GIP derivatives, long-acting conjugates thereof, and pharmaceutical compositions containing the same

Abstract

Provided is a GIP derivative, a pharmaceutically acceptable salt thereof, a solvate thereof, or a long-acting conjugate thereof, or a pharmaceutical composition containing the same for the prevention or treatment of inflammatory diseases or autoimmune diseases.

Description

[Technical Field]

[0001] The present invention relates to a GIP derivative, a long-acting conjugate thereof, and a pharmaceutical composition containing the same for the prevention or treatment of inflammatory diseases or autoimmune diseases. [Background technology]

[0002] Vasculitis is a disease caused by immune cell attack on blood vessels or their walls, inducing inflammation within the vessel walls. Vasculitis is classified by various methods, but the most commonly used classification method is based on the size of the affected vessels proposed by Jennette et al. (Jennette JC, Falk RJ, Andrassy K et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 37:187-92, 1994).

[0003] Takayasu arteritis (TA) and giant cell arteritis (GCA) are representative large-vessel vasculitis (LVV) diseases that affect large blood vessels such as the aorta. Vasculitis symptoms can result from direct damage to blood vessels or indirect damage to tissues due to obstructed or reduced blood supply. Symptoms vary depending on the size, location, and extent of damage to the vessels where inflammation occurs. Vasculitis is difficult to diagnose early due to its diverse and nonspecific symptoms. It is often diagnosed only after significant vascular deformity has occurred, making treatment difficult. Furthermore, the causes of both TA and GCA are unknown. While incidence varies by race, region, and gender, these diseases are rare and therefore not widely studied.

[0004] Glucocorticoids are often used to treat vasculitis to alleviate inflammation, but the disadvantage of steroids is that they can cause significant side effects when used in high doses or for long periods of time.Furthermore, if glucocorticoid administration is discontinued or the dose is reduced, the alleviated symptoms may recur.

[0005] LVV is one of the areas where there is a high demand for treatment as there is still a lack of fundamental treatments. There is a need for the development of appropriate treatments with minimal side effects that can prevent vasculitis from progressing to irreversible vascular lesions and prevent future complications.

[0006] Vasculitis and arteriosclerosis share the commonalities of being caused by blood vessels and being chronic inflammatory diseases, but they are also distinguished by whether lipids are involved in the onset of the disease. Atherosclerosis develops when blood lipids accumulate in the vascular wall, narrowing the blood vessels, while vasculitis develops when an inflammatory response invades the vascular wall. Therefore, vasculitis and arteriosclerosis differ not only in the mechanism of disease onset but also in their pathophysiological and therapeutic approaches.

[0007] Glucose-dependent insulinotropic polypeptide (GIP) is a typical hormone (incretin hormone) secreted in the gastrointestinal tract and is also a neurohormone that is secreted in response to food intake. GIP is a hormone composed of 42 amino acids secreted from K cells in the small intestine. It is known to promote insulin or glucagon secretion from the pancreas depending on blood glucose concentration, thereby helping to maintain blood glucose homeostasis. Recent studies have reported its food-suppressing effect.

[0008] On the other hand, when native GIP is cleaved at the N-terminus by the enzyme DPP-4 (dipeptidyl peptidase-4), it loses its activity, and this reaction occurs very rapidly in the body. Therefore, the half-life of GIP in the human body is known to be very short, about 7 minutes (J Clin Endocrinol Metab. 2000 Oct; 85 (10):3 575-81). Therefore, in order to utilize the efficacy of GIP and use it in the development of therapeutic agents, it is necessary to develop derivatives with increased durability in the body.

[0009] To this end, the present inventors developed a long-acting GIP derivative conjugate that exhibits high activity at the human GIP receptor and has improved durability in the body, and confirmed its potential as a therapeutic agent for vasculitis, leading to the completion of the present invention. Summary of the Invention [Problem to be solved by the invention]

[0010] The present invention provides novel GIP derivatives.

[0011] The present invention provides polynucleotides encoding the GIP derivatives.

[0012] The present invention provides a vector comprising the polynucleotide.

[0013] The present invention provides a host cell comprising the polynucleotide or vector thereof.

[0014] The present invention provides a conjugate of the GIP derivative with a biocompatible substance that increases the in vivo half-life.

[0015] The present invention provides a pharmaceutical composition for preventing or treating an inflammatory disease or an autoimmune disease, comprising the GIP derivative, a pharmaceutically acceptable salt thereof, a solvate thereof, or the conjugate.

[0016] The present invention provides a method for preventing or treating an inflammatory disease or an autoimmune disease, comprising administering an effective amount of the GIP derivative, a pharmaceutically acceptable salt thereof, a solvate thereof, or the conjugate, or the pharmaceutical composition to an individual in need thereof.

[0017] The present invention provides use of the GIP derivative, a pharmaceutically acceptable salt thereof, a solvate thereof, or the conjugate thereof for the manufacture of a medicament for the prevention or treatment of an inflammatory disease or an autoimmune disease. [Means for solving the problem]

[0018] Throughout this specification, the usual one-letter and three-letter codes for naturally occurring amino acids are used, as well as the commonly accepted three-letter codes for other amino acids, such as Aib (α-amino-isobutyric acid). Also, amino acids referred to herein by abbreviations are described according to the IUPAC-IUB nomenclature system.

[0019] Alanine Ala,A Arginine Arg,R Asparagine Asn,N Aspartic acid Asp,D Cysteine ​​Cys,C Glutamic acid Glu,E Glutamine Gln,Q Glycine Gly,G Histidine His,H Isoleucine Ile,I Leucine (Leu,L) Lysine Lys,K Methionine Met,M Phenylanine Phe,F Proline Pro,P Serine Threonine Thr,T Tryptophan Trp,W TyrosineTyr,Y Valine

[0020] One embodiment provides a GIP derivative.

[0021] GIP (glucose-dependent insulinotropic polypeptide or gastric inhibitory polypeptide) is a hormone secreted from K cells in the small intestine in response to food intake, and was first reported as a substance involved in regulating blood glucose levels.

[0022] The "GIP derivative" may be a derivative of native GIP in which at least one amino acid in the native GIP sequence has been altered. The alteration may be selected from the group consisting of substitution, addition, deletion, modification, and a combination of two or more thereof. The added amino acid sequence may be derived from the native GIP amino acid sequence, but is not limited thereto.

[0023] The GIP derivative may be a peptide active at the GIP receptor. The term "peptide active at the GIP receptor" refers to a peptide having a significant level of activity at the GIP receptor, specifically, a peptide exhibiting in vitro activity at the GIP receptor of approximately 0.1% or more, 1% or more, 2% or more, 3% or more, 4% or more, 5% or more, 6% or more, 7% or more, 8% or more, 9% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 100% or more, 100% to 500%, or 100% to 200% of that of the natural ligand (native GIP). The in vitro activity of such a peptide active at the GIP receptor can be measured by referring to Example 2 of the present specification, but is not limited thereto. Any suitable method known in the art can be used to measure in vitro activity.

[0024] "About" includes, but is not limited to, ranges of ±0.5, ±0.4, ±0.3, ±0.2, ±0.1, etc., including any range of numbers equal to or similar to the number following the term "about."

[0025] In one specific embodiment, the GIP derivative may be, but is not limited to, one, two, three, four, five, six, seven, eight, nine, ten, or more amino acid conservative substitutions in a native or unmutated GIP protein.

[0026] "Conservative substitution" refers to the replacement of one amino acid with another amino acid having similar structural and / or chemical properties. The GIP derivative may have, for example, one or more conservative substitutions while still retaining the biological activity of the native or unmutated GIP protein. Such amino acid substitutions may generally be made based on similarities in the polarity, charge, solubility, hydrophobicity, hydrophilicity, and / or amphipathic nature of the residues. For example, positively charged (basic) amino acids include arginine, lysine, and histidine; negatively charged (acidic) amino acids include glutamic acid and aspartic acid; aromatic amino acids include phenylalanine, tryptophan, and tyrosine; and hydrophobic amino acids include alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan. Amino acids are further classified into those with electrically charged side chains and those with uncharged side chains. Amino acids with electrically charged side chains include aspartic acid, glutamic acid, lysine, arginine, and histidine, while amino acids with uncharged side chains are further classified as nonpolar or polar amino acids. Nonpolar amino acids include glycine, alanine, valine, leucine, isoleucine, methionine, and proline, while polar amino acids may include serine, threonine, cysteine, asparagine, and glutamine. Conservative substitutions of amino acids with similar properties, as described above, are expected to exhibit identical or similar activity.

[0027] The GIP derivatives may be non-naturally occurring.

[0028] The GIP derivative may be an isolated peptide.

[0029] In one embodiment, the GIP derivative is a peptide comprising an amino acid sequence represented by the following general formula 1: [General formula 1] Tyr-Aib(aminoisobutyric acid)-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Xaa13-Xaa14-Xaa15-Xaa16-Xaa17-Ala-Xaa19-Xaa20-Xaa21-Phe-Xaa23-Xaa 24-Trp-Leu-Xaa27-Xaa28-Xaa29-Xaa30-Xaa31-Xaa32-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38-Xaa39-Xaa40-Xaa41-Xaa42-Xaa43

[0030] In the general formula 1, Xaa13 is alanine (Ala, A), Aib, tyrosine (Tyr, Y) or glutamine (Gln, Q); Xaa14 is methionine (Met, M) or leucine (Leu, L), Xaa15 is aspartic acid (Asp, D) or glutamic acid (Glu, E), Xaa16 is alanine (Ala, A), lysine (Lys, K) or glycine (Gly, G), Xaa17 is isoleucine (Ile, I) or glutamine (Gln, Q), Xaa19 is glutamine (Gln, Q) or alanine (Ala, A), Xaa20 is glutamine (Gln, Q), Aib, or lysine (Lys, K); Xaa21 is aspartic acid (Asp, D) or glutamic acid (Glu, E), Xaa23 is valine (Val, V) or isoleucine (Ile, I), Xaa24 is asparagine (Asn, N), alanine (Ala, A) or glutamine (Gln, Q); Xaa27 is leucine (Leu, L) or isoleucine (Ile, I), Xaa28 is alanine (Ala, A) or Aib, Xaa29 is glutamine (Gln, Q) or glycine (Gly, G), Xaa30 is lysine (Lys, K), glycine (Gly, G) or histidine (His, H), Xaa31 is proline (Pro, P), glycine (Gly, G) or cysteine ​​(Cys, C), Xaa32 is serine (Ser, S) or lysine (Lys, K) or is absent; Xaa33 is serine (Ser, S) or lysine (Lys, K), or is absent; Xaa34 is glycine (Gly, G) or asparagine (Asn, N) or is absent; Xaa35 is alanine (Ala, A) or aspartic acid (Asp, D) or is absent; Xaa36 is proline (Pro, P) or tryptophan (Trp, W) or is absent; Xaa37 is proline (Pro, P) or lysine (Lys, K) or is absent; Xaa38 is proline (Pro, P) or histidine (His, H) or is absent; Xaa39 is serine (Ser, S), asparagine (Asn, N), cysteine ​​(Cys, C), or is absent; Xaa40 is cysteine ​​(Cys, C) or isoleucine (Ile, I), or is absent; Xaa41 is threonine (Thr, T) or is absent; Xaa42 is glutamine (Gln,Q) or is absent; Xaa43 is cysteine ​​(Cys, C) or is absent.

[0031] An exemplary type of such peptide may be one that comprises any one amino acid sequence selected from the group formed by SEQ ID NOs: 1-26.

