WO2022164222A2 - Gip 유도체 또는 이의 지속형 결합체를 포함하는 폐질환의 예방 또는 치료용 약학적 조성물 - Google Patents
Gip 유도체 또는 이의 지속형 결합체를 포함하는 폐질환의 예방 또는 치료용 약학적 조성물 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
Definitions
- compositions for the prevention or treatment of lung disease comprising a GIP derivative or a long-acting conjugate thereof.
- the lung is an organ mainly responsible for respiration, and lung diseases occur due to harmful substances, viruses, and immune abnormalities. Since lung disease causes decreased lung function and respiratory discomfort, appropriate treatment is required according to the cause of the disease.
- Lung-related diseases include interstitial lung disease, progressive fibrotic interstitial lung disease, idiopathic interstitial pneumonia, non-specific interstitial pneumonia, pulmonary fibrosis, interstitial pulmonary fibrosis, idiopathic pulmonary fibrosis, alveolitis, pneumonia, emphysema, bronchitis, chronic obstructive pulmonary disease (COPD), combined pulmonary fibrosis and emphysema (CPFE), asthma, and respiratory infections (e.g., coronavirus (COVID-19)). Since these lung diseases are related to each other and various symptoms appear mixed, it is known that it is necessary to be careful in selecting a therapeutic agent.
- the main pathogenesis of lung disease includes lung injury and inflammatory response, and fibrosis.
- inflammatory cytokines eg, IL-1, IL-6, TNF- ⁇
- alveolar macrophages e.g. IL-1, IL-6, TNF- ⁇
- protease eg, elastase
- COPD Chronic obstructive pulmonary disease
- COPD a typical example of lung disease
- COPD refers to a disease in which airway obstruction occurs gradually as the airway narrows due to an abnormal inflammatory response of the lungs by tobacco, air pollution, or toxic inhaled substances. It is characterized by bronchitis and emphysema.
- smoking is known to be a major cause of chronic obstructive pulmonary disease.
- Smoking acts as a strong irritant in the lung tissue, increases the production of various pro-inflammatory factors, growth factors, oxidative substances, and chemotactic factors, and activates the inflammatory signaling system for migration of many inflammatory cells, including neutrophils and macrophages.
- lung inflammation which in turn causes abnormal changes in lung tissue, such as airway wall thickening and pulmonary fibrosis, leading to decreased lung function. Accordingly, improvement of lung inflammation is understood as a treatment method for the prevention and treatment of chronic obstructive pulmonary disease.
- lung inflammation and fibrosis are major causes of the onset and development of lung diseases, and improvement of lung inflammation and fibrosis has been studied as a treatment mechanism for various lung diseases.
- GIP glucose-dependent insuliontropic polypeptide
- GIP glycose-dependent insuliontropic polypeptide
- GIP is a representative gastrointestinal hormone and a neurohormone that is secreted upon stimulation by food intake.
- GIP is a hormone composed of 42 amino acids secreted from the K cells of the small intestine. It functions to promote insulin secretion from the pancreas and lower the blood glucose level depending on the blood glucose concentration, and has the effect of increasing the activity of GLP-1 and anti-inflammatory. effects have been reported.
- the GIP receptor is expressed in several tissues, and the lung is one of them. Therefore, GIP can be expected to be effective as a therapeutic agent for lung diseases through an anti-inflammatory effect by acting directly on the lungs.
- the present inventors have developed a long-acting GIP derivative conjugate that exhibits high activity at the human GIP receptor and has improved persistence in the body, and has completed the present invention by confirming its potential as a therapeutic agent for lung diseases.
- compositions for preventing or treating lung disease comprising a GIP derivative, a pharmaceutically acceptable salt thereof, a solvate thereof, or a conjugate thereof.
- a method for preventing or treating a lung disease comprising administering an effective amount of the GIP derivative, a pharmaceutically acceptable salt thereof, a solvate thereof, or a conjugate thereof, or the pharmaceutical composition to an individual in need thereof to provide.
- GIP derivative a pharmaceutically acceptable salt thereof, a solvate thereof, or a conjugate thereof for use in the preparation of a medicament for the prevention or treatment of lung disease.
- amino acids referred to by abbreviation herein are described according to the IUPAC-IUB nomenclature.
- One aspect provides a pharmaceutical composition for preventing or treating lung disease, comprising a GIP derivative, a pharmaceutically acceptable salt or solvate thereof.
- GIP glucose-dependent insulinotropic polypeptide or gastric inhibitory polypeptide
- the "GIP derivative” may be a derivative of native GIP in which at least one amino acid is modified in the native GIP sequence.
- the modification may be selected from the group consisting of substitution, addition, deletion, modification, and combinations of two or more thereof.
- the added amino acid sequence may be derived from a native GIP amino acid sequence, but is not limited thereto.
- the GIP derivative may be a peptide having activity against a GIP receptor.
- the "peptide having activity on the GIP receptor” has a significant level of activity on the GIP receptor, and specifically, the in vitro activity on the GIP receptor is about 0.1% or more compared to the native ligand (native GIP), 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%.
- Example 2 of the present specification but is not particularly limited thereto, and any method known in the art may be appropriately used to measure the in vitro activity can do.
- “About” is a range including all of ⁇ 0.5, ⁇ 0.4, ⁇ 0.3, ⁇ 0.2, ⁇ 0.1, etc., including, but not limited to, all numerical values in a range equal to or similar to the numerical value following the term "about”. .
- the GIP derivative may be one in which 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acids are conservatively substituted in the native or unmutated GIP protein. However, it is not limited thereto.
- Constant substitution means substituting one amino acid for 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 unmodified GIP protein.
- Such amino acid substitutions may generally occur based on similarity in the polarity, charge, solubility, hydrophobicity, hydrophilicity and/or amphipathic nature of the residues.
- 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
- Hydrophobic amino acids include alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine and tryptophan.
- Amino acids can also be classified into amino acids with electrically charged side chains and amino acids with uncharged side chains.
- Amino acids having a charged side chain include aspartic acid, glutamic acid, lysine, arginine, and histidine, and amino acids having an uncharged side chain may be classified as nonpolar amino acids or polar amino acids.
- the non-polar amino acids are glycine, alanine, valine, leucine, and isoleucine. methionine, proline; Polar amino acids may include serine, threonine, cysteine, asparagine, glutamine. Conservative substitutions with amino acids having similar properties as described above can be expected to exhibit the same or similar activity.
- the GIP derivative may be non-naturally occurring.
- the GIP derivative may be an isolated peptide.
