Composition for treating autoimmune diseases comprising CD38 or a fragment thereof

Abstract

The present invention relates to a polypeptide comprising a fragment of CD38. The present invention also relates to a composition for preventing or treating autoimmune diseases, comprising CD38 or a fragment thereof. CD38 or a fragment thereof according to the present invention increases regulatory T cells (Tregs) and alleviates various symptoms of autoimmune diseases, and can therefore be used as an agent for preventing or treating autoimmune diseases.

Description

Detailed Description of the Invention

[0001] [Technical field] The present invention relates to a composition for preventing or treating autoimmune diseases, which comprises soluble CD38 or a fragment thereof.

[0002] [Background technology] Autoimmune diseases are illnesses that arise from an immune response against the body's own cells or tissues, and occur when the immune system misreacts against normal physiological substances and certain cells of the body. Autoimmune diseases include over 100 types of diseases, including rheumatoid arthritis, autoimmune thyroiditis, psoriasis, inflammatory bowel diseases such as Crohn's disease, systemic lupus erythematosus (lupus), multiple sclerosis, and type 1 diabetes (insulin-dependent).

[0003] Autoimmune diseases are believed to be caused by rapid changes in the environment in which humans live. One of the causes is the sudden decline in parasitic and bacterial infections. The body's immune system has evolved over time to resist a variety of parasitic and bacterial infections. However, with the development of modern antibiotics and anti-parasitic drugs, the various infection sources to which the immune system responded have disappeared. As a result, the body's immune system has begun to overreact to various environmental factors that it did not previously recognize as antigens. These include allergens such as pollen, house dust, and dust mites, which are harmless to the human body, as well as the body's various autoantigens.

[0004] In addition, increased stress due to modern complex social activities, hormonal abnormalities, and abnormal reactions of the body due to environmental pollutants and various food additives have also been pointed out as causes of autoimmune diseases.

[0005] Currently, small-molecule drugs such as corticosteroids and immunosuppressants, as well as antibody drugs, dominate the global pharmaceutical market for the treatment of autoimmune diseases. Corticosteroids, or corticosteroids, are commonly used to treat autoimmune diseases, but both drugs weaken the body's overall immune system, making long-term use difficult. Corticosteroids include prednisone, dexamethasone, triamcinolone, betamethasone, and fluticasone. Immunosuppressants include cyclosporine, cyclophosphamide, azathioprine, chlorambucil, and methotrexate. Relatively recently developed TNF-α inhibitors have fewer side effects than conventional immunosuppressants and act selectively, resulting in better efficacy. Currently available TNF-α inhibitors include etanercept and infliximab. As antibody therapeutics, these are proteins that cannot be taken orally and must be administered by injection. TNF-α inhibitors have the disadvantage of increasing vulnerability to microbial infections during long-term treatment (Simard et al., Open J Rheumatol Autoimmune Dis. 14, 2012), and their use may be limited because they may worsen multiple sclerosis or affect the homeostasis of oligodendrocytes, which are important for myelin formation in brain tissue (Kemanetzoglou & Andreadou. Curr Neurol Neurosci Rep. 17:36, 2017. Napolitano et al., G Ital Dermatol Venereol. 153:567, 2018).

[0006] The current state of development for autoimmune disease treatments includes those that induce immune tolerance through modulation of costimulatory factors, those that regulate immunosuppressive T cells (Tregs) and T17 cells, and those based on dendritic cells. Inhibition of costimulatory factors induces T cell deactivation, and in recent years, anti-CD3 antibody therapy, an antibody directed against the T cell receptor (TCR), has been attempted. The anti-CD3 antibody teplizumab induces non-responsiveness of autologous immune T cells and increases tolerance. Teplizumab is also currently undergoing clinical trials for the treatment of autoimmune type 1 diabetes (Gaglia & Kissler, Biochemistry, 58:4107, 2019). In particular, in patients with early-stage diabetes, teplizumab has been reported to not only induce T cell tolerance but also promote the proliferation of Tregs (Christen & Kimmel, Front Endocrinol. 11:591083, 2020). Furthermore, CTLA4-Ig fusion proteins such as abatacept and belatacept were developed as T cell surface proteins that use a protein structure similar to CD28 to induce binding to the costimulator B7 (Paul et al., Clin Exp Rheumatol. 38:1008, 2020). CTLA4-Ig acts as a competitive inhibitor of CD28, suppressing T cell costimulatory signals by binding to B7 on antigen-presenting cells and inducing tolerance (Ouewole-Said et al., Front Immunol. 11:608024, 2020). These drugs are used to treat rheumatoid arthritis. LFA3-Ig (alefacept), which inhibits CD3-LFA3, is FDA-approved for the treatment of psoriasis, is used as an autoimmune suppressant for kidney transplants, and is undergoing clinical trials for type 1 diabetes (Georgakopoulou et al., Acta Dermatovenerol Croat. 21:24, 2013).

[0007] The activity and regulatory mechanisms of Treg / Th17 cells in regulating autoimmunity may be important therapeutic approaches for autoimmune diseases. Treg activity acts as a suppressive factor, maintaining immune tolerance and preventing autoimmune reactions, while Th17 cells regulate autoimmunity and inflammatory responses (Amaya-Uribe et al., J Autoimmun. 99:52, 2019). Expression of IL-17 released by these cells has been reported as a major cause of autoimmune diseases. Inhibition of IL-17 through therapeutic techniques, such as IL-17 monoclonal antibodies, has been utilized in lupus research (Robert & Miossec. Lupus. 29:6, 2020). Furthermore, research is underway to block signals such as IL-1, IL-23, and IL-6 to inhibit the activation mechanism of Th17 cells, and research on inhibitory signaling cytokines such as IL-27 is also ongoing (Tran et al., Acta Trop. 6:1058-23, 2021). Research is currently focused on the FoxP3 gene, which is known to play an important role in the differentiation of Treg cells. Decreased expression of FOXP3 during autoimmune responses has been suggested as a key factor (Ali et al., Cells. 11;9(12):2665, 2020). Tregs secrete inhibitory cytokines such as IL-10 and TGF-β and function in the suppression of Th12 activity, including IL-2 uptake (Terry & Oo, Front Immunol. 11:565-18, 2020). Tregs have been reported to function through costimulatory signaling systems, including CTLA-4 and LFA-1 (Tocci et al., Expert Rev Clin Immunol. 10:1395, 2014). Therefore, Treg activation and its regulatory mechanisms may be utilized as a key mechanism for regulating Th17-associated autoimmune diseases and may be a subject for therapeutic development (Ohue & Nishikawa. Cancer Sci. 110:2080, 2019).

[0008] T cell tolerance can be induced by inhibiting the maturation of dendritic cells, which are antigen-presenting cells (De Winde et al., Med Microbiol Immunol. 209:515, 2020). In addition, cell therapy agents are being developed that induce suppressive tolerance by inducing undifferentiated dendritic cells into tolerogenic cells for the purpose of activating T cells (Philips et al., Front Immunol 8:1279).

[0009] Molecular cloning of CD38 revealed that it is a type II transmembrane protein [Jackson & Bell. J Immunol. 144:2811, 1990]. Shortly after cloning, CD38 was found to be a member of the NADase family, sharing sequence homology with Aplysia ADP-ribosyl cyclase (ARC) (States et al., Trends Biochem. 17:495, 1992). Through various enzymatic studies, it was found that CD38 is a Ca 2+ It has been shown to be an enzyme that generates the signal transduction messengers cADPR and NAADP (Howard et al., Science. 262:1056, 1993; Aarhus et al., J. Biol. Chem. 270:30327, 1995).

[0010] The items described above as background art are merely intended to enhance understanding of the background of the present invention and should not be construed as acknowledging that they correspond to prior art already known to those skilled in the art.

[0011] [Summary of the Invention] [Problem to be solved by the invention] Therefore, the present inventors confirmed that soluble CD38 or a fragment thereof known in mammals can be used to treat autoimmune diseases by effectively inducing immune tolerance, and thus completed the present invention.

[0012] Accordingly, it is an object of the present invention to provide a polypeptide comprising an amino acid sequence (from N-terminus to C-terminus) represented by the following mathematical formula: [Number I] X1-LQCVKNPE-X2-X3-SC, In the above Formula I, X1 is F or L; X2 is H or D; X3 is P or S.

[0013] Another object of the present invention is to provide a nucleic acid molecule encoding said polypeptide.

[0014] It is yet another object of the present invention to provide a vector containing the nucleic acid molecule.

[0015] It is yet another object of the present invention to provide a host cell transformed with the vector.

[0016] It is yet another object of the present invention to provide a pharmaceutical composition for preventing or treating a disease or disorder, comprising the polypeptide, a nucleic acid molecule encoding the polypeptide, a vector containing the nucleic acid molecule, or an isolated cell containing the vector, and a pharmaceutically acceptable carrier.

[0017] It is yet another object of the present invention to provide a pharmaceutical composition for preventing or treating an autoimmune disease, comprising the polypeptide, a nucleic acid molecule encoding the polypeptide, a vector containing the nucleic acid molecule, or an isolated cell containing the vector, and a pharmaceutically acceptable carrier.