[0032] In another embodiment, the peptide may comprise an amino acid sequence represented by the following general formula 2: [General formula 2] Tyr-Aib(aminoisobutyric acid)-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Xaa13-Xaa14-Xaa15-Xaa16-Xaa17-Ala-Xaa19-Xaa20-Xaa21-Phe-Val-Xaa2 4-Trp-Leu-Xaa27-Xaa28-Xaa29-Xaa30-Xaa31-Xaa32-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38-Xaa39-Xaa40-Xaa41-Xaa42-Xaa43

[0033] In the general formula 2, Xaa13 is alanine (Ala, A), Aib, or tyrosine (Tyr, Y); Xaa14 is methionine (Met, M) or leucine (Leu, L), Xaa15 is aspartic acid (Asp, D) or glutamic acid (Glu, E), Xaa16 is alanine (Ala, A) or lysine (Lys, K), Xaa17 is isoleucine (Ile, I) or glutamine (Gln, Q), Xaa19 is glutamine (Gln, Q) or alanine (Ala, A), Xaa20 is glutamine (Gln, Q), Aib, or lysine (Lys, K); Xaa21 is aspartic acid (Asp, D) or glutamic acid (Glu, E), Xaa24 is asparagine (Asn, N) or glutamine (Gln, Q), Xaa27 is leucine (Leu, L) or isoleucine (Ile, I), Xaa28 is alanine (Ala, A) or Aib, Xaa29 is glutamine (Gln, Q) or glycine (Gly, G), Xaa30 is lysine (Lys, K), glycine (Gly, G) or histidine (His, H), Xaa31 is proline (Pro, P) or glycine (Gly, G), Xaa32 is serine (Ser, S) or lysine (Lys, K), Xaa33 is serine (Ser, S) or lysine (Lys, K), Xaa34 is glycine (Gly, G) or asparagine (Asn, N), Xaa35 is alanine (Ala, A) or aspartic acid (Asp, D), Xaa36 is proline (Pro,P) or tryptophan (Trp,W), Xaa37 is proline (Pro, P) or lysine (Lys, K), Xaa38 is proline (Pro, P) or histidine (His, H), Xaa39 is serine (Ser, S), asparagine (Asn, N) or cysteine ​​(Cys, C); Xaa40 is cysteine ​​(Cys, C) or isoleucine (Ile, I), or is absent; Xaa41 is threonine (Thr, T) or is absent; Xaa42 is glutamine (Gln,Q) or is absent; Xaa43 is cysteine ​​(Cys, C) or is absent.

[0034] An exemplary type of such peptide may be one comprising any one amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 17, and SEQ ID NOs: 19-26.

[0035] In yet another embodiment, the peptide may comprise an amino acid sequence represented by the following general formula 3: [General formula 3] Tyr-Aib(aminoisobutyric acid)-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Xaa13-Xaa14-Xaa15-Xaa16-Xaa17-Ala-Xaa19-Xaa20-Xaa21-Phe-Val-As n-Trp-Leu-Leu-Xaa28-Xaa29-Xaa30-Xaa31-Xaa32-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38-Xaa39-Xaa40-Xaa41-Xaa42-Xaa43

[0036] In the general formula 3, Xaa13 is alanine (Ala, A) or Aib, Xaa14 is methionine (Met, M) or leucine (Leu, L), Xaa15 is aspartic acid (Asp, D) or glutamic acid (Glu, E), Xaa16 is alanine (Ala, A) or lysine (Lys, K), Xaa17 is isoleucine (Ile, I) or glutamine (Gln, Q), Xaa19 is glutamine (Gln, Q) or alanine (Ala, A), Xaa20 is glutamine (Gln,Q) or Aib; Xaa21 is aspartic acid (Asp, D) or glutamic acid (Glu, E), Xaa28 is alanine (Ala, A) or Aib, Xaa29 is glutamine (Gln, Q) or glycine (Gly, G), Xaa30 is lysine (Lys, K), glycine (Gly, G) or histidine (His, H), Xaa31 is proline (Pro, P) or glycine (Gly, G), Xaa32 is serine (Ser, S) or lysine (Lys, K), Xaa33 is serine (Ser, S) or lysine (Lys, K), Xaa34 is glycine (Gly, G) or asparagine (Asn, N), Xaa35 is alanine (Ala, A) or aspartic acid (Asp, D), Xaa36 is proline (Pro,P) or tryptophan (Trp,W), Xaa37 is proline (Pro, P) or lysine (Lys, K), Xaa38 is proline (Pro, P) or histidine (His, H), Xaa39 is serine (Ser, S) or asparagine (Asn, N), Xaa40 is cysteine ​​(Cys, C) or isoleucine (Ile, I), Xaa41 is threonine (Thr, T) or is absent; Xaa42 is glutamine (Gln,Q) or is absent; Xaa43 is cysteine ​​(Cys, C) or is absent.

[0037] An exemplary type of such peptide may be one that comprises any one amino acid sequence selected from the group formed by SEQ ID NOs: 11, 17, 21, and 24.

[0038] In another embodiment, in the general formula 3, Xaa13 is alanine (Ala, A) or Aib, Xaa14 is leucine (Leu, L), Xaa15 is aspartic acid (Asp, D) or glutamic acid (Glu, E), Xaa16 is lysine (Lys, K), Xaa17 is glutamine (Gln,Q), Xaa19 is glutamine (Gln, Q) or alanine (Ala, A), Xaa20 is glutamine (Gln,Q) or Aib; Xaa21 is aspartic acid (Asp, D) or glutamic acid (Glu, E), Xaa28 is alanine (Ala, A) or Aib, Xaa29 is glutamine (Gln,Q), Xaa30 is glycine (Gly, G) or histidine (His, H), Xaa31 is proline (Pro,P), Xaa32 is serine (Ser, S), Xaa33 is serine (Ser, S), Xaa34 is glycine (Gly, G), Xaa35 is alanine (Ala, A), Xaa36 is proline (Pro,P), Xaa37 is proline (Pro,P), Xaa38 is proline (Pro,P), Xaa39 is serine (Ser,S), Xaa40 is cysteine ​​(Cys, C), Xaa41 to Xaa43 may be absent.

[0039] An exemplary type of such peptide may be one that comprises any one amino acid sequence selected from the group formed by SEQ ID NOs: 17, 21 and 24.

[0040] In another embodiment, in the general formula 1, Xaa13 is alanine (Ala, A), Xaa14 is methionine (Met, M), Xaa15 is aspartic acid (Asp, D), Xaa16 is alanine (Ala, A), Xaa17 is isoleucine (Ile, I), Xaa19 is glutamine (Gln,Q), Xaa20 is glutamine (Gln,Q), Xaa21 is aspartic acid (Asp, D), Xaa23 is valine (Val, V), Xaa24 is asparagine (Asn, N), Xaa27 is leucine (Leu, L), Xaa28 is alanine (Ala, A), Xaa29 is glutamine (Gln,Q), Xaa30 is lysine (Lys, K), Xaa31 is glycine (Gly, G), Xaa32 is lysine (Lys, K), Xaa33 is lysine (Lys, K), Xaa34 is asparagine (Asn, N), Xaa35 is aspartic acid (Asp, D), Xaa36 is tryptophan (Trp,W), Xaa37 is lysine (Lys, K), Xaa38 is histidine (His, H), Xaa39 is asparagine (Asn, N), Xaa40 is isoleucine (Ile, I), Xaa41 is threonine (Thr, T), Xaa42 is glutamine (Gln,Q), Xaa43 can be cysteine ​​(Cys, C).

[0041] However, in the above general formulas 1 to 3, if any one of Xaa32 to Xaa43 is absent, the subsequent amino acid sequence may be absent. For example, if Xaa32 is absent, Xaa33 to Xaa43 may be absent. For another example, if Xaa41 is absent, Xaa42 to Xaa43 may be absent.

[0042] In another embodiment, the peptide may comprise any one amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 26. Alternatively, the peptide may consist essentially of any one amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 26.

[0043] In another embodiment, the peptide may comprise any one amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 17, and 19 to 26. Alternatively, the peptide may consist essentially of any one amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 17, and 19 to 26, or may consist of any one amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 17, and 19 to 26.

[0044] In other embodiments, the peptide may comprise any one amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 17, 21, and 24. Alternatively, the peptide may consist essentially of any one amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 17, 21, and 24, or may consist of any one amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 17, 21, and 24.

[0045] In other embodiments, the peptide may comprise any one amino acid sequence selected from the group consisting of SEQ ID NOs: 17, 21, and 24. Alternatively, the peptide may consist essentially of any one amino acid sequence selected from the group consisting of SEQ ID NOs: 17, 21, and 24, or the peptide may be capable of consisting of any one amino acid sequence selected from the group consisting of SEQ ID NOs: 17, 21, and 24.

[0046] In the present application, even if a peptide is described as "a peptide consisting of a specific SEQ ID NO," it does not exclude meaningless additions to the amino acid sequence of the SEQ ID NO, or naturally occurring mutations, or silent mutations thereof, as long as it is identical to or has the activity of a peptide consisting of the amino acid sequence of the SEQ ID NO. It is clear that even if there are partial sequence differences, a peptide that shows a certain level of sequence identity and exhibits activity against the GIP receptor may be included in the scope of the present invention. Specifically, the peptide may comprise an amino acid sequence having 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% or more identity to the amino acid sequence of SEQ ID NO: 1 to 26, but is not limited thereto.

[0047] "Homology" or "identity" refers to the degree to which two given amino acid or nucleotide sequences are related to one another, and may be expressed as a percentage. Whether any two peptide sequences have homology, similarity, or identity can also be determined using known computer algorithms such as the "FASTA" program, using default parameters, e.g., as in Pearson et al. (1988) [Proc. Natl. Acad. Sci. USA 85]: 2444. Alternatively, the Needleman-Wunsch algorithm (Needleman and Wunsch, 1970, J. Mol. Biol. 48: 443-453) may be used, as implemented in the Needleman program of the EMBOSS package (EMBOSS: The European Molecular Biology Open Software Suite, Rice et al., 2000, Trends Genet. 16: 276-277) (version 5.0.0 or later) (GCG program package (Devereux, J., et al., Nucleic Acids Research 12: 387 (1984), BLASTP, BLASTN, FASTA (Atschul, [S.] [F.] [ET AL, J MOLEC BIOL 215]: 403 (1990); Guide to Huge Computers, Martin J. Bishop, [Ed.] Academic Press, San Diego, 1994, and [CARILLO ETA / .](1988) SIAM J Applied Math 48: 1073). For example, BLAST or ClustalW from the National Database Center for Biotechnology Information can be used to determine homology, similarity, or identity.

[0048] Peptide homology, similarity, or identity can also be determined by comparing sequence information using the GAP computer program, e.g., Needleman et al. (1970), J Mol Biol. 48: 443, as known, e.g., in Smith and Waterman, Adv. Appl. Math (1981) 2: 482. Briefly, the GAP program defines homology as the number of similarly aligned symbols (i.e., amino acids) divided by the total number of symbols in the shorter of the two sequences. Default parameters for the GAP program may include: (1) a binary comparison matrix (containing a value of 1 for identity and 0 for non-identity) and the weighted comparison matrix of Gribskov et al. (1986) Nucl. Acids Res. 14:6745 (or the EDNAFULL (the EMBOSS version of NCBI NUC4.4) substitution matrix) as disclosed by Schwartz and Dayhoff, eds., Atlas of Protein Sequence and Structure, National Biomedical Research Foundation, pp. 353-358 (1979); 2) a penalty of 3.0 for each gap and an additional 0.10 penalty for each symbol in each gap (or a gap open penalty of 10 and a gap extension penalty of 0.5); and (3) no penalty for end gaps. Thus, as used herein, the terms "homology" or "identity" indicate the relatedness between sequences.

[0049] In one embodiment, a peptide comprising the amino acid sequence of general formula 1 according to one aspect can be produced by a combination of various methods for producing various peptides.

[0050] Depending on their length, peptides according to one embodiment can be synthesized by methods well known in the art, such as automated peptide synthesizers, or can be produced by genetic engineering techniques. Specifically, the peptides can be produced by standard synthetic methods, recombinant expression systems, or any other method known in the art. Thus, peptides according to one embodiment can be synthesized by a number of methods, including, but not limited to, the following: (a) synthesis of peptides by means of solid phase or liquid phase methods, either stepwise or by fragment assembly, followed by isolation and purification of the final peptide product; (b) expressing a nucleic acid construct encoding the peptide in a host cell and recovering the expression product from the host cell culture; (c) cell-free in vitro expression of a nucleic acid construct encoding the peptide and recovering the expression product; or A method of obtaining peptide fragments by any combination of (a), (b) and (c), then ligating the fragments to obtain a peptide, and recovering the peptide.

[0051] The peptides may be prepared by using L-amino acids, D-amino acids, and / or non-natural amino acids, and / or by modifying the natural sequence, such as by modifying the side chain functional group, intramolecular covalent bonding, ring formation between side chains, methylation, acylation, ubiquitination, phosphorylation, aminohexylation, biotinylation, etc. The modifications may also include substitution with non-natural compounds.

[0052] The amino acids substituted or added for the above modifications can be any of the 20 amino acids commonly found in human proteins, as well as any atypical or non-naturally occurring amino acids. Commercial sources of atypical amino acids include, but are not limited to, Sigma-Aldrich, ChemPep, and Genzyme Pharmaceuticals. For example, aminoisobutyric acid (Aib) can be prepared by Strecker amino acid synthesis from acetone, but is not limited thereto. Peptides and typical peptide sequences containing such atypical or non-naturally occurring amino acids can be synthesized and purchased through commercial peptide synthesizers, such as, but not limited to, American Peptide Company and Bachem in the United States, or Anygen in Korea.