- the GIP derivative is a peptide comprising an amino acid sequence represented by the following 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- Xaa24-Trp-Leu-Xaa27-Xaa28-Xaa29-Xaa30-Xaa31-Xaa32-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38-Xaa39-Xaa40-Xaa41-Xaa42-Xaa43 (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 absent,
- Xaa33 is serine (Ser, S) or lysine (Lys, K) or absent,
- Xaa34 is glycine (Gly, G) or asparagine (Asn, N) or absent,
- Xaa35 is alanine (Ala, A) or aspartic acid (Asp, D) or absent;
- Xaa36 is proline (Pro, P) or tryptophan (Trp, W) or absent,
- Xaa37 is proline (Pro, P) or lysine (Lys, K) or absent,
- Xaa38 is proline (Pro, P) or histidine (His, H) or absent,
- Xaa39 is serine (Ser, S), asparagine (Asn, N), or cysteine (Cys, C) or absent;
- Xaa40 is cysteine (Cys, C) or isoleucine (Ile, I) or absent,
- Xaa41 is threonine (Thr, T) or absent
- Xaa42 is glutamine (Gln, Q) or absent,
- Xaa43 is cysteine (Cys, C) or absent.
- Exemplary types of such peptides may include any one amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 26.
- the peptide may include an amino acid sequence represented by the following 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- Xaa24-Trp-Leu-Xaa27-Xaa28-Xaa29-Xaa30-Xaa31-Xaa32-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38-Xaa39-Xaa40-Xaa41-Xaa42-Xaa43 (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 absent,
- Xaa41 is threonine (Thr, T) or absent
- Xaa42 is glutamine (Gln, Q) or absent,
- Xaa43 is cysteine (Cys, C) or absent.
- Exemplary types of such peptides may include any one amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 17, and 19 to 26.
- the peptide may include an amino acid sequence represented by the following 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- Asn-Trp-Leu-Leu-Xaa28-Xaa29-Xaa30-Xaa31-Xaa32-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38-Xaa39-Xaa40-Xaa41-Xaa42-Xaa43 (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 absent
- Xaa42 is glutamine (Gln, Q) or absent,
- Xaa43 is cysteine (Cys, C) or absent.
- An exemplary kind of such a peptide may include any one amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 17, 21 and 24.
- 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.
- An exemplary type of such a peptide may include any one amino acid sequence selected from the group consisting of SEQ ID NOs: 17, 21 and 24.
- 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 isoleucine (Ile, I)
- Xaa41 is threonine (Thr, T)
- Xaa42 is glutamine (Gln, Q),
- Xaa43 may be cysteine (Cys, C).
- the peptide may include any one amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 26.
- the peptide may be essentially composed of any one amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 26, or the peptide may be composed of any one amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 26 .
- the peptide comprising (or essentially consisting of, or consisting of) the amino acid sequence of any one of SEQ ID NOs: 1 to 26 may have an in vitro activity against the GIP receptor of about 1% or more compared to the native GIP. Therefore, the peptides of SEQ ID NOs: 1 to 26 may exhibit superior pharmacological effects by exhibiting higher activity than native GIP.
- the peptide may include any one amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 7 and 10 to 26.
- the peptide is essentially composed of any one amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 7 and 10 to 26, or the peptide is any one selected from the group consisting of SEQ ID NOs: 1 to 7 and 10 to 26 It may be composed of an amino acid sequence of The in vitro activity of the peptide comprising (or consisting essentially of, or consisting of) the amino acid sequence of any one of SEQ ID NOs: 1 to 7 and 10 to 26 may be about 10% or more compared to native GIP. Accordingly, the peptides of SEQ ID NOs: 1 to 7 and 10 to 26 may exhibit significantly higher activity than native GIP, thereby exhibiting excellent pharmacological effects.
- the peptide may include any one amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 11 to 13, 15, 17, and 19 to 26.
- the peptide is essentially composed of any one amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 11 to 13, 15, 17, and 19 to 26, or the peptide is SEQ ID NO: 1, 11 to 13, 15 , 17, and may be composed of any one amino acid sequence selected from the group consisting of 19 to 26.
- the peptide comprising (or consisting essentially of, or consisting of) the amino acid sequence of any one of SEQ ID NOs: 1, 11 to 13, 15, 17, and 19 to 26 has in vitro activity against GIP receptor compared to native GIP. It may be about 30% or more. Accordingly, the peptides of SEQ ID NOs: 1, 11 to 13, 15, 17, and 19 to 26 may exhibit significantly higher activity than native GIP, thereby exhibiting excellent pharmacological effects.
- the peptide may include any one amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 17, and 19 to 26.
- the peptide consists essentially of any one amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 17, and 19 to 26, or the peptide is selected from the group consisting of SEQ ID NOs: 11, 17, and 19 to 26 It may be composed of any one amino acid sequence.
- the peptide comprising (or consisting essentially of, or consisting of) the amino acid sequence of any one of SEQ ID NOs: 11, 17, and 19 to 26 may have an in vitro activity against GIP receptor of about 60% or more compared to native GIP. . Therefore, the peptides of SEQ ID NOs: 11, 17, and 19 to 26 may exhibit significantly higher activity than native GIP, thereby exhibiting significantly superior pharmacological effects.
- the peptide may include any one amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 17, 21 and 24.
- the peptide is essentially composed of any one amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 17, 21 and 24, or the peptide is any one selected from the group consisting of SEQ ID NOs: 11, 17, 21 and 24 It may be composed of an amino acid sequence of
- the peptide comprising (or consisting essentially of, or consisting of) the amino acid sequence of any one of SEQ ID NOs: 11, 17, 21 and 24 has an in vitro activity against GIP receptor of about 100% or more compared to native GIP, specifically It may be about 110% or more. Accordingly, the peptides of SEQ ID NOs: 11, 17, 21 and 24 exhibit significantly higher activity than native GIP, thereby exhibiting significantly superior pharmacological effects.
- the peptide may include any one amino acid sequence selected from the group consisting of SEQ ID NOs: 17, 21 and 24.
- the peptide is essentially composed of any one amino acid sequence selected from the group consisting of SEQ ID NOs: 17, 21 and 24, or the peptide is composed of any one amino acid sequence selected from the group consisting of SEQ ID NOs: 17, 21 and 24 may be configured.
- the peptide comprising (or consisting essentially of, or consisting of) the amino acid sequence of any one of SEQ ID NOs: 17, 21 and 24, particularly in the form of a long-acting conjugate exhibits in vitro activity against the GIP receptor compared to native GIP. It may be about 120% or more. Therefore, the peptides of SEQ ID NOs: 17, 21 and 24, particularly in the form of a long-acting conjugate, exhibit significantly higher activity than native GIP, thereby exhibiting significantly superior pharmacological effects.