[0018] It is yet another object of the present invention to provide a pharmaceutical composition for preventing or treating rheumatoid arthritis, comprising the polypeptide, a nucleic acid molecule encoding the polypeptide, a vector containing the nucleic acid molecule, or an isolated cell containing the vector, and a pharmaceutically acceptable carrier.

[0019] It is yet another object of the present invention to provide a pharmaceutical composition for preventing or treating uveitis, comprising the polypeptide, a nucleic acid molecule encoding the polypeptide, a vector containing the nucleic acid molecule, or an isolated cell containing the vector, and a pharmaceutically acceptable carrier.

[0020] It is yet another object of the present invention to provide a pharmaceutical composition for preventing or treating inflammatory bowel disease, comprising the polypeptide, a nucleic acid molecule encoding the polypeptide, a vector containing the nucleic acid molecule, or an isolated cell containing the vector, and a pharmaceutically acceptable carrier.

[0021] It is yet another object of the present invention to provide a method for preventing or treating a disease or disorder, comprising administering to a subject in need thereof the polypeptide, a nucleic acid molecule encoding the polypeptide, a vector containing the nucleic acid molecule, or an isolated cell containing the vector.

[0022] It is yet another object of the present invention to provide a method for preventing or treating an autoimmune disease, the method comprising administering to a subject in need thereof the polypeptide, a nucleic acid molecule encoding the polypeptide, a vector containing the nucleic acid molecule, or an isolated cell containing the vector.

[0023] It is yet another object of the present invention to provide a method for preventing or treating inflammatory bowel disease, comprising administering to a subject in need thereof the polypeptide, a nucleic acid molecule encoding the polypeptide, a vector containing the nucleic acid molecule, or an isolated cell containing the vector.

[0024] Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, the claims and the drawings.

[0025] [Means for solving the problem] To facilitate understanding of the disclosure provided herein, a number of terms and phrases are defined. Additional definitions are set forth throughout the detailed description.

[0026] I. Definition Throughout this disclosure, the terms "a" or "any" entity refer to one or more of that entity; for example, "a polypeptide" is understood to refer to one or more polypeptides. Thus, the terms "a" (or "any"), "one or more," and "at least one" can be used interchangeably herein.

[0027] When an embodiment herein is described using the term "comprising," it is understood that other similar embodiments described in terms of "consisting of" and / or "essentially consisting of" are also provided.

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. For example, Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and Oxford Dictionary of Biochemistry and Molecular Biology, Revised, 2000, Oxford University Press provide those skilled in the art with a general dictionary of many of the terms used in this disclosure.

[0029] Units, prefixes, and symbols are denoted in their SI (Systeme International de Unites) recognized form. Numerical ranges are inclusive of the numbers limiting the range. Unless otherwise indicated, amino acid sequences are written left to right in the amino-carboxy orientation. The headings provided herein are not limitations on the various aspects of the disclosure, which may be read by reference to the specification as a whole. Accordingly, each term defined immediately below is more fully defined by reference to the specification as a whole.

[0030] As used herein, the terms "administration," "administering," and grammatical variations thereof refer to introducing a composition (e.g., a composition comprising a polypeptide, nucleic acid molecule, vector, or isolated cell described herein) into a subject via a pharmaceutically acceptable route. The composition may be introduced into a subject by any appropriate route, including oral, cutaneous, intrapulmonary, intranasal, parenteral (intravenous, intraarterial, intramuscular, intraperitoneal, or subcutaneous), rectal, intralymphatic, intraspinal, periocular, intraocular, or topical administration. Administration includes self-administration and administration by another person. A composition or formulation will perform its intended function via an appropriate route of administration. For example, if the appropriate route is intravenous, the composition is administered by introducing the composition or formulation into the subject's vein.

[0031] As used herein, the term "conserved" refers to each nucleotide or amino acid residue of a polynucleotide or polypeptide sequence that appears unchanged in the same position in two or more sequences being compared. A relatively conserved nucleotide or amino acid is one that is more conserved among related sequences than a nucleotide or amino acid that appears elsewhere in the sequence.

[0032] As used herein, the term "amino acid" refers to the 22 standard amino acids naturally incorporated into peptides (e.g., arginine (R), lysine (K), histidine (H), glutamic acid (E), aspartic acid (D), glutamine (Q), asparagine (N), leucine (L), isoleucine (I), valine (V), methionine (M), phenylalanine (F), tryptophan (W), tyrosine (Y), glycine (G), alanine (A), serine (S), threonine (T), proline (P), and cysteine ​​(C)), as well as D-isomers and modified versions of each amino acid. Additionally, the peptides may contain non-standard amino acids that have undergone post-translational modification. Post-translational modifications may include, but are not limited to, phosphorylation, glycosylation, acylation (e.g., acetylation, myristoylation, and palmitoylation), alkylation, carboxylation, hydroxylation, glycation, biotinylation, ubiquitinylation, chemical changes (e.g., β-elimination deimidation, deamidation), and structural changes (e.g., disulfide bridge formation). The peptide may be a wild-type peptide identified and isolated from a natural source. Alternatively, the peptide may be an artificial variant comprising an amino acid sequence in which one or more amino acids have been substituted, deleted, and / or inserted. Amino acid changes in wild-type polypeptides, as well as artificial variants, include conservative amino acid substitutions that do not significantly affect protein folding and / or activity.For example, such conservative substitutions may include basic amino acids (arginine (R), lysine (K), and histidine (H)), acidic amino acids (glutamic acid (E) and aspartic acid (D)), polar amino acids (glutamine (Q) and asparagine (N)), hydrophobic amino acids (leucine (L), isoleucine (I), valine (V), and methionine (M)), aromatic amino acids (phenylalanine (F), tryptophan (W), and tyrosine (Y)), and small amino acids (glycine (G), alanine (A), serine (S), and threonine (T)). In general, amino acid substitutions that do not alter specific activity are known in the art. The most frequently occurring exchanges can include Ala / Ser, Val / Ile, Asp / Glu, Thr / Ser, Ala / Gly, Ala / Thr, Ser / Asn, Ala / Val, Ser / Gly, Tyr / Phe, Ala / Pro, Lys / Arg, Asp / Asn, Leu / Ile, Leu / Val, Ala / Glu, and Asp / Gly.

[0033] In some embodiments, two or more sequences are 100% identical to each other, indicating "completely conserved" or "identical." In some embodiments, two or more sequences are at least 70% identical, at least 80% identical, at least 90% identical, or at least 95% identical to each other, indicating "highly conserved." In some embodiments, two or more sequences are about 70% identical, about 80% identical, about 90% identical, about 95%, about 98%, or about 99% identical to each other, indicating "highly conserved." In some embodiments, two or more sequences are at least 30% identical, at least 40% identical, at least 50% identical, at least 60% identical, at least 70% identical, at least 80% identical, at least 90% identical, or at least 95% identical to each other, indicating "conserved." In some embodiments, two or more sequences are "conserved" if they are about 30% identical, about 40% identical, about 50% identical, about 60% identical, about 70% identical, about 80% identical, about 90% identical, about 95% identical, about 98% identical, or about 99% identical to one another. Sequence conservation can apply to the entire length of a polynucleotide or polypeptide, or to a portion, region, or feature thereof.

[0034] The terms "complementary" and "complementarity" refer to two or more oligomers (i.e., each comprising a nucleobase sequence) that are related to each other according to the Watson-Crick base-pairing rules, or between an oligomer and a target gene. For example, the nucleobase sequence "TGA(5'→3')" is complementary to the nucleobase sequence "ACT(3'→5')." Complementarity may be "partial" when fewer than all nucleobases of a given nucleobase sequence match another nucleobase sequence according to the base-pairing rules. For example, in some embodiments, the complementarity between a given nucleobase sequence and another nucleobase sequence may be about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%. Thus, in certain embodiments, the term "complementary" refers to at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identity or complementarity with a target nucleic acid sequence. Alternatively, to continue by way of illustration, there may be "perfect" or "perfect" (100%) complementarity between a given nucleobase sequence and another nucleobase sequence. In some embodiments, the degree of complementarity between nucleobase sequences has a significant impact on the efficiency and strength of hybridization between the sequences.

[0035] As used herein, the term "expression" refers to the process by which a polynucleotide produces a gene product, e.g., an RNA or a polypeptide. This includes, but is not limited to, transcription of a polynucleotide into messenger RNA (mRNA) and translation of mRNA into a polypeptide. Expression produces a "gene product." As used herein, a gene product can be a nucleic acid, such as an RNA produced by transcription of a gene. As used herein, a gene product can be a nucleic acid or a polypeptide translated from a transcript. Gene products as described herein further include nucleic acids that have been modified post-transcriptionally, e.g., by polyadenylation or splicing, or polypeptides that have been modified post-translationally, e.g., by phosphorylation, methylation, glycosylation, lipid addition, association with other protein subunits, or proteolytic cleavage.

[0036] As used herein, the term "identity" refers to overall monomer conservation between individual polymer molecules, e.g., individual polynucleotide molecules. The term "identical" without any additional modifiers, e.g., polynucleotide A is identical to polynucleotide B, means that the polynucleotide sequences are 100% identical (100% sequence identity). Describing two sequences as being, e.g., "70% identical," is the same as describing them as having, e.g., "70% sequence identity."