[0053] Furthermore, the peptide may have an unmodified N-terminus and / or C-terminus, but the peptide may have an N-terminus and / or C-terminus that are chemically modified, organically protected, or modified by adding an amino acid to the peptide terminus to protect it from in vivo protease cleavage and increase its stability. When the C-terminus is unmodified, the peptide terminus has a free carboxylic acid, but is not particularly limited thereto.

[0054] In particular, in the case of chemically synthesized peptides, the N-terminus and C-terminus are charged, and therefore, to remove such charges, the N-terminus and / or C-terminus can be modified, for example, by acetylation of the N-terminus and / or amidation of the C-terminus, but is not particularly limited thereto.

[0055] In one embodiment, the peptide may have an unmodified or amidated C-terminus, but is not limited thereto.

[0056] The peptide includes the peptide itself, a salt thereof (eg, a pharmaceutically acceptable salt of the peptide), or a solvate form thereof.

[0057] The type of the salt is not particularly limited, provided that it is in a form that is safe and effective for individuals, for example, mammals, but is not particularly limited thereto.

[0058] Additionally, the peptide may be in any pharmaceutically acceptable form.

[0059] The term "pharmaceutically acceptable" means a sufficient amount to exhibit a therapeutic effect and not cause side effects, and can be easily determined by a person skilled in the art based on factors well known in the medical field, such as the type of disease, the patient's age, weight, health, and sex, the patient's sensitivity to the drug, the administration route, administration method, number of doses, treatment period, combination, or drugs used concomitantly.

[0060] In one embodiment, the peptide may be in the form of a pharmaceutically acceptable salt. The salts include conventional acid addition salts used in the pharmaceutical field, e.g., the field of inflammatory or autoimmune diseases, such as salts derived from inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, sulfamic acid, phosphoric acid, or nitric acid; and salts derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, citric acid, maleic acid, malonic acid, methanesulfonic acid, tartaric acid, malic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, oxalic acid, or trifluoroacetic acid. The salts may also be base addition salts, such as ammonium, dimethylamine, monomethylamine, monoethylamine, or diethylamine. The salts may also be conventional metal salts, such as salts derived from metals such as lithium, sodium, potassium, magnesium, or calcium. The acid addition salts, base addition salts, or metal salts may be prepared by conventional methods. Pharmaceutically acceptable salts and general methodologies for producing them are widely known in the relevant technical field, and reference can be made, for example, to P. Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use, 2nd Revised Edition (Wiley-VCH, 2011), and S. M. Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977.

[0061] For the condensation of protected amino acids or peptides, various activating reagents useful in peptide synthesis, particularly preferably trisphosphonium salts, tetramethyluronium salts, carbodiimides, etc., can be used. Examples of trisphosphonium salts include benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), bromotris(pyrrolidino)phosphonium hexafluorophosphate (PyBroP), and 7-azabenzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyAOP). Examples of tetramethyluronium salts include 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), and 7-azabenzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyAOP). Examples of carbodiimides include N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIPCDI), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI·HCl), and the like. For condensation using these, the addition of a racemization inhibitor (e.g., N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide (HONB), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HOOBt), ethyl 2-cyano-2-(hydroxyimino)acetate (Oxyma), etc.) is desirable. The solvent used in the condensation is appropriately selected from those known to be useful in peptide condensation reactions.For example, acid amides such as anhydrous N,N-dimethylformamide or aqueous N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone; halogenated hydrocarbons such as methylene chloride and chloroform; alcohols such as trifluoroethanol and phenol; sulfoxides such as dimethyl sulfoxide; tertiary amines such as pyridine; ethers such as dioxane and tetrahydrofuran; nitriles such as acetonitrile and propionitrile; esters such as methyl acetate and ethyl acetate; or appropriate mixtures thereof can be used. The reaction temperature is appropriately selected from the range known to be usable for peptide coupling reactions, usually from about −20° C. to 90° C. The activated amino acid derivative is usually used in a 1.5- to 6-fold excess. In solid-phase synthesis, if a test using the ninhydrin reaction indicates insufficient condensation, sufficient condensation can also be achieved by repeating the condensation reaction without removing the protecting group. If the condensation is still insufficient after repeated reactions, the unreacted amino acid can be acetylated with an acid anhydride, acetylimidazole, etc., to avoid any adverse effect on the subsequent reaction.

[0062] Examples of protecting groups for the amino group of the starting amino acid include benzyloxycarbonyl (Z), tert-butoxycarbonyl (Boc), tert-pentyloxycarbonyl, isobornyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl (Cl-Z), 2-bromobenzyloxycarbonyl (Br-Z), adamantyloxycarbonyl, trifluoroacetyl, phthaloyl, formyl, 2-nitrophenylsulfenyl, diphenylphosphinothioyl, 9-fluorenylmethyloxycarbonyl (Fmoc), trityl, and the like.

[0063] Examples of carboxyl protecting groups for the starting amino acids include the aforementioned C1-C6 alkyl groups, C3-C 10 Cycloalkyl groups, C7-C 14In addition to aralkyl groups, examples include aryl, 2-adamantyl, 4-nitrobenzyl, 4-methoxybenzyl, 4-chlorobenzyl, phenacyl, and benzyloxycarbonylhydrazide, tert-butoxycarbonylhydrazide, tritylhydrazide, and the like.

[0064] The hydroxyl group of serine or threonine can also be protected, for example, by esterification or etherification. Examples of groups suitable for esterification include lower (C2-C4) alkanoyl groups such as acetyl, aroyl groups such as benzoyl, and groups derived from organic acids. Examples of groups suitable for etherification include benzyl, tetrahydropyranyl, tert-butyl (But), trityl (Trt), and the like.

[0065] Examples of protecting groups for the phenolic hydroxyl group of tyrosine include Bzl, 2,6-dichlorobenzyl, 2-nitrobenzyl, Br-Z, tert-butyl, and the like.

[0066] Examples of protecting groups for the imidazole of histidine include p-toluenesulfonyl (Tos), 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), dinitrophenyl (DNP), benzyloxymethyl (Bom), tert-butoxymethyl (Bum), Boc, Trt, Fmoc, and the like.

[0067] Examples of protecting groups for the guanidino group of arginine include Tos, Z, 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), p-methoxybenzenesulfonyl (MBS), 2,2,5,7,8-pentamethylchroman-6-sulfonyl (Pmc), mesitylene-2-sulfonyl (Mts), 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), Boc, Z, NO, and the like.

[0068] Examples of protecting groups for the side chain amino group of lysine include Z, Cl-Z, trifluoroacetyl, Boc, Fmoc, Trt, Mtr, 4,4-dimethyl-2,6-dioxocyclohexylidenyl (Dde), and the like.

[0069] Examples of protecting groups for the indolyl of tryptophan include formyl (For), Z, Boc, Mts, Mtr, and the like.

[0070] Examples of protecting groups for asparagine and glutamine include Trt, xanthyl (Xan), 4,4'-dimethoxybenzhydryl (Mbh), 2,4,6-trimethoxybenzyl (Tmob), and the like.

[0071] Examples of activated carboxyl groups in the starting materials include the corresponding acid anhydrides, azides, active esters [esters with alcohols (e.g., pentachlorophenol, 2,4,5-trichlorophenol, 2,4-dinitrophenol, cyanomethyl alcohol, paranitrophenol, HONB, N-hydroxysuccinimide, 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt)], etc. Examples of activated amino groups in the starting materials include the corresponding ynamides.

[0072] Examples of methods for removing protecting groups include catalytic reduction in a hydrogen stream in the presence of a catalyst such as Pd-black or Pd-carbon; acid treatment using anhydrous fluorohydrogen, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid (TFA), trimethylsilyl bromide (TMSBr), trimethylsilyl trifluoromethanesulfonate, tetrafluoroboric acid, tris(trifluoro)boric acid, boron tribromide, or a mixture thereof; base treatment using diisopropylethylamine, triethylamine, piperidine, piperazine, or the like; and reduction with sodium in liquid ammonia. The removal reaction by acid treatment is generally carried out at a temperature of −20° C. to 40° C., and is efficiently carried out by adding a cation scavenger such as anisole, phenol, thioanisole, meta-cresol, and para-cresol; dimethyl sulfide, 1,4-butanedithiol, 1,2-ethanedithiol, or triisopropylsilane. In addition, the 2,4-dinitrophenyl group used as the imidazole protecting group for histidine can be removed by thiophenol treatment, and the pormyl group used as the indole protecting group for tryptophan can be removed by deprotection not only by acid treatment in the presence of 1,2-ethanedithiol, 1,4-butanedithiol, etc., but also by alkaline treatment with diluted sodium hydroxide, diluted ammonia, etc.

[0073] Protection of a functional group that should not be involved in the reaction between a starting material and a protecting group, removal of a protecting group, activation of a functional group that participates in the reaction, etc. can be appropriately selected from known protecting groups and known means.

[0074] For peptides referred to herein, the left end is the N-terminus (amino terminus) and the right end is the C-terminus (carboxyl terminus), in accordance with conventional peptide marking. The C-terminus of a peptide can be any one of amide (-CONH), carboxyl (-COOH), carboxylate (-COO-), alkylamide (-CONHR', where R' is alkyl), and ester (-COOR', where R' is alkyl or aryl).

[0075] In the method for producing peptide amides, they can be formed by solid-phase synthesis using a resin for amide synthesis, or by amidating the α-carboxyl group of the carboxy-terminal amino acid, elongating the peptide chain toward the amino group to the desired chain length, and then preparing a peptide in which the protecting group on the N-terminal α-amino group of the peptide chain alone has been removed, and a peptide in which only the protecting group on the C-terminal carboxyl group has been removed from the peptide chain alone. These two peptides are then condensed in the aforementioned mixed solvent. Details regarding the condensation reaction are as described above. After the protected peptide obtained by condensation is purified, all protecting groups are removed by the aforementioned method to obtain the desired peptide. The desired peptide amide can be produced by purifying the major fraction and purifying it using various publicly known means, such as lyophilization.

[0076] In one embodiment, the peptide may be in the form of a solvate thereof. "Solvate" refers to the peptide or its salt complexed with solvent molecules.

[0077] Another aspect provides polynucleotides encoding the GIP derivatives.

[0078] The GIP derivatives are as described above.

[0079] The polynucleotide may be an isolated polynucleotide.

[0080] The polynucleotides include DNA and RNA that encode target proteins.

[0081] The polynucleotide may be modified, including by adding, deleting, or making non-conservative or conservative substitutions of nucleotides.

[0082] The polynucleotide may be composed of a nucleotide sequence having 80% or more, 85% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more sequence identity with the sequence.

[0083] Another aspect provides a vector comprising the polynucleotide.

[0084] The term "vector" refers to a means for expressing a gene of interest in a host cell, and includes, for example, viral vectors such as plasmid vectors, cosmid vectors, bacteriophage vectors, adenovirus vectors, retrovirus vectors, and adeno-associated virus vectors. These vectors, which are also used as recombinant vectors, can be prepared by manipulating plasmids commonly used in the art (e.g., pSC101, pGV1106, pACYC177, ColE1, pKT230, pME290, pBR322, pUC8 / 9, pUC6, pBD9, pHC79, pIJ61, pLAFR1, pHV14, pGEX series, pET series, pUC19, and p426GPD), phages (e.g., λgt4λB, λ-Charon, λΔz1, and M13), or viruses (e.g., CMV and SV40), but are not limited thereto. Because plasmids are currently the most commonly used form of vector, the terms "plasmid" and "vector" are sometimes used interchangeably herein.

[0085] In the recombinant vector, the polynucleotide encoding the GIP derivative is also operably linked to a promoter. The term "operably linked" means that the polynucleotide sequence is functionally linked to a promoter sequence that initiates and mediates transcription of the polynucleotide encoding the target protein.

[0086] The recombinant vector is typically constructed as a vector for cloning or expression. The expression vector may be a vector commonly used in the art to express foreign proteins in plants, animals, or microorganisms. The recombinant vector may be constructed by various methods known in the art.

[0087] The recombinant vector can be constructed for either prokaryotic or eukaryotic host cells. For example, when the vector used is an expression vector and a prokaryotic host cell is used, it generally contains a strong promoter capable of driving transcription (e.g., pLλ promoter, trp promoter, lac promoter, tac promoter, T7 promoter, etc.), a ribosome binding site for initiating transcription, and a transcription / transcription termination sequence. When a eukaryotic host cell is used, the vector may contain an origin of replication that functions in eukaryotic cells, including, but not limited to, the f1 origin of replication, the SV40 origin of replication, the pMB1 origin of replication, the adenovirus origin of replication, the AAV origin of replication, the CMV origin of replication, and the BBV origin of replication. In addition, promoters derived from the genome of mammalian cells (e.g., metallothionine promoter) or promoters derived from mammalian viruses (e.g., adenovirus late promoter, vaccinia virus 7.5K promoter, SV40 promoter, cytomegalovirus (CMV) promoter, and HSV tk promoter) can be used, and generally have a polyadenylation sequence as a transcription termination sequence.