- the peptide has an amino acid sequence of SEQ ID NOs: 1 to 26 and 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 It may include, but is not limited to, amino acid sequences having identity.
- “Homology” or “identity” refers to the degree to which two given amino acid sequences or base sequences are related to each other and can be expressed as a percentage. Whether any two peptide sequences have homology, similarity or identity can be determined, for example, by Pearson et al (1988) [Proc. Natl. Acad. Sci. USA 85]: 2444, using a known computer algorithm such as the "FASTA” program. or, as performed 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), Needleman-Wunsch algorithm (Needleman and Wunsch, 1970, J. Mol. Biol.
- GAP program is defined as the total number of symbols in the shorter of two sequences divided by the number of similarly aligned symbols (ie, amino acids).
- Default parameters for the GAP program are: (1) a binary comparison matrix (containing values of 1 for identity and 0 for non-identity) and Schwartz and Dayhoff, eds., Atlas Of Protein Sequence And Structure, National Biomedical Research Foundation, pp.
- a peptide comprising the amino acid sequence of Formula 1 according to an aspect can be prepared by a combination of various methods for preparing various peptides.
- the length of the peptide may be synthesized by a method well known in the art, for example, an automatic peptide synthesizer, or may be produced by a genetic engineering technique.
- the peptide may be prepared by standard synthetic methods, recombinant expression systems, or any other method in the art.
- a peptide according to an aspect can be synthesized by a number of methods including, but not limited to, for example, methods including:
- a method for obtaining a fragment of a peptide by any combination of (a), (b) and (c), and then ligating the fragments to obtain a peptide, and recovering the peptide.
- the preparation of the peptide may include modification with L- or D-form amino acids, and/or non-natural amino acids; and/or by modifying the native sequence, e.g., modification of side chain functional groups, intramolecular covalent bonds, such as inter-side chain ring formation, methylation, acylation, ubiquitination, phosphorylation, aminohexylation, biotinylation, etc. includes all that Also, the above modifications include all substitutions with non-naturally occurring compounds.
- Substituted or added amino acids used in the above modifications may use atypical or non-naturally occurring amino acids as well as the 20 amino acids commonly found in human proteins.
- Commercial sources of atypical amino acids may include, but are not limited to, Sigma-Aldrich, ChemPep and Genzyme pharmaceuticals.
- aminoisobutyric acid (Aib) may be prepared by synthesizing amino acids of Streker in acetone, but is not limited thereto.
- Peptides containing such atypical or non-naturally occurring amino acids and canonical peptide sequences may be synthesized and purchased from commercial peptide synthesis companies, for example, American peptide company or Bachem in the United States, or Anygen in Korea, but limited thereto. doesn't happen
- the peptide may have an unmodified N-terminus and/or C-terminus, but its N-terminus and/or C-terminus may be chemically modified to protect it from proteolytic enzymes in vivo and to increase stability. Modified, protected with an organic group, or modified by adding amino acids to the end of the peptide, etc., are also included in the scope of the peptide according to the above aspect.
- the end of the peptide has a free carboxyl group, but is not particularly limited thereto.
- the N-terminus and/or the C-terminus may be modified to remove these charges.
- the N-terminus may be acetylated and/or the C-terminal amidation may be performed, but the present invention is not particularly limited thereto.
- the peptide may have its C-terminus unmodified or amidated, but is not limited thereto.
- the peptide may be an amidated C-terminus.
- the peptide includes both the peptide itself, a salt thereof (eg, a pharmaceutically acceptable salt of the peptide), or a solvate thereof.
- the type of the salt is not particularly limited. However, it is preferably in a form that is safe and effective for an individual, such as a mammal, but is not particularly limited thereto.
- the peptide may be in any pharmaceutically acceptable form.
- pharmaceutically acceptable means that it does not cause side effects and in an amount sufficient to exhibit a therapeutic effect, the type of disease, the patient's age, weight, health, sex, the patient's sensitivity to the drug, the route of administration , can be easily determined by those skilled in the art according to factors well known in the medical field, such as administration method, administration frequency, treatment period, combination or concurrently used drugs.
- the peptide may be in the form of a pharmaceutically acceptable salt thereof.
- the salts include conventional acid addition salts used in the pharmaceutical field, for example, in the field of treating lung diseases, for example, salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid or nitric acid; and 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 salts derived from organic acids such as trifluoroacetic acid.
- inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phospho
- the salt may be a base addition salt such as ammonium, dimethylamine, monomethylamine, monoethylamine, or diethylamine.
- the salts also include conventional metal salt forms, for example salts derived from metals such as lithium, sodium, potassium, magnesium, or calcium.
- the acid addition salt, base addition salt or metal salt may be prepared according to a conventional method.
- Pharmaceutically acceptable salts and general methodologies for their preparation are well known in the art. For example, in P. Stahl, et al. Handbook of Pharmaceutical Salts: Properties, Selection and Use, 2nd Revised Edition (Wiley-VCH, 2011)]; [S.M. Berge, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977].
- triphosphonium salts include benzotriazol-1-yloxytris (pyrrolagino) phosphonium hexafluorophosphate (PyBOP), bromotris (pyrrolazino) phosphonium hexafluorophosphate (PyBroP), 7 -Azabenzotriazol-1-yloxytris(pyrrolazino)phosphonium hexafluorophosphate (PyAOP), examples of tetramethyluronium salts are 2-(1H-benzotriazol-1-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-
- racemization inhibitors eg, 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- (hydroxyl mino)acetate (Oxyma), etc.
- the solvent used for the condensation may be appropriately selected from those known to be useful for the peptide condensation reaction.
- acid amides such as anhydrous or water-containing N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.
- halogenated hydrocarbons such as methylene chloride, chloroform, etc.
- Alcohols such as fluoroethanol, phenol, sulfoxides such as dimethylsulfoxide, tertiary amines such as pyridine, ethers such as dioxane, tetrahydrofuran, nitriles such as acetonitrile, propionitrile, methyl acetate, ethyl Esters such as acetates and the like, suitable mixtures thereof, and the like can be used.
- the reaction temperature is appropriately selected from the known ranges usable for the peptide binding reaction, and is usually selected from the range of about -20°C to 90°C.
- Activated amino acid derivatives are usually used in 1.5 to 6-fold excess.
- solid-phase synthesis when the test using the ninhydrin reaction indicates that the condensation is insufficient, sufficient condensation can be carried out by repeating the condensation reaction without removing the protecting group. If the condensation is still insufficient after repeating the reaction, the unreacted amino acid may be acetylated with an acid anhydride, acetylimidazole, or the like, so that the influence on the subsequent reaction can be avoided.