[0037] For example, calculations of percent identity between two polypeptide or polynucleotide sequences can be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced into one or both of the first and second polypeptide or polynucleotide sequences for optimal alignment, and non-identical sequences can be disregarded for comparison purposes). In certain embodiments, the length of an aligned sequence for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% of the length of the reference sequence. Amino acids at corresponding amino acid positions, or bases in the case of polynucleotides, are then compared.

[0038] When a particular position in the first sequence is occupied by the same amino acid or nucleotide as that position in the second sequence, the molecules are identical at that position. The percent identity between two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps that need to be introduced for optimal alignment of the two sequences and the length of each of those gaps. Sequence comparison and determination of percent identity between two sequences can be performed using a mathematical algorithm.

[0039] Suitable software programs that can be used to align different sequences (e.g., polynucleotide sequences) with each other are available from a number of sources. For determining percent sequence identity, one suitable program is bl2seq, which is part of the BLAST suite of programs available from the U.S. government's National Center for Biotechnology Information BLAST website (blast.ncbi.nlm.nih.gov). bl2seq performs comparisons between two sequences using the BLASTN or BLASTP algorithm. BLASTN is used to compare nucleic acid sequences, while BLASTP is used to compare amino acid sequences. Other suitable programs include, for example, Needle, Stretcher, Water, or Matcher, which are part of the EMBOSS suite of bioinformatics programs and are available from the European Bioinformatics Institute (EBI) at www.ebi.ac.uk / Tools / psa.

[0040] Sequence alignment can be performed using methods known in the art, such as MAFFT, Clustal (ClustalW, Clustal X, or Clustal Omega), and MUSCLE.

[0041] Different regions within a single polynucleotide or polypeptide target sequence that are aligned with a polynucleotide or polypeptide reference sequence can each have their own percent sequence identity. Note that percent sequence identity values ​​are rounded up / down to the nearest tenth. For example, 80.11, 80.12, 80.13, and 80.14 are rounded down to 80.1, and 80.15, 80.16, 80.17, 80.18, and 80.19 are rounded up to 80.2. Note also that length values ​​can always be integers.

[0042] In certain embodiments, the percent identity (%ID) of a first amino acid sequence (or nucleic acid sequence) to a second amino acid sequence (or nucleic acid sequence) is calculated as %ID = 100 x (Y / Z), where Y is the number of amino acid residues (or nucleobases) scored as identical matches in an alignment of the first and second sequences (when aligned by visual inspection or by a particular sequence alignment program), and Z is the total number of residues in the second sequence. If the first sequence is longer than the second sequence, the percent identity of the first sequence to the second sequence may be higher than the percent identity of the second sequence to the first sequence.

[0043] Those skilled in the art will understand that the generation of sequence alignments for calculating percent sequence identity is not limited to binary sequence-sequence comparisons that are driven entirely by primary sequence data. They will also understand that sequence alignments can be performed by integrating sequence data with data from heterogeneous sources, such as structural data (e.g., crystallographic protein structures), functional data (e.g., mutation locations), or phylogenetic data. Suitable programs for integrating heterogeneous data and performing multiple sequence alignments are available at www.tcoffee.org, and alternatively, for example, T-Coffee, available from EBI. They will also understand that the final alignment used to calculate percent sequence identity can be organized automatically or manually.

[0044] As used herein, the term "fragment" refers to a fragment (e.g., a sequence of SEQ ID NO: 1-30) derived from a full-length sequence (e.g., full-length sCD38), which is meant to exclude the full-length sequence.

[0045] In some embodiments, the nucleic acid molecules or polynucleotides described herein can include a promoter and / or other expression (e.g., transcription) regulatory elements operably associated with one or more coding regions. In operably associated relationships, a coding region for a gene product is associated with one or more regulatory regions in a manner that places expression of the gene product under the influence or control of the regulatory regions. For example, a coding region and a promoter are "operably associated" if induction of promoter function results in transcription of mRNA encoding the gene product encoded by the coding region, and the nature of the link between the promoter and the coding region does not interfere with the promoter's ability to direct expression of the gene product or the ability of the DNA template to be transcribed. In addition, other expression regulatory elements besides promoters, such as enhancers, operators, repressors, and transcription termination signals, can be operably associated with a coding region to direct expression of a gene product.

[0046] As used herein, the terms "subject," "patient," "individual," and "host," and variations thereof, are used interchangeably and refer to any mammalian subject to which any of the compositions described herein (e.g., polypeptides, polynucleotides, vectors, cells, or pharmaceutical compositions) is administered. Non-limiting examples include humans, domestic animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., monkeys, rats, mice, rabbits, guinea pigs, etc.), particularly humans, in need of diagnosis, treatment, or therapy. The methods described herein are applicable to both human prophylactic or therapeutic and veterinary uses.

[0047] As used herein, the phrase "subject in need" includes subjects, such as mammalian subjects, who may benefit from the administration of the compositions described herein.

[0048] As used herein, the term "therapeutically effective amount" refers to the amount of a reagent or pharmaceutical conjugate, including a composition of the present disclosure, sufficient to achieve the desired therapeutic, pharmacological, and / or physiological effect in a subject in need thereof. A therapeutically effective amount may be a "prophylactically effective amount," as prevention may be considered treatment.

[0049] As used herein, the terms "treat," "treatment," and the like refer to providing a beneficial effect to a subject with a disease or disorder, for example, reducing the severity of the disease or disorder, reducing the duration of the disease, improving or eliminating one or more symptoms associated with the disease or disorder, without necessarily curing the disease or disorder. The terms also include preventing or preventing a disease or disorder or its symptoms.

[0050] As used herein, the term "vector" or "construct" refers to any vehicle into which a nucleic acid molecule or gene can be inserted, e.g., a transfer vehicle that can be introduced into a cell where a nucleic acid sequence can be inserted and replicated. The nucleic acid sequence inserted into a vector can be exogenous or heterologous. The nucleic acid sequence can be full-length sCD38 or a fragment thereof. Examples of constructs include, but are not limited to, plasmids, cosmids, and viruses (e.g., AAV). Those skilled in the art can prepare such vectors or constructs using standard recombinant techniques (e.g., Maniatis, et al., Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, NY, 1988; and Ausubel et al., In: Current Protocols in Molecular Biology, John, Wiley & Sons, Inc., NY, 1994). As used herein, the term "expression vector" or "expression construct" refers to a vector or construct containing a nucleotide sequence encoding at least a portion of a transcribed gene product. In some cases, the RNA molecules are then translated into proteins, polypeptides, or peptides. Expression constructs can include a variety of regulatory elements. In addition to regulatory sequences that control transcription and translation, vectors and expression vectors can also include nucleotide sequences that provide other functions. Viruses that can be used in the present invention include, but are not limited to, retroviruses, herpes simplex viruses, lentiviruses, poxviruses, vaccinia viruses, rhabdoviruses, adenoviruses, helper-dependent adenoviruses, and adeno-associated viruses (AAVs).

[0051] Vectors can be engineered to encode a selectable marker or reporter that provides for the selection or identification of cells containing the vector. Expression of the selectable marker or reporter allows for the identification and / or selection of host cells that integrate and express other coding regions contained in the vector. Examples of selectable marker genes known and used in the art include genes that provide resistance to ampicillin, streptomycin, gentamicin, kanamycin, hygromycin, the herbicide bialaphos, sulfonamides, etc.; and genes used as phenotypic markers, i.e., anthocyanin regulatory genes, isopentenyltransferase genes, etc. Examples of reporters known and used in the art include luciferase (Luc), green fluorescent protein (GFP), chloramphenicol acetyltransferase (CAT), β-galactosidase (LacZ), β-glucuronidase (Gus), etc. Selectable markers can also be considered reporters.

[0052] The term "cell" as used herein includes eukaryotic and prokaryotic cells and refers to any transformable cell that can replicate the vector or express a gene encoded by the vector. A cell may be transfected, transduced, or transformed by the vector. This refers to the process by which an exogenous polynucleotide (nucleic acid molecule) is transferred or introduced into a host cell. The term "transformation" as used herein encompasses both transfection and transduction.

[0053] The (host) cells of the present invention are preferably, but not limited to, insect cells or mammalian cells, more preferably Sf9 insect cells, and HEK293 cells, HeLa cells, ARPE-19 cells, RPE-1 cells, HepG2 cells, Hep3B cells, Huh-7 cells, C8D1a cells, Neuro2A cells, CHO cells, MES13 cells, BHK-21 cells, COS7 cells, COP5 cells, A549 cells, MCF-7 cells, HC70 cells, HCC1428 cells, BT-549 cells, PC3 cells, LNCaP cells, Capan-1 cells, Panc-1 cells, MIA cells, and the like. PaCa-2 cells, SW480 cells, HCT166 cells, LoVo cells, A172 cells, MKN-45 cells, MKN-74 cells, Kato-III cells, NCI-N87 cells, HT-144 cells, SK-MEL-2 cells, SH-SY5Y cells, C6 cells, HT-22 cells, PC-12 cells, NIH3T3 cells, etc. can be used. In some embodiments, the host cells are isolated host cells.

[0054] II. Polypeptides The present disclosure relates to a polypeptide comprising the amino acid sequence of CD38 (e.g., soluble CD38) or a fragment (functional fragment) thereof. The polypeptide has the activity of reducing the amount of TNF-α. The polypeptide has the activity of reducing the amount of IFN-γ. The polypeptide has the activity of reducing the amount of IL-17. The polypeptide has the activity of increasing the amount of Treg cells.