[0088] Another aspect provides a host cell comprising the polynucleotide or vector thereof.

[0089] The host cell may be an isolated cell.

[0090] Host cells that can be transformed with a recombinant vector typically have high DNA transfection and DNA expression efficiencies, including, but not limited to, well-known eukaryotic and prokaryotic hosts such as Escherichia coli, Pseudomonas, Bacillus, Streptomyces, fungi, and yeast, insect cells such as Spodoptera frugiperda (SF9), and animal cells such as CHO, COS1, COS7, BSC1, BSC40, and BMT10.

[0091] A polynucleotide or a recombinant vector containing the same can be inserted into a host cell by a method well known in the art, including, but not limited to, the calcium chloride (CaCl) method or electroporation when the host cell is a prokaryotic cell, or microinjection, calcium acetate precipitation, electroporation, liposome-mediated transfection, and gene bombardment when the host cell is a eukaryotic cell.

[0092] The polynucleotide may be introduced into a host cell in the form of an expression cassette, which is a genetic construct containing all elements necessary for autonomous expression. The expression cassette typically contains a promoter, a transcription termination signal, a ribosome binding site, and a translation termination signal operably linked to the polynucleotide. The expression cassette may be in the form of an expression vector capable of self-replicating. The polynucleotide may also be introduced into a host cell in its own form and operably linked to sequences necessary for expression in the host cell, but is not limited thereto.

[0093] Another embodiment provides a conjugate comprising the GIP derivative and a biocompatible substance that increases its in vivo half-life.

[0094] The GIP derivatives are as described above.

[0095] The biocompatible material is also mixed with a carrier.

[0096] The conjugate may be an isolated conjugate.

[0097] The conjugate exhibits activity against the GIP receptor that is equal to or greater than that of native GIP, and can exhibit an increased duration of efficacy compared to native GIP or a GIP derivative not conjugated to a carrier. Therefore, the conjugate can be a long-acting conjugate. The term "long-acting conjugate" refers to a conjugate that has an increased duration of efficacy compared to native GIP or a GIP derivative not conjugated to a biocompatible substance. Therefore, the conjugate can also be referred to as a "long-acting GIP derivative conjugate," "long-acting GIP derivative," or "long-acting GIP conjugate." Such conjugates include not only the above-mentioned forms, but also forms encapsulated in biodegradable nanoparticles, etc.

[0098] The conjugate may be non-naturally occurring.

[0099] The biocompatible substance may be bonded to the GIP derivative by a covalent or non-covalent chemical bond, or may be bonded to the GIP derivative by a linker (L) through a covalent or non-covalent chemical bond, or a combination thereof. One or more amino acid side chains in the GIP derivative may be conjugated to such a biocompatible substance to increase solubility and / or half-life and / or bioavailability in vivo. Such modifications may also reduce the clearance of therapeutic proteins and peptides. The biocompatible substance may be water-soluble (amphiphilic or hydrophilic), non-toxic, and / or pharmaceutically acceptable.

[0100] The biocompatible substance may be selected from the group consisting of high molecular weight polymers, fatty acids, cholesterol, albumin and fragments thereof, albumin-binding substances, polymers of repeating units of specific amino acid sequences, antibodies, antibody fragments, FcRn-binding substances, in vivo connective tissue, nucleotides, fibronectin, transferrin, saccharides, heparin, and elastin, but is not particularly limited thereto.

[0101] Examples of the polymer may include a polymer selected from the group consisting of polyethylene glycol (PEG), polypropylene glycol, ethylene glycol-propylene glycol copolymer, polyoxyethylated polyol, polyvinyl alcohol, polysaccharides, polyvinyl ethyl ether, biodegradable polymers, lipid polymers, chitin, hyaluronic acid, oligonucleotides, and combinations thereof, and the polysaccharide may include dextran, but is not particularly limited thereto.

[0102] The polyethylene glycol is a term that encompasses any of ethylene glycol homopolymers, PEG copolymers, and monomethyl-substituted PEG polymers (mPEG), but is not particularly limited thereto.

[0103] The fatty acid may be one that has a binding ability to albumin in vivo, but is not particularly limited thereto.

[0104] The biocompatible materials include, but are not limited to, polyamino acids such as polylysine, polyaspartic acid, and polyglutamic acid.

[0105] In the case of elastin, it may be a water-soluble precursor, human tropoelastin, or a polymer of a partial sequence or partial repeating unit thereof, such as an elastin-like polypeptide, but is not particularly limited thereto.

[0106] In one embodiment, the biocompatible substance may be an FcRn-binding substance. Specifically, the FcRn-binding substance may be an immunoglobulin Fc region, more specifically an IgG Fc region, and even more specifically an unglycosylated IgG4 Fc region, but is not particularly limited thereto.

[0107] The term "immunoglobulin Fc region" refers to a portion of an immunoglobulin that includes the heavy chain constant region 2 (CH2) and / or the heavy chain constant region 3 (CH3), excluding the heavy chain variable region and the light chain variable region. The immunoglobulin Fc region may be one component constituting a moiety of a conjugate according to one embodiment.

[0108] Such an immunoglobulin Fc region may include, but is not limited to, a hinge portion in a heavy chain constant region.

[0109] In one embodiment, the immunoglobulin Fc region may include a particular hinge sequence at the N-terminus.

[0110] The term "hinge sequence" refers to the site located in a heavy chain that forms a dimer of immunoglobulin Fc fragments via an inter disulfide bond.

[0111] In one embodiment, the hinge sequence may be a mutated hinge sequence having the following amino acid sequence, in which a portion is deleted and the hinge sequence has only one cysteine ​​residue, but is not limited thereto: Glu-Ser-Lys-Tyr-Gly-Pro-Pro-Cys-Pro-Ser-Cys-Pro (SEQ ID NO: 27).

[0112] The hinge sequence may be the hinge sequence of SEQ ID NO: 27, with the 8th or 11th cysteine ​​residue deleted and containing only one cysteine ​​residue. The hinge sequence according to one embodiment may be composed of 3 to 12 amino acids containing only one cysteine ​​residue, but is not limited thereto. More specifically, the hinge sequence according to one embodiment may have the following sequence: Glu-Ser-Lys-Tyr-Gly-Pro-Pro-Pro-Ser-Cys-Pro (SEQ ID NO: 28), Glu-Ser-Lys-Tyr-Gly-Pro-Pro-Cys-Pro-Ser-Pro (SEQ ID NO: 29), Glu-Ser-Lys-Tyr-Gly-Pro-Pro-Cys-Pro-Ser (SEQ ID NO: 30), G lu-Ser-Lys-Tyr-Gly-Pro-Pro-Cys-Pro-Pro (SEQ ID NO: 31), Lys-Tyr-Gly-Pro-Pro-Cys-Pro-Ser (SEQ ID NO: 32), Glu-Ser-Lys-Tyr-Gly-Pro-Pro-Cys (SEQ ID NO: 33), Glu-Lys-Tyr-Gly-Pro-Pro-Cys (SEQ ID NO: 34), Glu-Ser-Pro-Ser-Cys-Pro (SEQ ID NO: No. 35), Glu-Pro-Ser-Cys-Pro (SEQ ID NO: 36), Pro-Ser-Cys-Pro (SEQ ID NO: 37), Glu-Ser-Lys-Tyr-Gly-Pro-Pro-Ser-Cys-Pro (SEQ ID NO: 38), Lys-Tyr-Gly-Pro-Pro-Pro-Ser-Cys-Pro (SEQ ID NO: 39), Glu-Ser-Lys-Tyr-Gly-Pro-Ser-Cys-Pro (SEQ ID NO: 40) 0), Glu-Ser-Lys-Tyr-Gly-Pro-Pro-Cys (SEQ ID NO: 41), Lys-Tyr-Gly-Pro-Pro-Cys-Pro (SEQ ID NO: 42), Glu-Ser-Lys-Pro-Ser-Cys-Pro (SEQ ID NO: 43), Glu-Ser-Pro-Ser-Cys-Pro (SEQ ID NO: 44), Glu-Pro-Ser-Cys (SEQ ID NO: 45), Ser-Cys-Pro (SEQ ID NO: 46).

[0113] More specifically, the hinge sequence may comprise, but is not limited to, the amino acid sequence of SEQ ID NO: 37 (Pro-Ser-Cys-Pro) or SEQ ID NO: 46 (Ser-Cys-Pro).

[0114] The immunoglobulin Fc region according to one embodiment may be in the form of a dimer formed by two immunoglobulin Fc chain molecules due to the presence of a hinge sequence, and the conjugate of Chemical Formula 1 according to one embodiment may be in the form in which one end of the linker is linked to one chain of the dimeric immunoglobulin Fc region, but is not limited thereto.

[0115] The term "N-terminus" refers to the amino terminus of a protein or polypeptide and may include the extreme amino terminus, or up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acids from the extreme amino terminus. The immunoglobulin Fc fragment of the present invention may include, but is not limited to, a hinge sequence at the N-terminus.

[0116] Furthermore, the immunoglobulin Fc region may be an extended Fc region that excludes only the heavy chain variable region and light chain variable region of an immunoglobulin and includes a part or the entire heavy chain constant region 1 (CH1) and / or light chain constant region 1 (CL1), so long as it has an effect substantially equivalent to or improved from that of a native type. Alternatively, it may be a region in which a fairly long partial amino acid sequence corresponding to CH2 and / or CH3 has been deleted.

[0117] For example, the immunoglobulin Fc region may be selected from the group consisting of, but not limited to, (a) a CH1 domain, a CH2 domain, a CH3 domain, and a CH4 domain; (b) a CH1 domain and a CH2 domain; (c) a CH1 domain and a CH3 domain; (d) a CH2 domain and a CH3 domain; (e) a combination of one or more domains selected from the group consisting of a CH1 domain, a CH2 domain, a CH3 domain, and a CH4 domain, and an immunoglobulin hinge region or a portion of a hinge region; and (f) a dimer of each domain of a heavy chain constant region and a light chain constant region.

[0118] The immunoglobulin Fc region may also be in a dimeric form, and one molecule of a GIP derivative may be covalently linked to one Fc region of the dimeric form, and the immunoglobulin Fc and the GIP derivative may be linked to each other via a non-peptidic polymer. Alternatively, two molecules of a GIP derivative may be symmetrically linked to one Fc region of the dimeric form. In this case, the immunoglobulin Fc and the GIP derivative may also be linked to each other via a non-peptidic linker. However, the present invention is not limited to the above examples.

[0119] The immunoglobulin Fc region includes not only naturally occurring amino acid sequences but also sequence derivatives thereof, where one or more amino acid residues in the naturally occurring amino acid sequence are different due to deletion, insertion, non-conservative substitution, conservative substitution, or a combination thereof.

[0120] For example, in the case of IgG Fc, amino acid residues 214 to 238, 297 to 299, 318 to 322, or 327 to 331, which are known to be important for binding, are suitable sites for modification. Various types of derivatives are possible, such as removing sites capable of forming disulfide bonds, removing several amino acids at the N-terminus of native Fc, or adding a methionine residue to the N-terminus of native Fc. Furthermore, to eliminate effector functions, complement binding sites, such as C1q binding sites, and ADCC (antibody dependent cell-mediated cytotoxicity) sites may be removed. Techniques for producing such sequence derivatives of immunoglobulin Fc regions are disclosed in International Patent Publication Nos. WO 97 / 34631 and WO 96 / 32478, among others.

[0121] Amino acid exchanges in proteins and peptides that do not overall alter the activity of the molecule are known in the art (H. Neurath, R.L. Hill, "The Proteins," Academic Press, New York, 1979). The most commonly occurring exchanges are among amino acid residues Ala / Ser, Val / Ile, Asp / Glu, Thr / Ser, Ala / Gly, Ala / Thr, Ser / Asn, Ala / Val, Ser / Gly, Thy / Phe, Ala / Pro, Lys / Arg, Asp / Asn, Leu / Ile, Leu / Val, Ala / Glu, and Asp / Gly. In some cases, modifications are also made by phosphorylation, sulfation, acrylation, glycosylation, methylation, farnesylation, acetylation, and amidation.