- protecting groups for the amino group of the starting amino acid are benzyloxycarbonyl (Z), tert-butoxycarbonyl (Boc), tert-pentyloxycarbonyl, isobornyloxycarbonyl, 4-methoxybenzyloxycarbonyl , 2-chlorobenzyloxycarbonyl (Cl-Z), 2-bromobenzyloxycarbonyl (Br-Z), adamantyloxycarbonyl, trifluoroacetyl, phthaloyl, formyl, 2-nitro phenylsulfenyl, diphenylphosphinothioyl, 9-fluorenylmethyloxycarbonyl (Fmoc), trityl, and the like.
- carboxyl-protecting groups for the starting amino acid are, in addition to the above-mentioned C 1-6 alkyl group, C 3-10 cycloalkyl group, C 7-14 aralkyl group, aryl, 2-adamantyl, 4-nitrobenzyl, 4 -methoxybenzyl, 4-chlorobenzyl, phenacyl and benzyloxycarbonylhydrazide, tert-butoxycarbonylhydrazide, tritylhydrazide and the like.
- the hydroxyl group of serine or threonine may be protected, for example, by esterification or etherification.
- groups suitable for esterification include lower (C 2-4 ) alkanoyl groups such as acetyl groups, aroyl groups such as benzoyl groups, and groups derived from organic acids and the like.
- groups suitable for etherification include benzyl, tetrahydropyranyl, tert-butyl (But t ), trityl (Trt), and the like.
- Examples of the protecting group for the phenolic hydroxyl group of tyrosine include Bzl, 2,6-dichlorobenzyl, 2-nitrobenzyl, Br-Z, tert-butyl and the like.
- Examples of the protecting group of histidine for imidazole include p-toluenesulfonyl (Tos), 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), dinitrophenyl (DNP), benzyloxymethyl (Bom), tert-butoxymethyl (Bum), Boc, Trt, Fmoc, and the like.
- 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 phonyl (Pbf), Boc, Z, NO 2 and the like.
- Mtr 4-methoxy-2,3,6-trimethylbenzenesulfonyl
- MSS p-methoxybenzenesulfonyl
- Pmc 2,2, 5,7,8-pentamethylchroman-6-sulfonyl
- Mts mesitylene-2-sulfonyl
- Pbf 2,2,4,6,7-p
- Examples of the protecting group for the side chain amino group of lysine include Z, Cl-Z, trifluoroacetyl, Boc, Fmoc, Trt, Mtr, 4,4-dimethyl-2,6-dioxocyclohexylidenyl (Dde), etc. includes
- Examples of the protecting group for indolyl of tryptophan include formyl (For), Z, Boc, Mts, Mtr, and the like.
- protecting groups for asparagine and glutamine include Trt, xantyl (Xan), 4,4'-dimethoxybenzhydryl (Mbh), 2,4,6-trimethoxybenzyl (Tmob), and the like.
- activated carboxyl groups in the starting material 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-hydroxysucciimide, 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt))] include Examples of activated amino groups in the starting material include the corresponding phosphorus amides.
- 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; Anhydrous hydrogen fluoride, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid (TFA), trimethylsilyl bromide (TMSBr), trimethylsilyl trifluoromethanesulfonate, tetrafluoroboric acid, tris(tris) acid treatment with a solution of fluoro)boric acid, boron tribromide, or a mixture thereof; base treatment with diisopropylethylamine, triethylamine, piperidine, piperazine or the like; and reduction with sodium in liquid ammonia and the like.
- a catalyst such as Pd-black or Pd-carbon
- Anhydrous hydrogen fluoride methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid (TFA
- the removal reaction by acid treatment described above is generally carried out at a temperature of -20°C to 40°C; Acid treatments include anisole, phenol, thioanisole, methacresol and paracresol; This is done efficiently by adding a cation scavenger such as dimethylsulfide, 1,4-butanedithiol, 1,2-ethanedithiol, triisopropylsilane, and the like.
- a cation scavenger such as dimethylsulfide, 1,4-butanedithiol, 1,2-ethanedithiol, triisopropylsilane, and the like.
- the 2,4-dinitrophenyl group used as the protecting group of the imidazole of histidine is removed by thiophenol treatment;
- the formyl group used as the protecting group of the indole of tryptophan is not only by acid treatment in the presence of 1,2-ethanedithiol, 1,4-butanedithiol, etc., but also by alkali treatment with diluted sodium hydroxide, diluted ammonia, etc. It is removed by deprotection.
- Protection of the functional group that should not be involved in the reaction of the starting material with the protecting group, removal of the protecting group, activation of the functional group involved in the reaction, and the like may be appropriately selected from known protecting groups and known means.
- the left end is the N-terminus (amino terminus) and the right end is the C-terminus (carboxyl terminus) according to conventional peptide markings.
- the C-terminus of the peptide is an amide (-CONH 2 ), a carboxyl group (-COOH), a carboxylate (-COO-), an alkylamide (-CONHR', where R' is alkyl) and an ester (-COOR',
- R' may be any one of alkyl or aryl.
- an amide of a peptide it is formed by solid-phase synthesis using a resin for amide synthesis, or the ⁇ -carboxyl group of a carboxy-terminal amino acid is amidated, and the peptide chain is extended to the desired chain length toward the amino group. Then, a peptide in which the protecting group for the N-terminal ⁇ -amino group of only the peptide chain has been removed and the peptide with only the protecting group for the C-terminal carboxyl group removed from the peptide chain are prepared, and these two peptides are mixed as described above condensed in a solvent. As for the details of the condensation reaction, the same applies as described above.
- the peptide may be in the form of a solvate thereof.
- “Solvate” means that the peptide or a salt thereof forms a complex with a solvent molecule.
- the peptide may be in the form of a long-acting conjugate.
- the conjugate may exhibit the same or higher activity on the GIP receptor than the native GIP, and at the same time exhibit increased potency and persistence compared to the native GIP or GIP derivative to which a carrier (or biocompatible material) is not bound.
- the binder may be a long-acting binder.
- long-acting conjugate refers to a conjugate with increased durability of efficacy compared to a natural GIP or GIP derivative to which a biocompatible material is not bound.
- the conjugate may be referred to as a “long-acting GIP derivative conjugate” or a “long-acting GIP derivative” or “long-acting GIP conjugate”.
- a binder includes not only the above-described form, but also a form encapsulated in biodegradable nanoparticles.
- the binder may be an isolated binder.
- the combination may be non-naturally occurring.
- the peptide may be in the form of a conjugate to which a biocompatible substance that increases the half-life in vivo is bound.