[0055] Specifically, the present specification provides a polypeptide comprising an amino acid sequence (from N-terminus to C-terminus) represented by the following mathematical formula: [Number I] X1-LQCVKNPE-X2-X3-SC, In the above Formula I, X1 is F or L; X2 is H or D; X3 is P or S.

[0056] According to a preferred embodiment of the present invention, the polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-3.

[0057] The sequence of SEQ ID NO: 1 is FLQCVKNPEHPSC, which is the sCD38 fragment sequence of mouse, rat, and horse. The sequence of SEQ ID NO: 2 is FLQCVKNPEDSSC, which is the sCD38 fragment sequence of human and chimpanzee. The sequence of SEQ ID NO: 3 is LLQCVKNPEHSSC, which is the sCD38 fragment sequence of dog.

[0058] According to one embodiment of the present invention, the 13 amino acid sCD38 fragment (eg, H13(284-296)) reduces LPS-induced TNF-α secretion from human dendritic cells (Example 11).

[0059] According to a preferred embodiment of the present invention, the polypeptide may be a polypeptide (from N-terminus to C-terminus) comprising an amino acid sequence represented by the following formula: [Mathematics II] X4-X1-LQCVKNPE-X2-X3-SC, In the above formula II, X4 is R or K; X1 is F or L; X2 is H or D; X3 is P or S.

[0060] According to a preferred embodiment, the polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 4-6.

[0061] The sequence of SEQ ID NO: 4 is RFLQCVKNPEHPSC, which is the sCD38 fragment sequence of mouse, rat, and horse. The sequence of SEQ ID NO: 5 is KFLQCVKNPEDSSC, which is the sCD38 fragment sequence of human and chimpanzee. The sequence of SEQ ID NO: 6 is RLLQCVKNPEHSSC, which is the sCD38 fragment sequence of dog.

[0062] According to one embodiment of the present invention, the 14 amino acid sCD38 fragment (eg, M14(287-300)) reduces LPS-induced TNF-α secretion from human dendritic cells (Example 4).

[0063] According to a preferred embodiment, the polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 7-10.

[0064] The sequence of SEQ ID NO: 7 is RFLQCVKNPEHPSCR, which is the mouse and rat sCD38 fragment sequence. The sequence of SEQ ID NO: 8 is KFLQCVKNPEDSSCT, which is the human and chimpanzee sCD38 fragment sequence. The sequence of SEQ ID NO: 9 is RLLQCVKNPEHSSCK, which is the dog sCD38 fragment sequence. The sequence of SEQ ID NO: 10 is RFLQCVKNPEHPSCT, which is the horse sCD38 fragment sequence.

[0065] According to a preferred embodiment, the polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 11-15.

[0066] The sequence of SEQ ID NO: 11 is RFLQCVKNPEHPSCRL, which is the mouse sCD38 fragment sequence. The sequence of SEQ ID NO: 12 is RFLQCVKNPEHPSCRL, which is the rat sCD38 fragment sequence. The sequence of SEQ ID NO: 13 is KFLQCVKNPEDSSCTS, which is the human and chimpanzee sCD38 fragment sequence. The sequence of SEQ ID NO: 14 is RLLQCVKNPEHSSCKY, which is the dog sCD38 fragment sequence. The sequence of SEQ ID NO: 15 is RFLQCVKNPEHPSCTS, which is the horse sCD38 fragment sequence.

[0067] According to one embodiment of the present invention, the 16 amino acid sCD38 fragment (eg, M16(287-302)) reduces LPS-induced TNF-α secretion from human dendritic cells (Example 4).

[0068] According to a preferred embodiment of the present invention, the polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 16 to 20.

[0069] The sequence of SEQ ID NO: 16 is RFLQCVKNPEHPSCRLNT, which is the mouse sCD38 fragment sequence. The sequence of SEQ ID NO: 17 is RFLQCVKNPEHPSCRLNV, which is the rat sCD38 fragment sequence. The sequence of SEQ ID NO: 18 is KFLQCVKNPEDSSCTSEI, which is the human and chimpanzee sCD38 fragment sequence. The sequence of SEQ ID NO: 19 is RLLQCVKNPEHSSCKYNL, which is the dog sCD38 fragment sequence. The sequence of SEQ ID NO: 20 is RFLQCVKNPEHPSCTSGI, which is the horse sCD38 fragment sequence.

[0070] According to one embodiment of the present invention, the 18 amino acid sCD38 fragment (eg, H18(283-300)) reduces LPS-induced TNF-α secretion from human dendritic cells (Example 11).

[0071] According to a preferred embodiment, the polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 21 to 25.

[0072] The sequence of SEQ ID NO: 21 is ARFLQCVKNPEHPSCRLNT, which is the mouse sCD38 fragment sequence. The sequence of SEQ ID NO: 22 is VRFLQCVKNPEHPSCRLNV, which is the rat sCD38 fragment sequence. The sequence of SEQ ID NO: 23 is DKFLQCVKNPEDSSCTSEI, which is the human and chimpanzee sCD38 fragment sequence. The sequence of SEQ ID NO: 24 is VRLLQCVKNPEHSSCKYNL, which is the dog sCD38 fragment sequence. The sequence of SEQ ID NO: 25 is VRFLQCVKNPEHPSCTSGI, which is the horse sCD38 fragment sequence.

[0073] According to one embodiment of the present invention, the 19 amino acid sCD38 fragment (e.g., M19(286-304)) prevents colon shortening caused by ulcerative colitis and reduces the progression of ulcerative colitis (Example 9).

[0074] According to a preferred embodiment of the present invention, the polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 26 to 30.

[0075] The sequence of SEQ ID NO:26 is LKMIVQKRNMIFACVDNYRPARFLQCVKNPEHPSCRLNT, which is the mouse sCD38 fragment sequence. The sequence of SEQ ID NO:27 is LKSIVNKRNMIFACQDNYRPVRFLQCVKNPEHPSCRLNV, which is the rat sCD38 fragment sequence. The sequence of SEQ ID NO:28 is LESIISKRNIQFSCKNIYRPDKFLQCVKNPEDSSCTSEI, which is the human and chimpanzee sCD38 fragment sequence. The sequence of SEQ ID NO:29 is LKQILKTRNIIFICQNNYRPVRLLQCVKNPEHSSCKYNL, which is the dog sCD38 fragment sequence. The sequence of SEQ ID NO:30 is LKSIISERNITFTCQNNYRPVRFLQCVKNPEHPSCTSGI, which is the horse sCD38 fragment sequence.

[0076] According to one embodiment of the present invention, the 39 amino acid sCD38 fragment (eg, peptide 4:266-304) is shown to reduce the progression of autoimmune uveitis (Example 5) and rheumatoid arthritis (Example 8).

[0077] According to a preferred embodiment of the present invention, the polypeptide may be a full-length CD38 sequence (eg, SEQ ID NOs: 31 to 36) or a fragment thereof.

[0078] In some embodiments, the polypeptide may consist of between 13 and 300, 13 and 250, 13 and 240, 13 and 230, 13 and 220, 13 and 210, 13 and 200, 13 and 190, 13 and 180, 13 and 170, 13 and 160, 13 and 150, 13 and 140, 13 and 130, 13 and 120, 13 and 110, 13 and 100, 13 and 90, 13 and 80, 13 and 70, 13 and 60, or 13 and 50 amino acids.

[0079] In some embodiments, the polypeptide can consist of 13 to 49, 13 to 48, 13 to 47, 13 to 46, 13 to 45, 13 to 44, 13 to 43, 13 to 42, 13 to 41, 13 to 40, or 13 to 39 amino acids.

[0080] According to a preferred embodiment, the CD38 may be soluble CD38.

[0081] The origin of the CD38 is not limited thereto, but is preferably mammalian, more preferably dog, horse, mouse, rat, human or chimpanzee, and most preferably human-derived CD38.

[0082] In some embodiments, the polypeptide has at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NOs: 1-36.

[0083] III. Nucleic acid molecules The present disclosure relates to nucleic acid molecules encoding polypeptides comprising the amino acid sequence of CD38 (e.g., soluble CD38) or a fragment (functional fragment) thereof. Specifically, the present disclosure provides nucleic acid molecules encoding a polypeptide comprising the amino acid sequence (from N-terminus to C-terminus) represented by the following mathematical formula: [Number I] X1-LQCVKNPE-X2-X3-SC, In the above Formula I, X1 is F or L; X2 is H or D; X3 is P or S.

[0084] According to a preferred embodiment, the nucleic acid molecule encodes a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-3.

[0085] According to a preferred embodiment of the present invention, the nucleic acid molecule may encode a polypeptide (from N-terminus to C-terminus) comprising an amino acid sequence represented by the following formula: [Mathematics II] X4-X1-LQCVKNPE-X2-X3-SC, In the above formula II, X4 is R or K; X1 is F or L; X2 is H or D; X3 is P or S.

[0086] According to a preferred embodiment, the nucleic acid molecule encodes a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 4-6.

[0087] According to a preferred embodiment, the nucleic acid molecule encodes a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 7-10.