[0122] The Fc derivatives described above may exhibit biological activity equivalent to that of the Fc region, and may have increased structural stability in terms of the sequence, pH, etc. of the Fc region.

[0123] Such Fc regions can also be obtained from natural forms isolated from the living bodies of animals such as humans, cows, goats, pigs, mice, rabbits, hamsters, rats, or guinea pigs, or from recombinant forms or derivatives thereof obtained from transformed animal cells or microorganisms. Here, methods for obtaining natural forms include isolating whole immunoglobulins from the living body of a human or animal and then treating them with protease. Treatment with papain results in cleavage from Fab and Fc, while treatment with pepsin results in cleavage from pF'c and F(ab)2. The Fc or pF'c can then be isolated using size-exclusion chromatography or other methods. In a more specific example, the Fc region is a recombinant immunoglobulin Fc region obtained from a microorganism.

[0124] Furthermore, the immunoglobulin Fc region may have native glycosylation, increased glycosylation compared to the native form, reduced glycosylation compared to the native form, or a form in which the glycosylation has been removed. Such increase, decrease, or removal of immunoglobulin Fc glycosylation can be achieved using common methods, such as chemical methods, enzymatic methods, and genetic engineering methods using microorganisms. Here, an immunoglobulin Fc region from which glycosylation has been removed from the Fc has significantly reduced complement (C1q) binding ability and reduced or eliminated antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity, and therefore does not induce unwanted immune responses in vivo. In this respect, a form more suited to the original purpose as a drug carrier can be said to be a form in which glycosylation has been removed or which has no glycosylation.

[0125] "Deglycosylation" refers to an Fc region that has had the glycosylation chains removed from the enzyme, and "aglycosylation" refers to an Fc region that is produced in a prokaryote, and more particularly in E. coli, and that is not glycosylated.

[0126] Furthermore, the immunoglobulin Fc region may be derived from IgG, IgA, IgD, IgE, or IgM, or a combination or hybrid thereof. In a more specific embodiment, it is derived from IgG or IgM, which are the most abundant in human blood, and in an even more specific embodiment, it is derived from IgG, which is known to improve the half-life of ligand-binding proteins. In an even more specific embodiment, the immunoglobulin Fc region is an IgG4 Fc region, and in the most specific embodiment, the immunoglobulin Fc region is a non-glycosylated Fc region derived from human IgG4, but is not limited thereto.

[0127] The term "combination" refers to the formation of a dimer or multimer in which a polypeptide encoding a single-chain immunoglobulin Fc region of the same origin is linked to a single-chain polypeptide of a different origin, i.e., a dimer or multimer can be produced from two or more fragments selected from the group consisting of IgGFc, IgAFc, IgMFc, IgDFc, and Fc fragments of IgE.

[0128] The GIP derivative can be linked to a biocompatible substance via a linker.

[0129] The linker can be a peptidic linker or a non-peptidic linker.

[0130] When the linker is a peptidic linker, it may contain one or more amino acids, for example, 1 to 1,000 amino acids, but is not limited thereto. The peptidic linker may contain Gly, Asn, and Ser residues, or neutral amino acids such as Thr and Ala. Various known peptidic linkers may be used to link the biocompatible substance and the GIP derivative. Furthermore, the copy number "n" may be adjusted to optimize the linker to achieve appropriate separation between functional moieties or maintain essential inter-moiety interactions. Other flexible linkers are known in the art, such as G linkers and S linkers, which contain polar amino acid residues to improve water solubility as well as amino acid residues such as T and A to maintain flexibility. Therefore, in one embodiment, the linker may be a flexible linker containing G, S, and / or T residues. The linker can have a general formula selected from (GpSs)n and (SpGs)n, where, independently, p is an integer from 1 to 10, s=0 or an integer from 0 to 10, p+s is an integer less than or equal to 20, and n is an integer from 1 to 20. More specifically, examples of the linker are (GGGGS)n, (SGGGG)n, (SRSSG)n, (SGSSC)n, (GKSSGSGSESKS)n, (RPPPPC)n, (SSPPPPC)n, (GSTSGSGKSSEGKG)n, (GSTSGSGKSSEGSGSTKG)n, (GSTSGSGKPGSGEGSTKG)n, or (EGKSSGSGSESKEF)n, where n is an integer from 1 to 20, or 1 to 10.

[0131] The "non-peptide linker" includes a biocompatible polymer having two or more repeating units linked together. The repeating units are linked to each other via any covalent bond other than a peptide bond. The non-peptide linker may be one component of the moiety of the conjugate.

[0132] The "non-peptide linker" can be used in combination with the "non-peptide polymer".

[0133] In one embodiment, the conjugate may be one in which the biocompatible substance and the GIP derivative are covalently linked to each other via a non-peptide linker containing reactive groups at both ends that can be bound to a biocompatible substance, specifically, an immunoglobulin Fc region and a GIP derivative.

[0134] Specifically, the non-peptide linker may be selected from the group consisting of fatty acids, saccharides, high molecular weight polymers, low molecular weight compounds, nucleotides, and combinations thereof.

[0135] In particular, the non-peptide linker may be selected from the group consisting of biodegradable polymers such as polyethylene glycol, polypropylene glycol, ethylene glycol-propylene glycol copolymer, polyoxyethylated polyol, polyvinyl alcohol, polysaccharides, polyvinyl ethyl ether, PLA (polylactic acid) and PLGA (polylactic-glycolic acid), lipid polymers, chitins, hyaluronic acid, oligonucleotides, and combinations thereof, although the polysaccharide may be, but is not limited to, dextran.

[0136] In a more specific embodiment, the non-peptidic polymer may be, but is not limited to, polyethylene glycol. Thus, the linker may contain ethylene glycol repeating units. Furthermore, derivatives thereof already known in the art and derivatives that can be easily prepared by those skilled in the art are also included within the scope of the present invention.

[0137] The non-peptidic linker may be any polymer that is resistant to in vivo protease degradation. The formula weight of the non-peptidic polymer may be, but is not limited to, 1 to 1,000 kDa, specifically 1 to 100 kDa, and more specifically 1 to 20 kDa. The non-peptidic linker may be a combination of different polymers, rather than a single polymer. In one embodiment, the formula weight of the ethylene glycol repeating unit moiety may be in the range of 1 to 100 kDa, more specifically 1 to 20 kDa.

[0138] In one embodiment, both ends of the non-peptide linker can be bound to a biocompatible substance, for example, an amine group or a thiol group of an immunoglobulin Fc region and an amine group or a thiol group of a GIP derivative, respectively.

[0139] Specifically, the non-peptidyl polymer may contain, at both ends, reactive groups that can be bonded to a biocompatible substance (e.g., an immunoglobulin Fc region) and a GIP derivative, respectively, specifically, reactive groups that can be bonded to an amine group located at the N-terminus or lysine of a GIP derivative or a biocompatible substance (e.g., an immunoglobulin Fc region), or a thiol group of cysteine, but are not limited thereto.

[0140] Furthermore, the reactive group of the nonpeptidic polymer, which can be bound to a biocompatible substance, such as an immunoglobulin Fc region or a GIP derivative, can be selected from the group consisting of an aldehyde group, a maleimide group, and a succinimide derivative, but is not limited thereto. In the above, examples of the aldehyde group include, but are not limited to, a propionaldehyde group or a butyraldehyde group. In the above, examples of the succinimide derivative include, but are not limited to, succinimidyl valerate, succinimidyl methyl butanoate, succinimidyl methyl propionate, succinimidyl butanoate, succinimidyl propionate, N-hydroxysuccinimide, hydroxysuccinimidyl, succinimidyl carboxymethyl, and succinimidyl carbonate.

[0141] Furthermore, the final product generated by reductive alkylation with an aldehyde bond is much more stable than that linked by an amide bond. The aldehyde reactive group selectively reacts with the N-terminus at low pH and can form covalent bonds with lysine residues at high pH, ​​e.g., pH 9.0.

[0142] Furthermore, the reactive groups at both ends of the nonpeptidic linker may be the same or different. For example, one end may have a maleimide group and the other end may have an aldehyde, propionaldehyde, or butyraldehyde group. However, the linker is not particularly limited as long as it can be used to bind a biocompatible substance, specifically, an immunoglobulin Fc region and a GIP derivative, to each end. For example, the nonpeptidic linker may have a maleimide group as a reactive group at one end and an aldehyde, propionaldehyde, or butyraldehyde group at the other end.

[0143] When polyethylene glycol having hydroxy reactive groups at both ends is used as the non-peptidic polymer, the hydroxy groups can be activated with the various reactive groups by known chemical reactions, or the long-acting conjugate can be produced by using commercially available polyethylene glycol having modified reactive groups.

[0144] In one embodiment, the non-peptidyl polymer may be linked to a cysteine ​​residue of the GIP derivative, more specifically, to the -SH group of cysteine, but is not limited thereto.

[0145] When maleimide-PEG-aldehyde is used, the maleimide group is linked to the -SH of the GIP derivative via a thioether bond, and the aldehyde group is linked to the biocompatible substance, specifically, the -NH2 of immunoglobulin Fc, via a reductive alkylation reaction, but this is one example and is not limited thereto.

[0146] In addition, in the conjugate, the reactive group of the non-peptidic polymer is -NH2 located at the N-terminus of the immunoglobulin Fc region. と It may be concatenated, but that is just one example.

[0147] Thus, the conjugate according to one embodiment can be represented by the following Chemical Formula 1:

[0148] [ka]

[0149] In this case, X is a GIP derivative, L is a linker, F is a biocompatible substance that increases the in vivo half-life of X; - indicates a bond between X and L, and a bond between L and F.

[0150] In Chemical Formula 1, the GIP derivative, linker, and biocompatible substance are as described above.

[0151] In the above formula 1, L can also be La, where a is 0 or a natural number, provided that when a is 2 or more, each L is independent of the others.

[0152] Specifically, the linker may be polyethylene glycol (PEG) represented by the following formula 2, but is not limited thereto:

[0153] [ka]

[0154] Here, n=10 to 2,400, n=10 to 480, or n=50 to 250, but is not limited thereto.

[0155] In the long-acting conjugate, the PEG moiety is -(CH2CH2O) n -Not only the structure, but also the linking elements and their -(CH2CH2O) n It may also contain an oxygen atom between -, but is not limited to this.

[0156] The polyethylene glycol is a term that encompasses any of ethylene glycol homopolymers, PEG copolymers, and monomethyl-substituted PEG polymers (mPEG), but is not particularly limited thereto.

[0157] In one embodiment, the - can represent a covalent bond between X and L, or a covalent bond between L and F.

[0158] The conjugate has been shown to reduce the expression levels of inflammation-related genes IL-1β, IL-6, IL-12, IFN-γ, and TNF-α both in vitro and in vivo, and is therefore also useful for the prevention or treatment of inflammatory diseases or autoimmune diseases.

[0159] The GIP derivative or its conjugate was confirmed to reduce the expression of inflammation-related genes in THP-1 cells, a monocyte / macrophage cell line. Macrophages are known to secrete cytokines and chemokines in vasculitis-infected tissues at the early stage of infection, recruit other immune cells, induce inflammatory progression, and form giant cells. The GIP derivative or its conjugate was also confirmed to reduce the expression of inflammation-related genes in the aorta of high-fat diet-induced obese mice. In a vasculitis disease model, the GIP derivative or its conjugate was also confirmed to reduce the expression of MMP-2 and MMP-9, vascular remodeling factors that play an important role in the progression of vasculitis. The GIP derivative or its conjugate was also confirmed to reduce the expression of inflammation-related genes (e.g., IL-6 and TNF-α) in angiotensin II-injected mice. Therefore, the GIP derivative or its conjugate can be used for the prevention or treatment of vasculitis.

[0160] The GIP derivative or its conjugate can exhibit the effect of preventing or treating vasculitis by any one of the following: (i) reducing or suppressing the expression of inflammation-related genes in macrophages (the inflammation-related genes are one or more selected from IL-1β, IL-6, IL-12, IFN-γ, and TNF-α); (ii) reducing or suppressing the expression of inflammation-related genes in blood vessels (the inflammation-related genes are one or more selected from MCP-1, IL-1α, IL-1β, IL-6, IFN-γ, and TNF-α); and (iii) The expression of angiogenesis factors is reduced or inhibited in blood vessels (the angiogenesis factors are one or more selected from MMP-2 and MMP-9).

[0161] Another embodiment provides a pharmaceutical composition for preventing or treating an inflammatory disease or an autoimmune disease, comprising the GIP derivative, a pharmaceutically acceptable salt thereof or a solvate thereof, or the conjugate.

[0162] The GIP derivative, its pharmaceutically acceptable salt or solvate thereof, or the conjugate thereof are as described above.