- the pharmaceutical composition may include a conjugate in which the GIP derivative is combined with a biocompatible material that increases the in vivo half-life.
- the biocompatible material may be mixed with a carrier.
- the biocompatible material may be bonded to each other by a covalent chemical bond or a non-covalent chemical bond with the GIP derivative, and may be bonded to each other through a linker (Linker, L) by a covalent chemical bond, a non-covalent chemical bond, or a combination thereof.
- Linker L
- One or more amino acid side chains in the GIP derivative may be conjugated to such biocompatible materials to increase solubility and/or half-life and/or increase bioavailability in vivo. Such modifications may also reduce clearance of therapeutic proteins and peptides.
- the biocompatible material described above may be water-soluble (amphiphilic or hydrophilic) and/or non-toxic and/or pharmaceutically acceptable.
- the biocompatible material includes high molecular weight polymers, fatty acids, cholesterol, albumin and fragments thereof, albumin binding materials, polymers of repeating units of specific amino acid sequences, antibodies, antibody fragments, FcRn binding materials, connective tissue in vivo, nucleotides, fibronectin, transferrin ( Transferrin), saccharides, may be selected from the group consisting of heparin, and elastin, but is not particularly limited thereto.
- polymer polymer examples include polyethylene glycol (PEG), polypropylene glycol, ethylene glycol-propylene glycol copolymer, polyoxyethylated polyol, polyvinyl alcohol, polysaccharide, polyvinyl ethyl ether, biodegradable polymer, lipid polymer, chitin, and a high molecular polymer selected from the group consisting of hyaluronic acid, oligonucleotides, and combinations thereof, and the polysaccharide may include dextran, but is not particularly limited thereto.
- PEG polyethylene glycol
- polypropylene glycol ethylene glycol-propylene glycol copolymer
- polyoxyethylated polyol polyvinyl alcohol
- polysaccharide polyvinyl ethyl ether
- biodegradable polymer lipid polymer
- chitin examples of the polysaccharide may include dextran, but is not particularly limited thereto.
- the polyethylene glycol is a term encompassing all forms of ethylene glycol homopolymer, PEG copolymer, or monomethyl-substituted PEG polymer (mPEG), but is not particularly limited thereto.
- the fatty acid may have a binding force with albumin in vivo, but is not particularly limited thereto.
- the biocompatible materials include, but are not limited to, poly-amino acids such as poly-lysine, poly-aspartic acid and poly-glutamic acid.
- the elastin may be human tropoelastin, a water-soluble precursor, and may be a polymer of some sequences or some repeating units of these, for example, all cases of an elastin-like polypeptide, but is not particularly limited thereto. .
- the biocompatible material may be an FcRn binding material.
- the FcRn-binding material may be an immunoglobulin Fc region, more specifically an IgG Fc region, more specifically an aglycosylated IgG4 Fc region, but is not particularly limited thereto.
- Immunoglobulin Fc region refers to a region comprising a heavy chain constant region 2 (CH2) and/or heavy chain constant region 3 (CH3) region, excluding the heavy and light chain variable regions of an immunoglobulin.
- the immunoglobulin Fc region may be a component constituting a moiety of the conjugate according to an aspect.
- the immunoglobulin Fc region may include a hinge region in the heavy chain constant region, but is not limited thereto.
- the immunoglobulin Fc region may include a specific hinge sequence at the N-terminus.
- flankinge sequence refers to a site located in the heavy chain to form a dimer of an immunoglobulin Fc fragment through an inter disulfide bond.
- the hinge sequence may be mutated to have only one cysteine residue by deleting a portion of the hinge sequence having the following amino acid sequence, but is not limited thereto:
- the hinge sequence may include only one cysteine residue by deleting the 8th or 11th cysteine residue in the hinge sequence of SEQ ID NO: 27.
- the hinge sequence according to one embodiment may be composed of 3 to 12 amino acids, including only one cysteine residue, but is not limited thereto.
- the hinge sequence 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), Glu-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
- the hinge sequence may include the amino acid sequence of SEQ ID NO: 37 (Pro-Ser-Cys-Pro) or SEQ ID NO: 46 (Ser-Cys-Pro), but is not limited thereto.
- the immunoglobulin Fc region may have a form in which two molecules of the immunoglobulin Fc chain form a dimer due to the presence of a hinge sequence.
- the conjugate of Formula 1 may be in a form in which one end of the linker is linked to one chain of the dimer immunoglobulin Fc region, but is not limited thereto.
- N-terminus refers to the amino terminus of a protein or polypeptide, and 1, 2, 3, 4, 5, 6, 7, 8 from the amino terminus, or from the most terminus. Dogs, 9, or may include up to 10 or more amino acids.
- the immunoglobulin Fc fragment of the present invention may include a hinge sequence at the N-terminus, but is not limited thereto.
- part or all of the heavy chain constant region 1 (CH1) and/or the light chain constant region 1 except for only the heavy and light chain variable regions of the immunoglobulin (CL1) may be an extended Fc region. It may also be a region in which some fairly long amino acid sequences corresponding to CH2 and/or CH3 have been removed.
- the immunoglobulin Fc region comprises (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 two or more of the CH1 domain, CH2 domain, CH3 domain and CH4 domain with an immunoglobulin hinge region or portion of a hinge region; And (f) it may be selected from the group consisting of a dimer of each domain of the heavy chain constant region and the light chain constant region, but is not limited thereto.
- the immunoglobulin Fc region may be in a dimeric form, and one molecule of the GIP derivative may be covalently linked to one Fc region in the dimeric form, wherein the immunoglobulin Fc and the GIP derivative are non-peptidyl polymers. can be connected to each other by On the other hand, it is also possible for two molecules of the GIP derivative to bind symmetrically to one Fc region in a dimeric form. In this case, the immunoglobulin Fc and the GIP derivative may be linked to each other by a non-peptide linker. However, it is not limited to the examples described above.
- the immunoglobulin Fc region includes a native amino acid sequence as well as a sequence derivative thereof.
- An amino acid sequence derivative means that one or more amino acid residues in a native amino acid sequence have a different sequence by deletion, insertion, non-conservative or conservative substitution, or a combination thereof.
- amino acid residues 214 to 238, 297 to 299, 318 to 322, or 327 to 331 known to be important for binding may be used as suitable sites for modification.
- various types of derivatives are possible, such as a site capable of forming a disulfide bond is removed, some amino acids at the N-terminus of the native Fc are removed, or a methionine residue may be added to the N-terminus of the native Fc do.
- the complement binding site eg, the C1q binding site, may be removed, or the ADCC (antibody dependent cell mediated cytotoxicity) site may be removed.