[0088] According to a preferred embodiment, the nucleic acid molecule encodes a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 11-15.

[0089] According to a preferred embodiment, the nucleic acid molecule encodes a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 16-20.

[0090] According to a preferred embodiment, the nucleic acid molecule encodes a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 21-25.

[0091] According to a preferred embodiment, the nucleic acid molecule encodes a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 26-30.

[0092] According to a preferred embodiment of the present invention, the nucleic acid molecule may encode the full-length CD38 sequence (eg, SEQ ID NOs: 31 to 36) or a fragment thereof.

[0093] In some embodiments, the nucleic acid molecule can encode a polypeptide consisting of 13 to 300, 13 to 250, 13 to 240, 13 to 230, 13 to 220, 13 to 210, 13 to 200, 13 to 190, 13 to 180, 13 to 170, 13 to 160, 13 to 150, 13 to 140, 13 to 130, 13 to 120, 13 to 110, 13 to 100, 13 to 90, 13 to 80, 13 to 70, 13 to 60, or 13 to 50 amino acids.

[0094] In some embodiments, the nucleic acid molecule can encode a polypeptide consisting of 13 to 49, 13 to 48, 13 to 47, 13 to 46, 13 to 45, 13 to 44, 13 to 43, 13 to 42, 13 to 41, 13 to 40, or 13 to 39 amino acids.

[0095] According to a preferred embodiment, the CD38 may be soluble CD38.

[0096] The origin of the CD38 is not limited thereto, but is preferably mammalian, more preferably dog, horse, mouse, rat, human or chimpanzee, and most preferably human-derived CD38.

[0097] In some embodiments, the nucleic acid molecule has at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, or at least 95% sequence identity to a sequence encoding a polypeptide comprising an amino acid sequence set forth in SEQ ID NOs: 1-36.

[0098] IV. Vectors and Cells The present disclosure relates to a vector containing a nucleic acid molecule encoding a polypeptide comprising the amino acid sequence of CD38 (e.g., soluble CD38) or a fragment (functional fragment) thereof, or a cell transformed with or containing the vector. Specifically, the present disclosure provides a vector containing a nucleic acid molecule encoding a polypeptide (from N-terminus to C-terminus) comprising the amino acid sequence represented by the following mathematical formula: [Number I] X1-LQCVKNPE-X2-X3-SC, In the above Formula I, X1 is F or L; X2 is H or D; X3 is P or S.

[0099] According to a preferred embodiment of the present invention, the nucleic acid molecule may be a vector containing a nucleic acid molecule encoding a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 3, or a cell transformed with the vector.

[0100] According to a preferred embodiment of the present invention, the nucleic acid molecule may be a vector or a cell transformed with the vector, which contains a nucleic acid molecule encoding a polypeptide (from N-terminus to C-terminus) comprising an amino acid sequence represented by the following formula: [Mathematics II] X4-X1-LQCVKNPE-X2-X3-SC, In the above formula II, X4 is R or K; X1 is F or L; X2 is H or D; X3 is P or S.

[0101] According to a preferred embodiment, the vector or cell may comprise a nucleic acid molecule encoding a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 4-6.

[0102] According to a preferred embodiment, the vector or cell may comprise a nucleic acid molecule encoding a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 7 to 10.

[0103] According to a preferred embodiment, the vector or cell may comprise a nucleic acid molecule encoding a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 11 to 15.

[0104] According to a preferred embodiment, the vector or cell may comprise a nucleic acid molecule encoding a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 16-20.

[0105] According to a preferred embodiment, the vector or cell may comprise a nucleic acid molecule encoding a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 21 to 25.

[0106] According to a preferred embodiment, the vector or cell may comprise a nucleic acid molecule encoding a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 26-30.

[0107] According to a preferred embodiment of the present invention, the vector or cell may comprise a nucleic acid molecule encoding the full-length CD38 sequence (eg, SEQ ID NOs: 31 to 36) or a fragment thereof.

[0108] Examples of viruses that can be used as vectors in the present disclosure include, but are not limited to, retroviruses, herpes simplex viruses, lentiviruses, poxviruses, vaccinia viruses, rhabdoviruses, adenoviruses, helper-dependent adenoviruses, adeno-associated viruses (AAVs), baculoviruses, and combinations thereof.In some embodiments, the vectors that can be used in the present disclosure include non-viral vectors.Non-limiting examples of such vectors include plasmids, cosmids, yeast artificial chromosomes (YACs), bacteriophages, and combinations thereof.

[0109] In some embodiments, the vector may further comprise a promoter sequence, an enhancer sequence, an exon sequence, an intron sequence, a signal sequence, a coding sequence, a splice donor sequence, or the like.

[0110] In some embodiments, the cells described herein are capable of producing the proteins encoded by the nucleic acid molecules in vitro. In certain embodiments, the cells described herein are capable of producing the encoded proteins in vivo. In some embodiments, the cells described herein are capable of producing the encoded proteins both in vitro and in vivo.

[0111] In some embodiments, cells that can be used to produce proteins encoded by the nucleic acid molecules (e.g., in vitro) include host cells. As used herein, the term "host cell" is intended to include cells of any organism that can be transduced with the expression construct (e.g., an AAV vector) and replicate the expression construct or express the genes encoded by the expression construct. Such cells include eukaryotic and prokaryotic cells. As used herein, the term "transduction" is intended to include transfection and transformation. The host cell may be transduced, transfected, or transformed with the expression construct. This process refers to the transfer or introduction of an exogenous nucleic acid molecule into the host cell. In some embodiments, the host cell is an isolated host cell. In some embodiments, the host cell is a transformed, isolated host cell.

[0112] In some embodiments, the host cell is a eukaryotic cell. In some embodiments, the host cell is selected from the group consisting of a mammalian cell, an insect cell, a yeast cell, a transgenic mammalian cell, and a plant cell. In some embodiments, the host cell is a prokaryotic cell. In some embodiments, the prokaryotic cell is a bacterial cell.

[0113] In some embodiments, the host cell is an insect cell. In some embodiments, the insect cell is Sf9. In some embodiments, the host cell is a mammalian cell. Non-limiting examples of mammalian cells that can be used in the present disclosure include HEK293, HeLa, ARPE-19, RPE-1, HepG2, Hep3B, Huh-7, C8D1a, Neuro2A, CHO, MES13, BHK-21, COS7, COP5, A549, MCF-7, HC70, HCC1428, BT-549, PC3, LNCaP, Capan-1, Panc-1, MIA PaCa-2, SW480, HCT166, LoVo, A172, MKN-45, MKN-74, Kato-III, NCI-N87, HT-144, SK-MEL-2, SH-SY5Y, C6, HT-22, PC-12, NIH3T3 cells, and combinations thereof.

[0114] In some embodiments, cells that can be used to produce (e.g., in vivo) proteins encoded by exogenous genes described herein include human cells. In some embodiments, the human cells are cells of a subject to which a nucleic acid molecule described herein has been administered. In certain embodiments, the human cells are derived from a donor (e.g., a healthy human subject).

[0115] V. Pharmaceutical Compositions The present disclosure relates to a pharmaceutical composition for preventing or treating a disease or disorder, comprising a polypeptide comprising the amino acid sequence of CD38 (e.g., soluble CD38) or a fragment (functional fragment) thereof, a nucleic acid molecule encoding the polypeptide, a vector containing the nucleic acid molecule, or a cell transformed with or containing the vector, and a pharmaceutically acceptable carrier.

[0116] In some embodiments, the disease or disorder is an autoimmune disease.

[0117] Examples of autoimmune diseases include, but are not limited to, rheumatoid arthritis, autoimmune thyroiditis, psoriasis, Crohn's disease, ulcerative colitis, lupus (systemic lupus erythematosus), uveitis, xerophthalmia, allergies, atopic dermatitis, rhinitis, asthma, multiple sclerosis, or type 1 diabetes.

[0118] In some embodiments, the disease or disorder is inflammatory bowel disease.

[0119] Examples of inflammatory bowel disease include, but are not limited to, ulcerative colitis or Crohn's disease.

[0120] Pharmaceutically acceptable carriers that can be used in the present disclosure are those commonly used in formulations. Examples of pharmaceutically acceptable carriers include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. The pharmaceutical compositions of the present disclosure may further contain one or more additives selected from the group consisting of lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, and preservatives. Details of suitable pharmaceutically acceptable carriers and formulations can be found in Remington's Pharmaceutical Sciences (19th ed., 1995).

[0121] A pharmaceutical composition of the present disclosure is formulated to be compatible with its intended route of administration. Routes of administration include oral or parenteral administration, and examples of suitable parenteral routes of administration include intravenous injection, transdermal injection, subcutaneous injection, intramuscular injection, intraocular (e.g., sub-Tenon, subconjunctival, suprachoroidal, subretinal, intravitreal, and any administration that can be delivered to similar locations), eye drop injection, intraventricular injection, intraspinal injection, intra-amniotic injection, intra-arterial injection, intra-articular injection, intracardiac injection, intracavernosal injection, intracerebral injection, cisternal injection, intracoronary injection, intracranial injection, intradural injection, epidural injection, intrahippocampal injection, intranasal injection, intraosseous injection, intraperitoneal injection, intrathoracic injection, intraspinal injection, intrathoracic injection, intrathymic injection, intrauterine injection, intravaginal injection, intraventricular injection, intravesical injection, subconjunctival injection, intratumoral injection, topical injection, peritoneal injection, and combinations thereof.