[0163] The term "prevention" refers to any action that inhibits or delays the onset of an inflammatory or autoimmune disease by administering the composition.

[0164] The term "treatment" refers to any action in which the administration of the composition ameliorates or otherwise renders desirable the symptoms of an inflammatory or autoimmune disease.

[0165] The term "inflammatory disease or autoimmune disease" refers to a disease caused by, resulting from, or inducing inflammation, or the presence of an autoimmune response (an immune response acting against a self-antigen or an autoantigen) in an individual. Autoimmune diseases include diseases caused by a breakdown of self-tolerance, in which the adaptive immune system reacts to self-antigens and mediates cell and tissue damage. Specifically, the inflammatory disease or autoimmune disease includes, but is not limited to, inflammatory diseases or autoimmune diseases in specific body sites, such as blood vessels, oral cavity, mucous membranes, gastrointestinal tract, pancreas, skin, eyes, pharynx, tonsils, ears, bones, joints, cartilage, brain, spinal cord, nerves, bone marrow, bladder, liver, muscles, thyroid, bile duct, kidneys, etc.; and systemic inflammatory diseases or autoimmune diseases.

[0166] In one embodiment, the inflammatory disease or the autoimmune disease is vasculitis, rheumatoid arthritis, Sjogren's syndrome, neuromyelitis optica (NMO), idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), autoimmune thrombocytopenia, psoriasis, IgA nephropathy, IgM polyneuropathies, myasthenia gravis, diabetes mellitus, Raynaud's syndrome, or The present invention may be any one selected from the group consisting of, but not limited to, glomerulonephritis (Glomerulonephritis) and glaucoma (Glomerulonephritis).

[0167] In one embodiment, the inflammatory disease or the autoimmune disease can be vasculitis. The vasculitis can also be classified according to the size of the affected blood vessels. The vasculitis can be large-vessel vasculitis, medium-vessel vasculitis, or small-vessel vasculitis. The vasculitis can also be classified as vasculitis involving large arteries, including the aorta and major branches, medium-sized arteries, small and medium-sized arteries, small arteries, or arteries and veins of various sizes.

[0168] In one embodiment, the vasculitis may be selected from the group consisting of, but not limited to: (1) Vasculitis involving large arteries, including giant cell arteritis (GCA), Takayasu's arteritis (TA), aortitis in Cogan's syndrome, aortitis in spondylarthropathies, and isolated aortitis; (2) Vasculitis involving medium-sized arteries, including Kawasaki disease and polyarteritis nodosa (PAN); (3) Vasculitides involving small and medium-sized arteries, including antineutrophil cytoplasmic antibody-associated vasculitis (ANCA), granulomatosis with polyangiitis (GPA) (formerly Wegener's granulomatosis (WG)), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA) (also known as Churg-Strauss syndrome), and primary angiitis of the central nervous system; and (4) Vasculitis involving small arteries, including IgA vasculitis (also known as Henoch-Schonlein purpura), vasculitis related to rheumatoid arthritis, systemic lupus erythematosus, and Sjogren's syndrome, cryoglobulinemic vasculitis, and drug-induced vasculitis.

[0169] The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, dyes, and flavorings for oral administration, buffers, preservatives, soothing agents, solubilizers, isotonicity agents, and stabilizers for injections, and bases, excipients, lubricants, and preservatives for topical administration.

[0170] In one embodiment, the pharmaceutical composition may further comprise a pharmaceutically acceptable excipient.

[0171] The pharmaceutical composition may be formulated into various dosage forms by mixing with the aforementioned pharmaceutically acceptable carriers. For example, for oral administration, it may be formulated into tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and for injections, it may be formulated into unit-dose ampoules or multiple-dose forms. It may also be formulated into solutions, suspensions, tablets, pills, capsules, sustained-release formulations, etc.

[0172] On the other hand, examples of carriers, excipients, and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia, alginate, gelatin, calcium acetate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil, etc. Furthermore, fillers, anticoagulants, lubricants, wetting agents, flavorings, emulsifiers, and preservatives may be further included.

[0173] The pharmaceutical composition may further comprise one or more other agents for treating inflammatory or autoimmune diseases. Specifically, the other agents may be, but are not limited to, anti-inflammatory agents or immunosuppressants. More specifically, the other agents may be, but are not limited to, agents for treating vasculitis.

[0174] "Anti-inflammatory agent" refers to a compound for the treatment of inflammatory diseases or conditions associated therewith. Non-limiting examples of the anti-inflammatory agent include nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen, naproxen, methyl salicylate, diflunisal, indomethacin, sulindac, diclofenac, ketoprofen, ketorolac, carprofen, fenoprofen, mefenamic acid, piroxicam, meloxicam, methotrexate, celecoxib, valdecoxib, parecoxib, etoricoxib, and nimesulide), corticosteroids (e.g., prednisone, betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, triamcinolone, and fluticasone), rapamycin (e.g., see Migita et al., Clin. Exp. Immunol. (1997) 108: 199-203); [Migita et al., Clin. Exp. Immunol. (1996) 104: 86-91]; [Foroncewicz et al., Transpl. Int. (2005) 18: 366-368]), high-density lipoprotein (HDL) and HDL cholesterol-raising compounds (e.g., see references [Birjmohun et al. (2007) Arterioscler. Thromb. Vasc. Biol., 27: 1153-1158]; [Nieland et al. (2007) J. Lipid Res., 48: 1832-1845]; the use of rosiglitazone as an anti-inflammatory agent has been disclosed [Bloedon et al. (2008) J. Lipid Res., Samaha et al. (2006) Arterioscler. Thromb. Vasc. Biol., 26: [Hu, E. (2006) Rec. Patents Cardiovasc. Drug Discov., 1:2 49-263), antimalarials (e.g., hydroxychloroquine and chloroquine), acetaminophen, glucocorticoids, steroids, beta-agonists, anticholinergics, methylxanthines, gold injections (e.g., gold sodium thiomalate), sulfasalazine, penicillamine, antiangiogenic agents, dapsone, psoralens, antivirals, statins (e.g., see Paraskevas et al. (2007) Curr. Pharm. Des., 13: 3622-36; Paraskevas, KI (2008) Clin. Rheumatol. 27: 281-287), and antibiotics (e.g., tetracycline). In certain embodiments, the anti-inflammatory agent is a statin or a high-density lipoprotein (HDL) and HDL cholesterol-raising compound.

[0175] "Immunosuppressant agent" and "immunosuppressant formulation" include compounds or compositions that suppress immune responses or conditions associated therewith. Non-limiting examples of such immunosuppressants include purine analogs (e.g., azathioprine), methotrexate, cyclosporine (e.g., cyclosporine A), cyclophosphamide, leflunomide, mycophenolate (mycophenolate mofetil), steroids (e.g., glucocorticoids, corticosteroids), methylprednisolone, prednisone, nonsteroidal anti-inflammatory drugs (NSAIDs), chloroquine, hydroxychloroquine, chlorambucil, CD20 antagonists (e.g., rituximab, ocrelizumab, veltuzumab, or ofatumumab), abatacept, TNF antagonists (e.g., infliximab, adalimumab, etanercept), macrolides (e.g., pimecrolimus, tacrolimus (FK506), and sirolimus), dehydroepiandrosterone, lenalidomide, CD40 antagonists (e.g., anti-CD40L antibodies), avetimus sodium, BLys antagonists (e.g., anti-BLyS (e.g., belimumab)), dactinomycin, bucillamine, penicillamine, leflunomide, mercaptopurine, pyrimidine analogs (e.g., cytosine arabinoside), mizoribine, alkylating agents (e.g., nitrogen mustard, phenylalanine mustard, busulfan, and cyclophosphamide), folate antagonists (e.g., aminopterin and methotrexate), antibiotics (e.g., rapamycin, actinomycin D, mitomycin C, furamycin, and chloramphenicol), human IgG, antilymphocyte globulin (ALG), antibodies (e.g., anti-CD3 (OKT3), anti-CD4 (OKT4), anti-CD5, anti-CD7, anti-IL-2 receptor (e.g., daclizumab and basiliximab), anti-α / β Antibodies against TCR, anti-ICAM-1, muromonab-CD3, anti-IL-12, alemtuzumab, and immunotoxins), 1-methyltryptophan, and derivatives and analogs thereof. In certain embodiments, the immunosuppressant is selected from the group consisting of methotrexate, hydroxychloroquine, CD20 antagonists (e.g., rituximab, ocrelizumab, veltuzumab, or ofatumumab), abatacept, TNF antagonists (e.g., infliximab, adalimumab, etanercept), sirolimus, and BLyS antagonists (e.g., anti-BLyS (e.g., belimumab)).

[0176] The term "therapeutic agent for vasculitis" includes compounds or compositions that suppress or treat symptoms associated with vasculitis. Known substances can be used as the therapeutic agent for vasculitis.

[0177] The dosage and frequency of the pharmaceutical composition are determined depending on the type of active ingredient, as well as various related factors such as the disease to be treated, the administration route, the age, sex and weight of the patient, and the severity of the disease.

[0178] The pharmaceutical composition has excellent in vivo durability and potency, and therefore the number and frequency of administration can be significantly reduced.

[0179] Another embodiment provides a method for preventing or treating an inflammatory disease or an autoimmune disease, comprising administering an effective amount of the GIP derivative, a pharmaceutically acceptable salt thereof, a solvate thereof, or the conjugate or the pharmaceutical composition to an individual in need thereof.

[0180] The GIP derivative, its pharmaceutically acceptable salt, its solvate, the conjugate, the pharmaceutical composition, and the inflammatory disease or autoimmune disease are as described above.

[0181] The term "effective amount" or "pharmaceutically effective amount" refers to the amount or dose of the GIP derivative, its pharmaceutically acceptable salt, solvate, or conjugate thereof that, when administered to a patient in single or multiple doses, provides the desired effect in a patient under diagnostic or therapeutic conditions. The effective amount can be readily determined by the attending physician, as a person skilled in the relevant art, through the use of known techniques and by observing results obtained under analogous circumstances. When determining the effective amount for a patient, numerous factors are taken into consideration by the attending physician, including, but not limited to, the mammalian species; its size, age, and general health; the specific disease or disorder involved; the relative extent or severity of the disease or disorder; the response of the individual patient; the specific compound administered; the mode of administration; the bioavailability characteristics of the administered formulation; the selected dosing regimen; the use of concurrent drug treatments; and other relevant circumstances.

[0182] "Individual" means a subject in need of treatment for a disease, and more specifically means a mammal, such as a human or non-human primate, mouse, rat, dog, cat, horse, or cow.

[0183] "Administration" refers to the introduction of a substance into a patient by any suitable method. The route of administration can be any common route that can reach the target in the patient's body. The administration can be, for example, but is not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, or rectal administration.

[0184] The administration may be 0.0001 mg to 1,000 mg of a composition according to one embodiment per individual, for example, 0.1 mg to 1,000 mg, 0.1 mg to 500 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 1 mg to 1,000 mg, 1 mg to 500 mg, 1 mg to 100 mg, 1 mg to 50 mg, or 1 mg to 25 mg. However, the dosage may vary depending on factors such as formulation method, administration mode, age, weight, sex, and pathological condition of the patient, diet, administration time, administration route, excretion rate, and reaction sensitivity, and those skilled in the art would be able to appropriately adjust the dosage taking such factors into consideration. The administration frequency can be once a day or two or more times a day within the range of clinically acceptable side effects. The administration site can be one or more sites, daily or every two to five days, with the total number of days of administration being one to 30 days per treatment. If necessary, the same treatment can be repeated after an appropriate period. For non-human animals, the same dose per kg as for humans can be administered, or the dose can be calculated by converting the aforementioned dose based on, for example, the organ (e.g., heart) volume ratio (e.g., average value) between the target animal and humans.

[0185] In the method, an effective amount of the GIP derivative, its pharmaceutically acceptable salt, solvate, or conjugate thereof can be administered simultaneously, separately, or sequentially with an effective amount of one or more other active ingredients, which may be, but are not limited to, one or more other preparations for treating inflammatory diseases or autoimmune diseases.

[0186] Another aspect provides the use of the GIP derivative, a pharmaceutically acceptable salt thereof, a solvate thereof, or the conjugate thereof for the manufacture of a medicament for the prevention or treatment of an inflammatory disease or an autoimmune disease.

[0187] The GIP derivative, its pharmaceutically acceptable salt, its solvate, the conjugate, and the inflammatory disease or autoimmune disease are as described above.