- Techniques for preparing such an immunoglobulin Fc region sequence derivative are disclosed in International Patent Publication Nos. WO 97/34631 and International Patent Publication No. 96/32478.
- Amino acid exchanges in proteins and peptides that do not entirely 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 common exchanges are amino acid residues Ala/Ser, Val/Ile, Asp/Glu, Thr/Ser, Ala/Gly, Ala/Thr, Ser/Asn, Ala/Val, Ser/Gly, Thy/Phe, Ala/ Exchange between Pro, Lys/Arg, Asp/Asn, Leu/Ile, Leu/Val, Ala/Glu, Asp/Gly.
- modifications such as phosphorylation, sulfation, acrylation, glycosylation, methylation, farnesylation, acetylation and amidation ( may be modified).
- the above-described Fc derivative may exhibit biological activity equivalent to that of the Fc region, and may have increased structural stability against heat, pH, etc. of the Fc region.
- the Fc region may be obtained from a native type isolated in vivo from animals such as humans, cows, goats, pigs, mice, rabbits, hamsters, rats or guinea pigs, or obtained from transformed animal cells or microorganisms. It may be recombinant or a derivative thereof.
- the method of obtaining from the native type may be a method of obtaining whole immunoglobulin by isolating it from a living body of a human or animal, and then treating it with a proteolytic enzyme. When treated with papain, it is cleaved into Fab and Fc, and when treated with pepsin, it is cleaved into pF'c and F(ab) 2 .
- Fc or pF'c may be separated using size-exclusion chromatography or the like.
- the human-derived Fc region is a recombinant immunoglobulin Fc region obtained from a microorganism.
- the immunoglobulin Fc region may have a native sugar chain, an increased sugar chain compared to the native type, a decreased sugar chain compared to the native type, or a form in which the sugar chain is removed.
- Conventional methods such as chemical methods, enzymatic methods, and genetic engineering methods using microorganisms may be used for the increase or decrease or removal of such immunoglobulin Fc sugar chains.
- the immunoglobulin Fc region from which the sugar chain is removed from the Fc has significantly reduced binding to complement (c1q) and reduced or eliminated antibody-dependent cytotoxicity or complement-dependent cytotoxicity, so that unnecessary immune responses in vivo are not induced.
- a form more suitable for the original purpose as a drug carrier may be an immunoglobulin Fc region in which sugar chains are removed or non-glycosylated.
- Deglycosylation refers to an Fc region from which sugars are removed by an enzyme, and aglycosylation refers to an Fc region that is not glycosylated by being produced in a prokaryote, in a more specific embodiment, in E. coli.
- the immunoglobulin Fc region may be an Fc region 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 is most abundant in human blood, and in a more specific embodiment it is derived from IgG, which is known to enhance the half-life of ligand binding proteins. In a more specific embodiment, the immunoglobulin Fc region is an IgG4 Fc region, and in the most specific embodiment, the immunoglobulin Fc region is an aglycosylated Fc region derived from human IgG4, but is not limited thereto.
- dimers or multimers means that, when forming dimers or multimers, polypeptides encoding single-chain immunoglobulin Fc regions of the same origin form bonds with single-chain polypeptides of different origins. That is, dimers or multimers can be prepared from two or more fragments selected from the group consisting of IgG Fc, IgA Fc, IgM Fc, IgD Fc and IgE Fc fragments.
- the GIP derivative may be linked to a biocompatible material through a linker.
- the linker may be a peptidic linker or a non-peptidyl linker.
- the linker when the linker is a peptidic linker, it may include one or more amino acids, for example, 1 to 1000 amino acids, but is not particularly limited thereto.
- the peptidic linker may include Gly, Asn and Ser residues, and neutral amino acids such as Thr and Ala may also be included.
- various known peptide linkers may be used.
- the copy number “n” can be adjusted to achieve proper separation between functional moieties or to allow for optimization of the linker to maintain the necessary inter-moiety interactions.
- Other flexible linkers are known in the art, for example, G and S linkers to which amino acid residues such as T and A are added to maintain flexibility as well as polar amino acid residues to improve water solubility.
- the linker may be a flexible linker comprising G, S, and/or T residues.
- linkers include (GGGGS)n, (SGGGG)n, (SRSSG)n, (SGSSC)n, (GKSSGSGSESKS)n, (RPPPPC)n, (SSPPPPC)n, (GSTSGSGKSSEGKG)n, (GSTSGSGKSSEGSGSSTKG) n, (GSTSGSGKPGSGEGSTKG)n, or (EGKSSGSGSESKEF)n, wherein n is an integer of 1 to 20, or 1 to 10.
- non-peptidyl linker includes a biocompatible polymer to which two or more repeating units are linked.
- the repeating units are linked to each other through any covalent bond other than a peptide bond.
- the non-peptidyl linker may be a component constituting a moiety of the conjugate.
- non-peptidyl linker may be used interchangeably with “non-peptidyl polymer”.
- the conjugate is a biocompatible material and a GIP derivative covalently bonded to each other through a non-peptide linker comprising a reactive group capable of binding to a biocompatible material, specifically an immunoglobulin Fc region, and a GIP derivative at both ends. may be negatively connected.
- non-peptidyl linker may be selected from the group consisting of fatty acids, saccharides, high molecular weight polymers, low molecular weight compounds, nucleotides, and combinations thereof.
- the non-peptidyl linker is polyethylene glycol, polypropylene glycol, ethylene glycol-propylene glycol copolymer, polyoxyethylated polyol, polyvinyl alcohol, polysaccharide, polyvinyl ethyl ether, polylactic acid (PLA) and It may be selected from the group consisting of biodegradable polymers such as polylactic-glycolic acid (PLGA), lipid polymers, chitins, hyaluronic acid, oligonucleotides, and combinations thereof.
- the polysaccharide may be dextran, but is not limited thereto.
- the non-peptidyl polymer may be, but is not limited to, polyethylene glycol.
- the linker may contain an ethylene glycol repeating unit.
- derivatives thereof already known in the art and derivatives that can be easily prepared at the level of skill in the art are also included in the scope of the present invention.
- the non-peptidyl linker may be used without limitation as long as it is a polymer resistant to proteolytic enzymes in vivo.
- the formula weight of the non-peptidyl polymer is in the range of 1 to 1000 kDa, specifically in the range of 1 to 100 kDa, more specifically in the range of 1 to 20 kDa, but is not limited thereto.
- the non-peptidyl linker not only one type of polymer, but also a combination of different types of polymers may be used.
- the formula weight of the ethylene glycol repeating unit moiety may be in the range of 1 to 100 kDa, more specifically, in the range of 1 to 20 kDa.