[0122] In some embodiments, the pharmaceutical composition is administered at a daily dosage of 0.0001 mg / kg to 100 mg / kg.

[0123] The pharmaceutical compositions of the present disclosure may be formulated with one or more pharmaceutically acceptable carriers and / or excipients. The pharmaceutical compositions may be provided in unit dosage form or dispensed in multi-dose containers. The dosage form may be in the form of a solution, suspension, or emulsion in an oily or aqueous medium, or in the form of an extract, powder, granules, tablet, or capsule. The dosage form may further include a dispersing agent or stabilizer.

[0124] VI.Applications The present disclosure provides polypeptides comprising CD38 (e.g., soluble CD38) or fragments thereof, nucleic acids encoding the polypeptides, vectors comprising such nucleic acids, cells comprising or transformed with the nucleic acids or vectors, and methods described herein, which have numerous in vitro and in vivo utilities. For example, the polypeptides, polynucleotides, vectors, and in vitro or ex vivo cells described herein can be administered in vivo, for example, to prevent or treat disease. Accordingly, in some aspects, the present disclosure provides therapeutic uses of the polypeptides described herein, any of the polynucleotides, vectors described herein, cells described herein, and pharmaceutical compositions described herein. In some aspects, the present disclosure provides methods for preventing or treating an autoimmune disease in a subject in need thereof, comprising administering to the subject a polypeptide, polynucleotide, vector, cell, or pharmaceutical composition disclosed herein.

[0125] In some aspects, a method for preventing or treating a disease or disorder can be provided, comprising administering to a subject in need thereof the polypeptide, a nucleic acid molecule encoding the polypeptide, a vector comprising the nucleic acid molecule, or an isolated cell comprising the vector.

[0126] In some aspects, a method for preventing or treating an autoimmune disease or an inflammatory bowel disease can be provided, comprising administering to a subject in need thereof: i) the polypeptide, a nucleic acid molecule encoding the polypeptide, a vector comprising the nucleic acid molecule, or an isolated cell comprising the vector; or ii) a pharmaceutical composition comprising the polypeptide, the nucleic acid molecule, the vector, or the isolated cell.

[0127] In some aspects, the present invention provides use of i) the polypeptide, the nucleic acid molecule encoding the polypeptide, the vector comprising the nucleic acid molecule, or the isolated cell comprising the vector, or ii) a pharmaceutical composition comprising the polypeptide, the nucleic acid molecule, the vector, or the isolated cell for the prevention or treatment of autoimmune diseases or inflammatory bowel diseases.

[0128] The disease or disorder may be, but is not limited to, preferably an autoimmune disease, more preferably selected from the group consisting of rheumatoid arthritis, autoimmune thyroiditis, psoriasis, Crohn's disease, ulcerative colitis, lupus (systemic lupus erythematosus), uveitis, xerophthalmia, allergy, atopic dermatitis, rhinitis, asthma, multiple sclerosis, or type 1 diabetes.

[0129] The disease or disorder may preferably be inflammatory bowel disease, more preferably ulcerative colitis or Crohn's disease.

[0130] In some embodiments, the method can further include administering an additional therapeutic agent (e.g., an immunosuppressant) to the subject. In some embodiments, the additional therapeutic agent can be administered to the subject simultaneously with, before, or after administration of the polypeptide, polynucleotide, vector, cell, recombinant virus, or pharmaceutical composition.

[0131] Diseases that can be prevented, improved, or treated by the present disclosure include, but are not limited to, all diseases that require a reduction in the frequency of drug administration.

[0132] In some embodiments, the polypeptide comprises an amino acid sequence represented by the following formula (from N-terminus to C-terminus): [Number I] X1-LQCVKNPE-X2-X3-SC, In the above Formula I, X1 is F or L; X2 is H or D; X3 is P or S.

[0133] In some embodiments, the polypeptide can comprise an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-3.

[0134] In some embodiments, the polypeptide comprises an amino acid sequence represented by the following formula (from N-terminus to C-terminus): [Mathematics II] X4-X1-LQCVKNPE-X2-X3-SC, In the above formula II, X4 is R or K; X1 is F or L; X2 is H or D; X3 is P or S.

[0135] In some embodiments, the polypeptide can comprise an amino acid sequence selected from the group consisting of SEQ ID NOs: 4-30.

[0136] In some embodiments, the polypeptides are 13 to 300, 13 to 250, 13 to 240, 13 to 230, 13 to 220, 13 to 210, 13 to 200, 13 to 190, 13 to 180, 13 to 170, 13 to 160, 13 to 150, 13 to 140, 13 to 130, 13 to 120, 13 It may consist of 13 to 110, 13 to 100, 13 to 90, 13 to 80, 13 to 70, 13 to 60, 13 to 50, 13 to 49, 13 to 48, 13 to 47, 13 to 46, 13 to 45, 13 to 44, 13 to 43, 13 to 42, 13 to 41, 13 to 40, or 13 to 39 amino acids.

[0137] In some embodiments, the polypeptide is a fragment of CD38.

[0138] In some embodiments, the CD38 is soluble CD38.

[0139] In some embodiments, the CD38 can be from a dog, horse, mouse, rat, human, or chimpanzee.

[0140] VII. Production Method The present disclosure relates to a method for producing a pharmaceutical composition for preventing or treating a disease or disorder, the method comprising producing a polypeptide comprising the amino acid sequence of CD38 (e.g., soluble CD38) or a fragment (functional fragment) thereof, a nucleic acid molecule encoding the polypeptide, a vector comprising the nucleic acid molecule, or a cell transformed with or comprising the vector.

[0141] [Effects of the invention] The features and advantages of the present invention can be summarized as follows: (i) The present invention provides polypeptides comprising fragments of CD38.

[0142] (ii) The present invention also provides a composition for preventing or treating an autoimmune disease, which comprises CD38 or a fragment thereof.

[0143] (iii) According to the present invention, a polypeptide comprising soluble CD38 or a fragment thereof or a nucleic acid molecule encoding the same can be used to treat a variety of diseases associated with autoimmunity.

[0144] [Brief description of the drawing] FIG. 1 shows a screening test for primary functional domains using CD38 recombinant protein.

[0145] FIG. 2 shows the secondary selection test for sCD38 functional domains after the primary selection for sCD38 functional domains.

[0146] FIG. 3 shows the tertiary selection test for sCD38 functional domains after the secondary selection for sCD38 functional domains.

[0147] FIG. 4 shows efficacy tests of the functional domain of sCD38 in an animal model of autoimmune uveitis.

[0148] FIG. 5 shows a comparative study of the functional domains of sCD38 on the amount of Treg cells in an animal model of autoimmune uveitis.

[0149] FIG. 6 shows a comparative study of cytokine levels in an animal model of autoimmune uveitis using functional domains of sCD38.

[0150] FIG. 7 shows efficacy tests of the functional domain of sCD38 in animal models of rheumatoid arthritis.

[0151] FIG. 8 shows a diagram showing the efficacy test of the functional domain of sCD38 in an animal model of ulcerative colitis.

[0152] FIG. 9 shows a diagram showing the efficacy test of the functional domain of human sCD38 in human dendritic cells.

[0153] FIG. 10 shows the results of a comparison of interspecies sequence homology of the CD38 of the present invention through alignment (human (59%), rat (88%), dog (57%), horse (58%), and chimpanzee (58%) based on mouse).

[0154] [Mode for Carrying Out the Invention] The present invention will be described in more detail with reference to the following examples. It will be obvious to those skilled in the art that these examples are provided merely to illustrate the present invention in more detail, and that the scope of the present invention is not limited by these examples in accordance with the gist of the present invention.

[0155] [Example] Example 1. Mouse bone marrow cell isolation and DCs differentiation To isolate bone marrow cells, mice (DAMOOL SCIENCE, South Korea) were anesthetized and sacrificed. The femur and bones were aseptically removed and any attached tissue was removed. After cutting both ends of the bone, 5-10 ml of cell culture medium or bone marrow isolation solution was slowly injected into the marrow cavity at one end using a syringe. The bone marrow was then collected and filtered through a 70 μm cell strainer (SPL Life Sciences, South Korea) and centrifuged to collect the bone marrow cells. To remove red blood cells, 1 ml of RBC lysis solution (Merck, Germany) was added for 2-5 minutes, and 10 ml of DPBS (Dulbecco's Phosphate-Buffered Saline) (Gibco, USA) was added. The bone marrow cells were then collected by centrifugation. After washing the bone marrow cells three times with DPBS, 10 ml of BMDC culture medium (RPMI-1640 (Welgene, Republic of Korea) medium containing 10% FBS (Gibco, USA) and 10 ng / ml GM-CSF (Peprotech, USA)) was added to disperse the bone marrow cells into single cells. 1 × 10 bone marrow cells were placed in a 24-well culture dish. 5 The cells are dispensed so that they can fit in the well, and differentiation is carried out in an incubator at 37°C with 5% CO2 maintained.