[0188] Each description and example disclosed in this application also applies to each other description and example. In other words, all combinations of the various elements disclosed in this application fall within the scope of the present invention. In addition, the following specific descriptions should not be construed as limiting the scope of the present invention. [Effects of the Invention]

[0189] The GIP derivative or its long-acting conjugate according to one embodiment has the effect of reducing the expression level of inflammation-related factors and reducing the expression level of vascular remodeling factors in a vasculitis disease model, and can therefore be used for the prevention or treatment of vasculitis caused by inflammatory or autoimmune reactions. [Brief explanation of the drawings]

[0190] [Figure 1] FIG. 1 shows the results of SDS-PAGE analysis of GIP derivative (SEQ ID NOs: 11, 17, 21, and 24)-PEG-immunoglobulin Fc region conjugates prepared. [Figure 2] Graph (A) shows the relative expression levels of inflammation-related genes IL-6, IL-12, IL-1β, and TNF-α after treatment with native GIP or a long-acting GIP conjugate, and graph (B) shows the concentration of the inflammation-related cytokine TNF-α after treatment with native GIP or a long-acting GIP conjugate. [Figure 3] 1 is a graph showing the relative expression levels of inflammation-related genes IL-1α, IL-1β, IL-6, IFN-γ, and TNF-α after administration of a control group or a long-acting GIP conjugate to mice. [Figure 4]Graph (A) shows the relative expression levels of inflammation-related genes MCP-1, IL-1β, IL-6, and TNF-α in the renal arteries of normal mouse control group, disease model (MRL / lpr) mouse control group, abatacept-treated group, and long-acting GIP conjugate-treated group. Graph (B) shows the relative expression levels of MMP-2 and MMP-9, which are known as vascular remodeling factors, in the renal arteries of normal mouse control group, disease model (MRL / lpr) mouse control group, abatacept-treated group, and long-acting GIP conjugate-treated group. [Figure 5] Graph (A) shows the relative expression levels of the IL-6 gene and the TNF-α gene in the aortic arch of a normal mouse control group, a disease model control group (Ang II-administered control group), and a test group (long-acting GIP conjugate 3.163 mg / kg). Graph (B) shows the relative expression levels of the IL-6 gene and the TNF-α gene in the abdominal aorta of a normal mouse control group, a disease model control group (Ang II-administered control group), and a test group (long-acting GIP conjugate 3.163 mg / kg). DETAILED DESCRIPTION OF THE INVENTION

[0191] The present invention will be described in more detail below through examples. However, these examples are for illustrative purposes only and the scope of the present invention is not limited by these examples.

[0192] Example 1: Preparation of GIP derivatives active against GIP receptors GIP derivatives that exhibit activity at the human GIP receptor were prepared, and their sequences are shown in Table 1 below.

[0193] [Table 1-1]

[0194] [Table 1-2]

[0195] In the sequences shown in Table 1, the amino acid represented by Aib is the unnatural amino acid Aib (aminoisobutyric acid). The GIP derivative peptide is used as a GIP derivative with an amidated C-terminus, if necessary.

[0196] Example 2: In vitro activity measurement of GIP derivatives To measure the activity of the GIP derivatives prepared in Example 1, a method for measuring cell activity in vitro was used using cell lines transformed with the GIP receptor. The lines were CHO (Chinese hamster ovary) transformed to express the human GIP receptor gene, and are suitable for measuring GIP activity.

[0197] To measure the activity of the GIP derivative prepared in Example 1 at the human GIP receptor, human GIP was serially diluted from 16 nM to 0.000015 nM in 4-fold increments, and the GIP derivative prepared in Example 1 was serially diluted from 16 nM to 0.000015 nM in 4-fold increments. The culture medium was removed from the cultured CHO cells expressing the human GIP receptor, and 5 μl of each serially diluted substance was added to the cells. Then, 5 μl of a buffer containing a cAMP antibody was added and the cells were incubated at room temperature for 15 minutes. Then, 10 μl of a detection mix containing a cell lysis buffer was added to the cells to lyse them, and the cells were incubated at room temperature for 90 minutes. The cell lysates after the reaction were applied to a LANCE cAMP kit (PerkinElmer, USA) to measure the EC2 activity via the accumulated cAMP. 50 The values ​​were calculated and then compared with each other.

[0198] The relative potencies at the human GIP receptor compared to human GIP are shown in Table 2 below.

[0199] [Table 2-1]

[0200] [Table 2-2]

[0201] Example 3: Preparation of long-acting GIP conjugate Long-acting conjugates were prepared containing the GIP derivatives prepared in Example 1. Specifically, the GIP derivatives of SEQ ID NOs: 11, 17, 21, and 24 were each linked to the immunoglobulin Fc region via PEG, a non-peptidic polymer.

[0202] The specific process for preparing long-acting conjugates is as follows. The same process was repeated to prepare GIP derivative conjugates of SEQ ID NOs: 11, 17, 21, and 24. To pegylate the N-terminus of the immunoglobulin Fc region, the immunoglobulin Fc region was reacted with MAL-10K PEG-ALD (10 kD aPEG (NOF, Japan) containing a maleimide group and a propionaldehyde group) at a molar ratio of 1:1-2, a total protein concentration of 40-60 mg / ml, pH 6.0-6.5, and 4-8°C for approximately 3-4 hours. Sodium cyanoborohydride (NaCNBH) was added as a reducing agent during the reaction, and the reaction mixture was passed through a CaptoQ ImpRes (GE Healthcare Life Science, USA) column to purify the monopegylated immunoglobulin Fc region.

[0203] To conjugate the purified mono-pegylated immunoglobulin Fc region with the GIP derivative, the mono-pegylated immunoglobulin Fc region and the GIP derivative (SEQ ID NOs: 11, 17, 21, and 24) were reacted in a buffer containing isopropanol at a molar ratio of 1:1 to 3, with a total protein concentration of 0.1 to 0.5 mg / ml, for approximately 14 to 18 hours at 4 to 8°C. The reaction mixture was purified using a Source 15ISO (GE Healthcare Life Science, USA) column, where the GIP derivatives (SEQ ID NOs: 11, 17, 21, and 24) were covalently linked to the immunoglobulin Fc region via PEG.

[0204] As a result, it was confirmed that the purified GIP derivative-PEG-immunoglobulin Fc region conjugate of SEQ ID NO: 11, the purified GIP derivative-PEG-immunoglobulin Fc region conjugate of SEQ ID NO: 17, the purified GIP derivative-PEG-immunoglobulin Fc region conjugate of SEQ ID NO: 21, and the purified GIP derivative-PEG-immunoglobulin Fc region conjugate of SEQ ID NO: 24 were produced with high purities of 90% or more, and the SDS-PAGE analysis results are shown in Figure 1.

[0205] Example 4: In vitro activity measurement of long-acting GIP conjugate To measure the activity of the long-acting GIP conjugate prepared in Example 3, the same method as in Example 2 was used to measure the cell activity in vitro using a cell line transfected with the GIP receptor.

[0206] Specifically, to measure the activity of the long-acting GIP conjugate at the human GIP receptor, human GIP was serially diluted from 16 nM to 0.000015 nM in 4-fold increments, and the long-acting GIP conjugate was serially diluted from 50 nM to 0.000048 nM in 4-fold increments. The culture medium was removed from the cultured CHO cells expressing the human GIP receptor, and 5 μl of each serially diluted substance was added to the cells. Then, 5 μl of a buffer containing a cAMP antibody was added and the cells were incubated at room temperature for 15 minutes. Then, 10 μl of a detection mix containing a cell lysis buffer was added to the cells to lyse them, and the cells were incubated at room temperature for 90 minutes. The cell lysate after the reaction was then applied to a LANCE cAMP kit (PerkinElmer, USA) to measure the EC2 activity via the accumulated cAMP. 50 The values ​​were calculated and then compared with each other.

[0207] The relative potency at the human GIP receptor compared to human GIP is shown in Table 3 below.

[0208] [Table 3]

[0209] The above examples demonstrate that the GIP derivatives of the present invention retain the activity of native GIP, and in particular, when prepared as long-acting conjugates, they exhibit activity equivalent to or even higher than that of native GIP while having an increased half-life, making them excellent drugs.

[0210] Example 5: Confirmation of anti-inflammatory in vitro efficacy of long-acting GIP conjugate To confirm the anti-inflammatory efficacy of the long-acting GIP derivative conjugate against vasculitis in vitro, we used the THP-1 cell line, a human monocyte / macrophage cell line. Macrophages are known to secrete cytokines and chemokines in the early stages of vasculitis-infected tissues, recruit other immune cells, induce the progression of inflammation, and form giant cells. Therefore, investigating the anti-inflammatory effect in macrophages is an appropriate in vitro system for evaluating the efficacy against vasculitis.

[0211] THP-1 cells were cultured at 37°C and 5% CO2 in RPMI 1640 medium supplemented with 10% FBS (fetal bovine serum), 100 μg / mL streptomycin, 100 U / mL penicillin, and 0.05 μM β-mercaptoethanol. Lipid polysaccharide (LPS) was added to the cells at 1 μg / mL to induce an inflammatory response. The effects of treatment with native GIP and long-acting GIP derivatives on the LPS-induced inflammatory response were examined. Native GIP was diluted to 10 μM, and the long-acting GIP derivatives were diluted to 1 or 10 μM. The long-acting GIP conjugate (SEQ ID NO: 17) prepared in Example 3 was used as the long-acting GIP derivative.

[0212] After the treatment, RNA was isolated from the THP-1 cell line using the RNeasy Mini Kit (Qiagen, USA), and cDNA was synthesized using the iScript® cDNA Synthesis Kit (Bio-Rad, USA). The synthesized cDNA was analyzed using the QuantStudio 6 Flex Real-Time PCR System (Applied Biosystems, USA). The expression levels of inflammation-related genes were analyzed using the Delta Delta Ct method, with β-actin as the housekeeping gene. The inflammation-related genes analyzed were IL-6, IL-12, IL-1β, and TNF-α.

[0213] FIG. 2(A) is a graph showing the relative expression levels of inflammation-related genes IL-6, IL-12, IL-1β, and TNF-α after treatment with native GIP or a long-acting GIP derivative.

[0214] As shown in Figure 2(A), LPS treatment induced an inflammatory response, increasing the expression of the inflammation-related genes. Treatment with native GIP and the long-acting GIP derivative further reduced these genes. These results confirmed that the long-acting GIP derivative conjugates were expressed in a concentration-dependent manner.

[0215] Furthermore, to measure the concentration of the inflammation-related cytokine TNF-α in the culture medium of THP-1 cells, cells were treated with 0.1 μg / mL LPS to induce an inflammatory response, and native GIP was diluted to 1 μM, and the long-acting GIP derivative was diluted to 0.1 or 1 μM. The culture medium was quantified using a Human TNF alpha ELISA Kit (Abcam, USA).

[0216] FIG. 2(B) is a graph showing the concentration (ng / mL) of the inflammation-related cytokine TNF-α after treatment with native GIP or a long-acting GIP conjugate.

[0217] As shown in Figure 2(B), the TNF-α concentration in the medium was confirmed to increase upon treatment with LPS, and further decreased upon treatment with native GIP and the long-acting GIP conjugate.

[0218] Therefore, we were able to confirm that the long-acting GIP conjugate acts directly on macrophages and exhibits anti-inflammatory activity that prevents LPS-induced inflammatory responses. Based on the results for native GIP, we can infer that the anti-inflammatory effect is due to the action of GIP.

[0219] Example 6: Confirmation of anti-inflammatory in vivo efficacy of long-acting GIP conjugate Similar to the in vitro efficacy confirmed in the previous examples, high-fat diet-induced obese mice were used to confirm the anti-inflammatory efficacy of the long-acting GIP derivative in vivo. The mice weighed approximately 40-60 g before administration. During the study period, the mice were housed in groups and allowed free access to water. Light was turned off from 6 AM to 6 PM.

[0220] The control group received vehicle, and the test group received 11.7 nmol / kg of the long-acting GIP conjugate. Administration was every two days, and the experiment was terminated on day 28. The long-acting GIP conjugate (SEQ ID NO: 17) prepared in Example 3 was used. After the experiment, the aorta was removed via autopsy, and RNA was extracted. RNA was extracted using an RNeasy Mini Kit (Qiagen, USA), and cDNA was synthesized using an iScript® cDNA Synthesis Kit (Bio-Rad, USA). The synthesized cDNA was used to examine the expression levels of inflammation-related genes using a QuantStudio 6 Flex Real-Time PCR System (Applied Biosystems, USA), and the differences between the control and test groups were compared.

[0221] FIG. 3 is a graph showing the relative expression levels of inflammation-related genes IL-1α, IL-1β, IL-6, IFN-γ, and TNF-α after administration of a control group or a long-acting GIP conjugate to mice.