- both ends of the non-peptidyl linker may be bound to a biocompatible material, such as 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.
- a biocompatible material such as 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.
- the non-peptidyl polymer has a reactive group capable of binding to a biocompatible material (eg, immunoglobulin Fc region) and a GIP derivative at both ends, specifically, a GIP derivative, or a biocompatible material (eg, immunoglobulin Fc). region) may include, but is not limited to, an amine group located at the N-terminus or lysine, or a reactive group capable of bonding to a thiol group of cysteine.
- the reactive group of the non-peptidyl polymer which can be bound to a biocompatible material, such as an immunoglobulin Fc region and a GIP derivative, may be selected from the group consisting of an aldehyde group, a maleimide group and a succinimide derivative, but is not limited thereto.
- the aldehyde group may be exemplified by a propion aldehyde group or a butyl aldehyde group, but is not limited thereto.
- succinimidyl valerate succinimidyl methylbutanoate, succinimidyl methylpropionate, succinimidyl butanoate, succinimidyl propionate, N-hydroxysuccini Mead, hydroxy succinimidyl, succinimidyl carboxymethyl or succinimidyl carbonate may be used, but not limited thereto.
- the final product resulting from reductive alkylation with aldehyde bonds is much more stable than those linked with amide bonds.
- the aldehyde reactive group selectively reacts with the N-terminus at a low pH, and can form a covalent bond with a lysine residue at a high pH, for example, pH 9.0.
- the reactive groups at both ends of the non-peptidyl linker may be the same or different from each other, for example, a maleimide group at one end and an aldehyde group, a propionaldehyde group, or a butyl aldehyde group at the other end. have.
- a biocompatible material specifically, an immunoglobulin Fc region and a GIP derivative can be bound to each end of the non-peptide linker, it is not particularly limited thereto.
- one end of the non-peptidyl linker may include a maleimide group as a reactive group and an aldehyde group, a propionaldehyde group, or a butyl aldehyde group at the other end of the non-peptidyl linker.
- polyethylene glycol having a hydroxyl reactive group at both ends is used as a non-peptidyl polymer
- the hydroxyl group can be activated into the various reactive groups by a known chemical reaction, or a commercially available polyethylene glycol having a modified reactive group is used.
- Long-acting binders can be prepared.
- the non-peptidyl polymer may be linked to a cysteine residue of a GIP derivative, more specifically, a -SH group of cysteine, but is not limited thereto.
- maleimide-PEG-aldehyde is used, the maleimide group is linked to the -SH group of the GIP derivative by a thioether bond, and the aldehyde group is reduced to the -NH 2 group of a biocompatible material, specifically, immunoglobulin Fc. It may be linked through an alkylation reaction, but is not limited thereto, and this corresponds to one example.
- the reactive group of the non-peptidyl polymer may be linked to -NH 2 located at the N-terminus of the immunoglobulin Fc region, but this corresponds to one example.
- binder according to the one aspect may be represented by the following Chemical Formula 1:
- X is a GIP derivative
- L is a linker
- F is a biocompatible material that increases the in vivo half-life of X
- L may be La, wherein a is 0 or a natural number, provided that when a is 2 or more, each L may be independent of each other.
- the linker may be polyethylene glycol (PEG) represented by the following formula (2), but is not limited thereto:
- the PEG moiety in the long-acting conjugate may include, but is not limited to, the -(CH2CH2O)n-structure as well as an oxygen atom intervening between the linking element and the -(CH2CH2O)n-.
- the polyethylene glycol is a term encompassing all forms of ethylene glycol homopolymer, PEG copolymer, or monomethyl-substituted PEG polymer (mPEG), but is not particularly limited thereto.
- the - may represent a covalent linkage between X and L and between L and F.
- the GIP derivative or its conjugate acts on macrophages to inhibit inflammation-related cytokines IL-6, IL-12/23 p40, IL-1 ⁇ , and TNF- ⁇ , thereby exhibiting an anti-inflammatory effect, and related to inflammation of alveolar epithelial cells It was confirmed that by inhibiting the genes IL-6, IL-12, and TNF- ⁇ , anti-inflammatory effects were exhibited, and pulmonary fibrosis could be improved by inhibiting the epithelial-mesenchymal transition (EMT) of alveolar epithelial cells. In addition, it was confirmed that the long-acting GIP derivative can improve lung inflammation and emphysema even in vivo .
- EMT epithelial-mesenchymal transition
- the pharmaceutical composition may have one or more of the following effects:
- EMT epithelial-mesenchymal transition
- the inhibition of lung inflammation may be by inhibiting any one or more of the inflammation-related cytokines IL-6, IL-12/23 p40, IL-1 ⁇ , and TNF- ⁇ .
- the inhibition of lung inflammation may be by inhibiting any one or more of the inflammation-related genes IL-6, IL-12 and TNF- ⁇ in alveolar epithelial cells.
- the pharmaceutical composition may improve pulmonary fibrosis by inhibiting epithelial-mesenchymal transition (EMT) of alveolar epithelial cells.
- EMT epithelial-mesenchymal transition
- the GIP derivative or a conjugate thereof may be used for the prevention or treatment of lung diseases, for example, the prevention or treatment of lung diseases related to lung inflammation, pulmonary fibrosis, and emphysema.
- prevention refers to any action that inhibits or delays the onset of lung disease by administration of the composition.
- treatment refers to any action in which the symptoms of lung disease are improved or beneficial by administration of the composition.
- the "lung diseases” refers to diseases occurring in the lungs, bronchial tubes, or a combination thereof.
- the lung disease may be a disease having a pathogenesis of inflammation of the lungs, pulmonary fibrosis, emphysema, or a combination of two or more thereof.
- the lung disease is interstitial lung disease, progressive fibrotic interstitial lung disease, idiopathic interstitial pneumonia, non-specific interstitial pneumonia, pulmonary fibrosis, interstitial pulmonary fibrosis, idiopathic pulmonary fibrosis, alveolitis, pneumonia, emphysema, It may be one or more selected from the group consisting of bronchitis, asthma, pulmonary fibrosis - emphysema complex disease (CPFE), chronic obstructive pulmonary disease (COPD), and coronavirus infection-19 (COVID-19), but is not limited thereto.
- CPFE pulmonary fibrosis - emphysema complex disease
- COVID-19 coronavirus infection-19
- interstitial lung disease is a generic term for diseases that show abnormal collagen deposition by infiltration and sometimes fibrosis of various inflammatory cells along with proliferation of the interstitial part of the lung.
- the interstitial lung disease includes progressive fibrotic interstitial lung disease.