[0156] Example 2. Primary functional domain selection test using CD38 recombinant protein To screen for the functional domain of sCD38 that induces DC tolerance, we divided the sCD38 domain into three major domains (CD38 amino acid sequence: 42-140 (1), 130-220 (2), and 210-304 (3)). Using these three domains, we observed TNF-α secretion, which is one of the indicators of DC tolerance induction.

[0157] As shown in Figure 1, the sCD38 domain was divided into three parts, and the ability of DCs to secrete TNF-α in response to LPS was examined. An E. coli expression system was used to express the sCD38 domain protein. The sCD38 domain protein expressed in E. coli was purified using a purification system and used for screening. To screen for sCD38 domain proteins, an ELISA method was adopted to measure the pro-inflammatory cytokine TNF-α, a fast and simple screening method. When DCs obtained by treating bone marrow cells with GM-CSF were treated with LPS, the DCs differentiated into mature DCs, resulting in increased TNF-α secretion. Treatment of these DCs with sCD38 (SEQ ID NO: 33) was confirmed to reduce LPS-induced TNF-α secretion from DCs. We treated sCD38 with the functional domains (1) 42-140, (2) 130-220, and (3) 210-304, and confirmed that the functional domain (3) of sCD38 reduced TNF-α secretion from dendritic cells induced by LPS (Merck, Germany).

[0158] Example 3: Secondary functional domain selection test after primary functional domain selection After initial selection of the functional domain of sCE38 that induces DC tolerance, the selected domain was divided into two parts (C-terminus 226-265 and C-terminus 266-304 (SEQ ID NO: 26) of CD38210-304(3)). Using the divided domain, TNF-α secretion, one of the indicators of DC tolerance induction, was observed.

[0159] As shown in Figure 2, the functional domain (3) of sCD38 identified in Figure 1 was again divided into two parts, and the ability of DCs to secrete TNF-α in response to LPS was examined. To express the divided parts of sCD38, an E. coli expression system was used. The functional domain (3) of sCD38 was divided into two parts (C-term 226-265 and C-term 266-304), and we confirmed that the C-term 266-304 functional domain of sCD38 reduced TNF-α secretion from DCs in response to LPS.

[0160] Example 4: Tertiary functional domain selection test after secondary functional domain selection After secondary screening of the functional domains of sCD38 that induce DC tolerance, the selected domains were again divided into seven parts and peptides were synthesized (sCD38 226-304 peptide 1:233-247, peptide 2:251-265, peptide 3:269-283, peptide 4:266-304 (SEQ ID NO: 26), peptide 5 (M19):286-304 (SEQ ID NO: 21), peptide 6 (M16):287-302 (SEQ ID NO: 11), peptide 7 (M14):287-300 (SEQ ID NO: 4)). TNF-α secretion, a measure of DC tolerance induction, was monitored using the seven divided domain peptides. In addition, we synthesized a domain peptide of human CD38, H18 (283-300) (sequence number 18), which has the same position as M19 (286-304), and treated it with dendritic cells, and observed TNF-α secretion, which is one of the measures of the degree of DC tolerance induction.

[0161] As shown in Figure 3, the functional domain C-terminus 226-304 of sCD38 was reconstructed into various peptide fragments, and the ability of DCs to secrete TNF-α in response to LPS was examined. Treatment with short peptides (peptide 4 (266-304), M19 (286-304), M16 (287-302), M14 (287-300), and H18 (283-300)) confirmed that LPS-induced TNF-α secretion from DCs was reduced by the functional domain peptides of sCD38.

[0162] Example 5. Efficacy test of sCD38 functional domains in an animal model of autoimmune uveitis C57BL / 6 mice (DAMOOL SCIENCE, Republic of Korea) were injected with IRBP (Interphotoreceptor retinoid-binding protein) peptide (Petron, Republic of Korea) into the hind leg muscles and then intraperitoneally injected with PTX (pertussis toxin) (List Labs, USA) to induce autoimmune uveitis. After 10–14 days, the mice's eyes were examined for the development of autoimmune uveitis. The functional domain of sCD38 (226–304) was injected twice weekly into the animal model with autoimmune uveitis, and the progression of autoimmune uveitis was monitored. The control group was an autoimmune uveitis animal model without injection of the functional domain of sCD38 (226–304), while the experimental group was injected with the functional domain of sCD38 (226–304). The severity of autoimmune uveitis was then measured in each experimental animal.

[0163] As shown in Figure 4, a comparison of the eyes of a control animal model with autoimmune uveitis with the eyes of an experimental animal model treated with the functional domain (226-304) of sCD38 confirmed that the progression of autoimmune uveitis was reduced in the eyes of the experimental animal model treated with the functional domain (226-304) of sCD38.

[0164] Example 6. Comparative study of functional domains of sCD38 on Treg cell levels in an animal model of autoimmune uveitis Next, to analyze the Treg levels in each experimental animal, each experimental animal was anesthetized and sacrificed, and lymph nodes and eyeballs were aseptically isolated. The isolated lymph nodes or eyeballs were minced using surgical scissors and placed on a 70 μm cell strainer (SPL Life Sciences, South Korea). The cells were then filtered through 10 ml of cell culture medium (RPMI-1640 medium) and centrifuged to collect lymph node or eyeball cells. To remove the small amount of red blood cells present in lymph node or eyeball cells, 1 ml of RBC lysis solution was added for 2–5 minutes, and 10 ml of DPBS (Dulbecco's Phosphate-Buffered Saline) (Gibco, USA) was added. Lymph node or eyeball cells were collected by centrifugation. After washing three times with DPBS, 10 ml of RPMI medium (containing 10% FBS (Gibco, USA)) was added to disperse lymph node or eyeball cells into single cells. 2-5 x 10 lymph node cells or ocular cells 5 The lymph node cells or ocular cells were analyzed for Treg levels by flow cytometry.

[0165] As shown in Figure 5, a comparison of the eyes of a control animal model with uveitis and the eyes of an experimental animal model treated with the functional domain (226-304) of sCD38 confirmed that the number of Treg cells increased in the eyes of the experimental animal model treated with the functional domain (226-304) of sCD38.

[0166] Example 7. Comparative study of cytokine levels in autoimmune uveitis animal models using functional domains of sCD38 Next, to analyze the amount of each cytokine (IL-17, INF-γ, etc.) secreted by each experimental animal, each experimental animal was anesthetized and sacrificed, and splenocytes were aseptically isolated. The isolated splenocytes were minced using surgical scissors, placed on a 70 μm cell strainer (SPL Life Sciences, South Korea), filtered through 10 ml of cell culture medium (RPMI-1640 medium), and then centrifuged to collect the splenocytes. To remove red blood cells contained in the splenocytes, 1 ml of RBC lysis solution was added for 2–5 minutes, and 10 ml of DPBS (Dulbecco's Phosphate-Buffered Saline) (Gibco, USA) was added and the splenocytes were collected by centrifugation. After washing three times with DPBS, 10 ml of RPMI medium (culture medium containing 10% FBS (Gibco, USA)) was added and the splenocytes were dispersed to single cells. The splenocytes were collected at a concentration of 1 × 10 6 The cells were then analyzed for the amount of each cytokine.

[0167] As shown in Figure 6, a comparison of the eyes of a control animal model with uveitis with the eyes of an experimental animal model treated with the functional domain (226-304) of sCD38 confirmed that the amount of cytokines was reduced in the eyes of the experimental animal model treated with the functional domain (226-304) of sCD38.

[0168] Example 8. Efficacy test of sCD38 functional domains in rheumatoid arthritis animal models To induce rheumatoid arthritis with collagen-induced arthritis (CIA), 8- to 9-week-old male DBA / 1 mice (Central Laboratory Animals, Republic of Korea) were immunized with bovine type II collagen (CII) (Central Laboratory Animals, Republic of Korea). CII was dissolved in 0.05N acetic acid at a concentration of 2 mg / ml and emulsified at a 1:1 ratio with complete Freund's adjuvant (CFA) (Central Laboratory Animals, Republic of Korea) at 4°C. For the first immunization, 150 μl of a mixture of 100 μg of CII and 100 μg of CFA was injected intradermally into the tail of the mice. Three weeks later, before the booster injection, mice were injected intra-ankle with either the functional domain of sCD38 (sCD38-3) (226-304) or saline. An equal volume of CII emulsified with incomplete Freund's adjuvant (IFA) (Merck, Germany) at a 1:1 ratio was then injected into the tail (booster injection). Three additional injections of the functional domain of sCD38 (sCD38-3) were administered weekly. Four weeks after the booster injection, mice were euthanized and analyzed. After the booster injection, the thickness of the hind ankles of the animal model was measured using a Vernier caliper.

[0169] As shown in Figure 7, the thickness of the hind ankles of the control animal model with rheumatoid arthritis was compared with that of the experimental animal model treated with the functional domain of sCD38 (sCD38-3). As a result, it was confirmed that the thickness of the hind ankles of the experimental animal model treated with the functional domain of sCD38 (sCD38-3) was significantly reduced compared to the thickness of the hind ankles of the animal model with advanced rheumatoid arthritis.