[0222] As shown in Figure 3, the expression levels of inflammation-related genes were measured, and it was confirmed that the expression levels of all inflammation-related genes were significantly reduced in the group administered with the long-acting GIP conjugate compared to the control group. Therefore, it was found that the long-acting GIP conjugate has an excellent anti-inflammatory effect.

[0223] <Example 7: Confirmation of efficacy of long-acting GIP conjugate in vasculitis disease model> To confirm the efficacy of the long-acting GIP conjugate against vasculitis in a disease model, MRL / lpr mice were used. It is known that vasculitis is observed in large blood vessels, including the aorta and major branches, caused by systemic inflammation in these mice (Arthritis Rheum. 2003 May; 48(5): 1445-51). Therefore, MRL / lpr mice were selected as a vasculitis disease model.

[0224] The study included a normal mouse control group administered with the vehicle and a disease model control group. The control group received abatacept (Orencia injection) at 5.7 mg / kg, which was used as a commercial control drug, and test groups received the long-acting GIP conjugate at 0.12, 1.05, or 3.16 mg / kg. The vehicle and drug were administered every two days, and the experiment was terminated at week 10. The long-acting GIP conjugate used was the long-acting GIP conjugate (SEQ ID NO: 17) prepared in Example 3.

[0225] Figure 4(A) is a graph showing the relative expression levels of inflammation-related genes MCP-1, IL-1β, IL-6, and TNF-α in the renal arteries of normal mouse control groups, disease model (MRL / lpr) mouse control groups, abatacept-treated groups, and long-acting GIP conjugate-treated groups.

[0226] As shown in Figure 4(A), the expression levels of inflammation-related genes were measured, and it was confirmed that the expression of all inflammation-related genes was significantly reduced in the abatacept-treated group or the long-acting GIP conjugate-treated group compared to the disease model control group.

[0227] Figure 4(B) is a graph showing the relative expression levels of MMP-2 and MMP-9, known vascular remodeling factors, in the renal arteries of normal mouse control group, disease model (MRL / lpr) mouse control group, abatacept-treated group, and long-acting GIP conjugate-treated group.

[0228] As shown in FIG. 4(B), unlike abatacept, the long-acting GIP conjugate administration group tended to have a reduced expression of vascular remodeling genes compared to the control group.

[0229] Therefore, it was confirmed that the long-acting GIP conjugate not only directly acts on blood vessels in disease models and exhibits anti-inflammatory effects that prevent inflammatory responses, but also reduces the expression of vascular remodeling factors that play an important role in the progression of vasculitis.

[0230] Example 8: Confirmation of efficacy of long-acting GIP conjugate in angiotensin II-infused mice To confirm the efficacy of the long-acting GIP conjugate against vasculitis in a disease model, we used angiotensin II-infused mice (Ang II mice). These Ang II mice were normal male C57BL / 6N mice (DBL Co., Ltd.) that received 1.4 mg of Ang II (Sigma-Aldrich) daily for 4 weeks. These mice are well known as a disease model for hypertension, and Ang II induces inflammation and thickening of the mouse arterial wall (Hypertension. 2004; 44: 264-270). Therefore, they were selected as a vasculitis disease model. During the study, mice were housed in groups and allowed free access to water. Light was turned off from 6 AM to 6 PM.

[0231] Normal mice (male C57BL / 6N mice, DBL Co., Ltd.), a control group, and a disease model control group (Ang II) were administered with the vehicle. The test group was administered with the long-acting GIP conjugate at 3.163 mg / kg. The vehicle and the long-acting GIP conjugate were administered every two days, and the experiment was terminated at week 4. The long-acting GIP conjugate used was the long-acting GIP conjugate (SEQ ID NO: 17) prepared in Example 3.

[0232] After the experiment, autopsy was performed and RNA was extracted from the aorta (the aortic arch and abdominal aorta). RNA was extracted using an RNeasy Mini Kit (Qiagen, USA), and cDNA was synthesized using an iScript® cDNA Synthesis Kit (Bio-Rad, USA). The expression levels of inflammation-related genes were measured and compared using the synthesized cDNA with a QuantStudio 6 Flex Real-Time PCR System (Applied Biosystems, USA).

[0233] Figure 5(A) is a graph showing the relative expression levels of the IL-6 gene and TNF-α gene in the aortic arch of the normal mouse control group, the disease model control group (Ang II-administered control group), and the test group (long-acting GIP conjugate 3.163 mg / kg).

[0234] Figure 5(B) is a graph showing the relative expression levels of the IL-6 gene and TNF-α gene in the abdominal aorta of the normal mouse control group, the disease model control group (Ang II-administered control group), and the test group (long-acting GIP conjugate 3.163 mg / kg).

[0235] As a result, as shown in Figures 5(A) and 5(B), it was confirmed that the expression of IL-6 gene and TNF-α gene was reduced in the test group administered with the long-acting GIP conjugate compared to the disease model control group at both locations of the aorta.

[0236] Therefore, it was confirmed that the long-acting GIP conjugate directly acts on the aorta in disease models and reduces the expression of inflammation-related genes, thereby exhibiting anti-inflammatory efficacy that prevents inflammatory responses.

Claims

1. A peptide comprising an amino acid sequence represented by the following general formula 1: [General formula 1] Tyr-Aib (aminoisobutyric acid) -Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Xaa13-Xaa14-Xaa15-Xaa16-Xaa17-Ala-Xaa19-Xaa20-Xaa21-Phe-Xaa23-Xaa2 4-Trp-Leu-Xaa27-Xaa28-Xaa29-Xaa30-Xaa31-Xaa32-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38-Xaa39-Xaa40-Xaa41-Xaa42-Xaa43; In the general formula 1, Xaa13 is alanine (Ala, A), Aib, tyrosine (Tyr, Y) or glutamine (Gln, Q); Xaa14 is methionine (Met, M) or leucine (Leu, L); Xaa15 is aspartic acid (Asp, D) or glutamic acid (Glu, E), Xaa16 is alanine (Ala, A), lysine (Lys, K) or glycine (Gly, G), Xaa17 is isoleucine (Ile, I) or glutamine (Gln, Q), Xaa19 is glutamine (Gln, Q) or alanine (Ala, A), Xaa20 is glutamine (Gln, Q), Aib, or lysine (Lys, K); Xaa21 is aspartic acid (Asp, D) or glutamic acid (Glu, E), Xaa23 is valine (Val, V) or isoleucine (Ile, I), Xaa24 is asparagine (Asn, N), alanine (Ala, A) or glutamine (Gln, Q); Xaa27 is leucine (Leu, L) or isoleucine (Ile, I), Xaa28 is alanine (Ala, A) or Aib, Xaa29 is glutamine (Gln, Q) or glycine (Gly, G), Xaa30 is lysine (Lys, K), glycine (Gly, G) or histidine (His, H); Xaa31 is proline (Pro, P), glycine (Gly, G) or cysteine ​​(Cys, C); Xaa32 is serine (Ser, S) or lysine (Lys, K) or is absent; Xaa33 is serine (Ser, S) or lysine (Lys, K), or is absent; Xaa34 is glycine (Gly, G) or asparagine (Asn, N) or is absent; Xaa35 is alanine (Ala, A) or aspartic acid (Asp, D) or is absent; Xaa36 is proline (Pro, P) or tryptophan (Trp, W) or is absent; Xaa37 is proline (Pro, P) or lysine (Lys, K), or is absent; Xaa38 is proline (Pro, P) or histidine (His, H) or is absent; Xaa39 is serine (Ser, S), asparagine (Asn, N), cysteine ​​(Cys, C), or absent; Xaa40 is cysteine ​​(Cys, C) or isoleucine (Ile, I), or is absent; Xaa41 is threonine (Thr, T) or is absent; Xaa42 is glutamine (Gln, Q) or is absent; Xaa43 is cysteine ​​(Cys, C) or is absent; The peptide comprises any one amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 17, 21 and 24; The peptide.

2. The peptide of claim 1, which has activity against the GIP (glucose-dependent insulinotropic peptide) receptor.

3. The peptide of claim 1 , wherein the C-terminus of the peptide is unmodified or amidated.

4. A conjugate comprising the peptide according to any one of claims 1 to 3 and a biocompatible substance that increases the in vivo half-life.

5. The biocompatible substance is composed of a high molecular weight polymer, a fatty acid, cholesterol, albumin and its fragments, an albumin-binding substance, a polymer of repeating units of a specific amino acid sequence, an antibody, an antibody fragment, an FcRn-binding substance, an in vivo connective tissue, a nucleotide, fibronectin, transferrin, a saccharide, heparin, and elastin.

5. The conjugate of claim 4, wherein the conjugate is selected from the group consisting of:

6. The conjugate of claim 5, wherein the polymer is selected from the group consisting of polyethylene glycol, polypropylene glycol, ethylene glycol-propylene glycol copolymer, polyoxyethylated polyol, polyvinyl alcohol, polysaccharides, polyvinyl ethyl ether, biodegradable polymers, lipid polymers, chitin, hyaluronic acid, oligonucleotides, and combinations thereof.

7. The conjugate of claim 4 , wherein the biocompatible substance is an FcRn-binding substance.

8. The conjugate of claim 7 , wherein the FcRn binding agent is an immunoglobulin Fc region.

9. The conjugate of claim 8, wherein the immunoglobulin Fc region is selected from the group consisting of: (a) a CH1 domain, a CH2 domain, a CH3 domain, and a CH4 domain; (b) a CH1 domain and a CH2 domain; (c) a CH1 domain and a CH3 domain; (d) a CH2 domain and a CH3 domain; (e) a combination of one or more domains selected from the CH1 domain, the CH2 domain, the CH3 domain, and the CH4 domain with an immunoglobulin hinge region or a portion of a hinge region; and (f) a dimer of each domain of a heavy chain constant region and a light chain constant region.

10. The conjugate of claim 8 , wherein the immunoglobulin Fc region is non-glycosylated.

11. The conjugate of claim 8 , wherein the immunoglobulin Fc region is an IgG4 Fc region.

12. The conjugate of claim 8 , wherein the immunoglobulin Fc region is a non-glycosylated Fc region derived from human IgG4.

13. The conjugate of claim 4 , wherein the peptide is linked to the biocompatible substance via a linker.

14. The conjugate of claim 13, wherein the linker is selected from the group consisting of peptides, fatty acids, saccharides, high molecular weight polymers, low molecular weight compounds, nucleotides, and combinations thereof.

15. The conjugate of claim 14, wherein the polymer is selected from the group consisting of polyethylene glycol, polypropylene glycol, ethylene glycol-propylene glycol copolymer, polyoxyethylated polyol, polyvinyl alcohol, polysaccharides, polyvinyl ethyl ether, biodegradable polymers, lipid polymers, chitin, hyaluronic acid, oligonucleotides, and combinations thereof.

16. The conjugate of claim 13 , wherein the linker comprises ethylene glycol repeating units.

17. 17. The conjugate of claim 16, wherein the formula weight of the ethylene glycol repeating unit moiety is in the range of 1 to 100 kDa.

18. A pharmaceutical composition for the prevention or treatment of an inflammatory disease or an autoimmune disease, comprising a peptide described in any one of claims 1 to 3, a pharmaceutically acceptable salt thereof or a solvate thereof, or a conjugate described in any one of claims 4 to 17.

19. 19. The pharmaceutical composition of claim 18, wherein the inflammatory disease or the autoimmune disease is any one selected from the group consisting of vasculitis, rheumatoid arthritis, Sjogren's syndrome, neuromyelitis optica, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, autoimmune thrombocytopenia, psoriasis, IgA nephropathy, IgM polyneuropathy, myasthenia gravis, diabetes, Raynaud's syndrome, and glomerulonephritis.

20. 20. The pharmaceutical composition of claim 19, wherein the vasculitis is large vessel vasculitis, medium vessel vasculitis, or small vessel vasculitis.

21. 20. The pharmaceutical composition of claim 19, wherein the vasculitis is any one selected from the group consisting of giant cell arteritis, Takayasu's arteritis, aortitis in Cogan's syndrome, aortitis in spondyloarthropathies, isolated aortitis, Kawasaki disease, polyarteritis nodosa, ANCA-associated vasculitis, granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, primary central nervous system vasculitis, IgA vasculitis, rheumatoid arthritis-associated vasculitis, systemic lupus erythematosus-associated vasculitis, Sjogren's syndrome-associated vasculitis, cryoglobulinemic vasculitis, and drug-induced vasculitis.

22. 20. The pharmaceutical composition of claim 18, further comprising a pharmaceutically acceptable excipient.

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