids, thereby forming lipid nanoparticles and / or lipoplexes.

34. The (pharmaceutical) composition or vaccine according to claim 33, wherein the artificial nucleic acid molecule is RNA.

35. The (pharmaceutical) composition or vaccine according to claim 33 or 34, wherein the above-mentioned artificial nucleic acid molecule forms a complex with one or more lipids, thereby forming a liposome.

36. A (pharmaceutical) composition or vaccine according to any one of claims 29 to 35, further comprising at least one further activator and / or at least one adjuvant.

37. A kit comprising an artificial nucleic acid molecule according to any one of claims 1 to 28, or a (pharmaceutical) composition or vaccine according to any one of claims 29 to 36, and a liquid vehicle and / or a technical instruction manual containing information regarding the use and dosage of the artificial nucleic acid molecule or the (pharmaceutical) composition or vaccine.

38. The kit according to claim 37, wherein the artificial nucleic acid molecule is RNA.

39. The above kit is a kit of parts, as described in claim 37 or 38.

40. An artificial nucleic acid molecule according to any one of claims 1 to 28, a (pharmaceutical) composition or vaccine according to any one of claims 29 to 36, or a kit according to any one of claims 37 to 39, for use as a pharmaceutical.

41. The above-mentioned pharmaceutical is a vaccine, an artificial nucleic acid molecule, (pharmaceutical) composition, vaccine, or kit for use as a pharmaceutical according to claim 40.

42. The artificial nucleic acid molecule, (pharmaceutical) composition, vaccine, or kit for use as a pharmaceutical, according to claim 40 or 41, wherein the artificial nucleic acid molecule is RNA.

43. An artificial nucleic acid molecule according to any one of claims 1 to 28, a (pharmaceutical) composition or vaccine according to any one of claims 29 to 36, or a kit according to any one of claims 37 to 39, for use in the treatment of genetic diseases, cancer, infectious diseases, inflammatory diseases, (auto)immune diseases, allergies, and / or for use in gene therapy and / or immunomodulation.

44. An artificial nucleic acid molecule, (pharmaceutical) composition, vaccine, or kit according to claim 43, wherein the artificial nucleic acid molecule is RNA, for use in the treatment of genetic diseases, cancer, infectious diseases, inflammatory diseases, (auto)immune diseases, allergies, and / or for use in gene therapy and / or immunomodulation.

45. The above artificial nucleic acid molecules, (pharmaceutical) compositions, or vaccines are adapted for liver-targeted delivery. The above artificial nucleic acid molecules, (pharmaceutical) compositions, or vaccines are adapted for subcutaneous, intracutaneous, intradermal, topical, or transdermal administration, and / or The above-mentioned artificial nucleic acid molecule, (pharmaceutical) composition, or vaccine is adapted for intramuscular administration, and is an artificial nucleic acid molecule, (pharmaceutical) composition, or vaccine, or kit for use according to any one of claims 40 to 44.

46. The artificial nucleic acid molecule, (pharmaceutical) composition, vaccine, or kit for use according to any one of claims 40 to 44, as described in claim 45, wherein the artificial nucleic acid molecule is RNA.

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