[0170] Example 9. Efficacy test of functional domains of sCD38 in an animal model of ulcerative colitis The control ulcerative colitis animal model was established by feeding C57BL / 6 mice (DAMOOL SCIENCE, Republic of Korea) water containing 2%-3% DSS (dextran sulfate sodium) (MP Biomedicals, China) for 6-7 days. DSS administration increases inflammatory cytokine levels and induces colitis in mice. Six to 7 days after DSS treatment, the experimental animal model was administered 20 μg of the functional domain of sCD38 (M19 peptide (Peptron, Republic of Korea)) into the anus of the ulcerative colitis-inducing animal model every day for 2 weeks to determine whether the progression of ulcerative colitis was reduced. LiCl (Merck, Germany) was used as a positive control instead of the functional domain of sCD38 (M19 peptide).

[0171] As shown in Figure 8, the colon of the control animal model with ulcerative colitis was shortened compared to the colon of animals without ulcerative colitis. Conversely, the colon of the experimental animal model treated with the functional domain of sCD38 (M19 peptide) was not shortened.

[0172] Example 10. Isolation of mononuclear cells from human whole blood and differentiation of mononuclear cell-derived dendritic cells To isolate human mononuclear cells, 20 ml of whole blood was collected and mixed with an equal volume of PBS. 15 ml of Ficoll (GE HealthCare, USA) was placed in a 50 ml tube, and 15 ml of the diluted whole blood was slowly placed on top of the Ficoll. Similarly, 15 ml of Ficoll was placed in a 50 ml tube with the remaining whole blood, and the same volume was slowly dispensed into each tube. The tube was centrifuged at 1000 × g for 20 minutes at room temperature. The plasma from the separated whole blood was carefully removed, and the peripheral blood mononuclear cells (PBMCs) were transferred to a new 50 ml tube. 10 ml of PBS was added to the tube containing the PBMCs, mixed smoothly, and centrifuged at 400 × g for 10 minutes at room temperature. The supernatant was carefully removed, and 1 ml of RPMI 1640 medium containing 10% FBS was added to the PBMC pellet, after which the cell count was determined. 1 × 10 cells per ml was counted.6 RPMI-1640 medium (Welgene, South Korea) containing 10% FBS was added to the cells, and 100 ng / ml GM-CSF (Peprotech, USA) and 50 ng / ml IL-4 (Peprotech, USA) were added and mixed. 500 μl of PMBCs were added to each well of a 24-well plate, and differentiation was carried out in an incubator at 37°C and 5% CO2 for 5 days.

[0173] Example 11. Efficacy testing of functional domains of sCD38 in human dendritic cells We investigated whether the functional domain of sCD38, which induces DC tolerance, also functions in human DCs. To identify the functional domain of human sCD38, peptides were prepared from the C-terminal portion of human CD38 (H18(283-300) and H13(284-296) (SEQ ID NO: 2)). Human sCD38 and M19 peptides were used as positive controls, and TNF-α secretion, a measure of DC tolerance induction, was monitored using the H18 and H13 peptides.

[0174] As shown in Figures 9 and 10, peptides were constructed from the C-terminus of human sCD38, H18 (283-300) and H13 (284-296), which are located at the C-terminus of mouse sCD38, and the ability of human dendritic cells to secrete TNF-α in response to LPS was examined. Human sCD38 and M19 peptides were used as positive controls, and treatment with H18 and H13 peptides confirmed that LPS-induced TNF-α secretion from human dendritic cells was reduced by the functional domain peptides of sCD38.

[0175] Hereinafter, formulation examples of pharmaceutical compositions containing the compositions of the present invention will be described, but these are not intended to limit the present invention but are merely for illustrative purposes.

[0176] Formulation example 1. Powder production NAD glycohydrolase (NADase) inhibitor 20mg Lactose 100mg Talc 10mg The above ingredients are mixed and packed into an airtight cloth to produce a powder.

[0177] Formulation Example 2: Tablet manufacturing NAD glycohydrolase (NADase) inhibitor 10mg 100mg corn starch Lactose 100mg Magnesium stearate 2mg After mixing the above ingredients, the mixture is compressed into tablets by a conventional tablet manufacturing method.

[0178] Formulation Example 3: Production of capsules NAD glycohydrolase (NADase) inhibitor 10mg Crystalline cellulose 3mg Lactose 14.8mg Magnesium stearate 0.2mg The above ingredients are mixed by a conventional method for producing capsules, and the mixture is filled into a gelatin capsule to produce the capsule.

[0179] Formulation Example 4. Manufacture of injections NAD glycohydrolase (NADase) inhibitor 10mg Mannitol 180mg Sterile distilled water for injection 2974mg Na2HPO42H2O 26mg The above-mentioned ingredients are prepared in an ampoule (2 ml) according to the usual method for preparing injections.

[0180] Formulation Example 5. Preparation of liquid formulation NAD glycohydrolase (NADase) inhibitor 20mg 10g of high fructose sugar 5g mannitol Appropriate amount of purified water Although the above describes various embodiments of the present invention, a person having ordinary knowledge in the art may modify and change the present invention in various ways by adding, changing, deleting or adding components within the scope of the concept of the present invention as set forth in the claims, and this also falls within the scope of the present invention. [Brief explanation of the drawings]

[0181] [Figure 1] FIG. 1 shows a primary functional domain selection test using CD38 recombinant protein. [Figure 2] FIG. 1 shows the secondary sCD38 functional domain selection test after primary sCD38 functional domain selection. [Figure 3] FIG. 1 shows the tertiary sCD38 functional domain selection test after the secondary sCD38 functional domain selection. [Figure 4] FIG. 1 shows efficacy tests of the functional domain of sCD38 in an animal model of autoimmune uveitis. [Figure 5] FIG. 1 shows a comparative study of the functional domains of sCD38 on the amount of Treg cells in an animal model of autoimmune uveitis. [Figure 6] FIG. 1 shows a comparative study of cytokine levels in an animal model of autoimmune uveitis using functional domains of sCD38. [Figure 7] FIG. 1 shows efficacy tests of the functional domain of sCD38 in animal models of rheumatoid arthritis. [Figure 8] FIG. 1 shows efficacy tests of the functional domain of sCD38 in an animal model of ulcerative colitis. [Figure 9] FIG. 1 shows efficacy testing of functional domains of human sCD38 on human dendritic cells. [Figure 10] FIG. 1 shows the results of a comparison of the homology of the CD38 sequences of the present invention between species through alignment (human (59%), rat (88%), dog (57%), horse (58%), and chimpanzee (58%) based on mouse).

Claims

1. A polypeptide comprising an amino acid sequence (from N-terminus to C-terminus) represented by the following mathematical formula: X1-L-Q-C-V-K-N-P-E-X2-X3-SC (number I), In the above Formula I, X1 is F or L; X2 is H or D; X3 is P or S.

2. The polypeptide of claim 1, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 3.

3. The polypeptide of claim 1, comprising an amino acid sequence represented by the following formula (from N-terminus to C-terminus): X4-X1-LQ-C-VK-N-P-E-X2-X3-SC (number II), In the above formula II, X4 is R or K; X1 is F or L; X2 is H or D; X3 is P or S.

4. The polypeptide of claim 3, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 4 to 30.

5. The polypeptides are selected from the group consisting of 13 to 300, 13 to 250, 13 to 240, 13 to 230, 13 to 220, 13 to 210, 13 to 200, 13 to 190, 13 to 180, 13 to 170, 13 to 160, 13 to 150, 13 to 140, 13 to 130, 13 to 120, 13 to 110, and 13 to 100.

2. The polypeptide of claim 1, characterized in that it consists of 13 to 90, 13 to 80, 13 to 70, 13 to 60, 13 to 50, 13 to 49, 13 to 48, 13 to 47, 13 to 46, 13 to 45, 13 to 44, 13 to 43, 13 to 42, 13 to 41, 13 to 40, or 13 to 39 amino acids.

6. The polypeptide according to claim 1, characterized in that the polypeptide is a fragment of CD38.

7. The polypeptide according to claim 6, wherein the CD38 is a soluble CD38.

8. The polypeptide according to claim 6, wherein the CD38 is derived from a dog, a horse, a mouse, a rat, a human, or a chimpanzee.

9. A nucleic acid molecule encoding the polypeptide of claim 1.

10. A vector comprising the nucleic acid molecule of claim 9.

11. A host cell comprising the vector of claim 10.

12. A host cell transformed with the vector of claim 10.

13. A pharmaceutical composition for preventing or treating an autoimmune disease or inflammatory bowel disease, comprising the polypeptide of claim 1, a nucleic acid molecule encoding said polypeptide, a vector containing said nucleic acid molecule, or an isolated cell containing said vector, and a pharmaceutically acceptable carrier.

14. A method for preventing or treating an autoimmune disease or inflammatory bowel disease, comprising administering to a subject in need thereof: i) a polypeptide of claim 1, a nucleic acid molecule encoding said polypeptide, a vector comprising said nucleic acid molecule, or an isolated cell comprising said vector; or ii) a pharmaceutical composition comprising said polypeptide, said nucleic acid molecule, said vector, or said isolated cell.

15. i) a polypeptide of claim 1, a nucleic acid molecule encoding said polypeptide, a vector containing said nucleic acid molecule, or an isolated cell containing said vector, or ii) a pharmaceutical composition containing said polypeptide, said nucleic acid molecule, said vector, or said isolated cell for the prevention or treatment of autoimmune diseases or inflammatory bowel diseases.

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