- IIP interstitial pneumonia
- non-specific interstitial pneumonia is a type of idiopathic interstitial pneumonia. It refers to interstitial pneumonia that cannot be classified into any of the following types: desquamative interstitial pneumonia (DIP), cryptogenic organizing pneumonia (COP), and acute interstitial pneumonia (AIP).
- DIP desquamative interstitial pneumonia
- COP cryptogenic organizing pneumonia
- AIP acute interstitial pneumonia
- the “pulmonary fibrosis” is a disease in which lung tissue is damaged and damaged and degenerated to be thick and hard, and the lungs do not function normally.
- the pulmonary fibrosis may include interstitial pulmonary fibrosis, idiopathic pulmonary fibrosis, and the like.
- the “alveolitis” refers to inflammation occurring in the alveoli.
- the "pneumonia” refers to an inflammatory respiratory disease occurring in the lung parenchyma consisting of peripheral bronchi and alveoli.
- the "emphysema” refers to a condition in which the peripheral airway alveoli are destroyed and irregularly expanded.
- the emphysema is one cause of chronic obstructive pulmonary disease.
- the most significant risk factor among the causes of emphysema is smoking, and occupational dust, chemicals, and indoor and outdoor air pollution are also related.
- the "bronchitis” is an inflammation that occurs in the bronchi of the lungs.
- the bronchitis is classified into acute bronchitis and chronic bronchitis.
- the bronchitis may be chronic bronchitis.
- the "asthma” is a disease in which symptoms such as cough and shortness of breath repeatedly occur due to severe narrowing of the bronchi due to inflammation of the bronchi when exposed to a specific causative agent.
- CPFE pulmonary fibrosis and emphysema
- COPD chronic obstructive pulmonary disease
- coronavirus disease is an infectious disease transmitted by a coronavirus.
- the coronavirus infection may be COVID-19, but is not limited thereto.
- the "coronavirus infection-19 (COVID-19)” is an infectious disease infected by severe acute respiratory syndrome coronavirus 2: SARS-CoV-2.
- COVID-19 can be transmitted when droplets (saliva) from an infected person penetrate the respiratory tract or the mucous membranes of the eyes, nose, or mouth. Symptoms of COVID-19 may include fever, malaise, cough, shortness of breath, pneumonia, sputum, sore throat, headache, hemoptysis and nausea, or diarrhea.
- the lung disease may be pneumonia (inflammation of the lungs) or pulmonary fibrosis caused by COVID-19.
- the pharmaceutical composition may further include a pharmaceutically acceptable carrier.
- Pharmaceutically acceptable carriers may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, dyes and fragrances, etc. for oral administration, and in the case of injections, buffers, preservatives, pain relief
- a topical agent, solubilizer, isotonic agent, and stabilizer may be mixed and used, and in the case of topical administration, a base, excipient, lubricant, and preservative may be used.
- the pharmaceutical composition may further include a pharmaceutically acceptable excipient.
- the formulation of the pharmaceutical composition may be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above.
- a pharmaceutically acceptable carrier for example, in the case of oral administration, it may be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups and wafers, and in the case of injections, it may be prepared in the form of unit dose ampoules or multiple doses.
- it can be formulated into solutions, suspensions, tablets, pills, capsules, sustained-release preparations, and the like.
- suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl Cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil may be used.
- fillers, anti-agglomeration agents, lubricants, wetting agents, fragrances, emulsifiers and preservatives may be further included.
- the pharmaceutical composition may further include one or more other agents for treating a lung disease.
- the other agent may be an anti-inflammatory agent or an immunosuppressive agent, but is not limited thereto. More specifically, the other agent may be a therapeutic agent for lung disease, but is not limited thereto.
- Anti-inflammatory agent refers to a compound for the treatment of an inflammatory disease or condition associated therewith.
- Anti-inflammatory agents include, but are not limited to, non-steroidal 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 (eg, prednisone, betamethasone) , budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, tramcinolone, and fluticasone),
- the anti-inflammatory agent is a statin or high-density lipoprotein (HDL) and HDL-cholesterol-raising compound.
- Immunosuppressant and “immunosuppressive agent” include compounds or compositions that inhibit an immune response or symptoms associated therewith.
- Immunosuppressants include, but are not limited to, purine analogs (eg, azathioprine), methotrexate, cyclosporine (eg, cyclosporine A), cyclophosphamide, leflunomide, mycophenolate (mycophenolate parent).
- steroids e.g., glucocorticoids, corticosteroids
- methylprednisone prednisone
- nonsteroidal anti-inflammatory drugs NSAIDs
- chloroquine hydroxychloroquine
- chlorambucil CD20 antagonists (e.g., rituximab, ocrelizumab) , beltuzumab or ofatumumab), abatacept
- TNF antagonists eg, infliximab, adalimumab, etanercept
- macrolides eg, pimecrolimus, tacrolimus (FK506), and siroli mus
- dihydroepiandrosterone lenalidomide
- CD40 antagonist eg anti-CD40L antibody
- BLys antagonist eg anti-BLyS (eg belimumab)
- dactinomycin bucilamine
- penicillamine leflunomide
- mer
- the immunosuppressive agent is methotrexate, hydroxychloroquine, a CD20 antagonist (eg, rituximab, ocrelizumab, veltuzumab, or ofatumumab), abatacept, a TNF antagonist (eg, infliximab, a dalimumab, etanercept), sirolimus, and a BLyS antagonist (eg, anti-BLyS (eg, belimumab)).
- a CD20 antagonist eg, rituximab, ocrelizumab, veltuzumab, or ofatumumab
- abatacept eg, a TNF antagonist (eg, infliximab, a dalimumab, etanercept)
- sirolimus eg, infliximab, a dalimumab, etanercept
- BLyS antagonist e
- a “therapeutic agent for lung disease” includes a compound or composition that inhibits or treats symptoms associated with lung disease.
- the lung disease therapeutic agent a known substance may be used.
- the lung disease therapeutic agent may be roflumilast or the like.
- the dosage and frequency of administration of the pharmaceutical composition is determined according to the type of drug as the active ingredient, along with several related factors such as the disease to be treated, the route of administration, the age, sex and weight of the patient, and the severity of the disease.
- the pharmaceutical composition Since the pharmaceutical composition has excellent in vivo persistence and potency, the number and frequency of administration can be significantly reduced.
- Another aspect is preventing or treating lung disease, comprising administering an effective amount of the GIP derivative, a pharmaceutically acceptable salt, a solvate thereof, or the conjugate thereof, or the pharmaceutical composition to an individual in need thereof provides a way to
- the GIP derivative, its pharmaceutically acceptable salt, its solvate, the conjugate, the pharmaceutical composition, and lung disease are the same as described above.
- an “effective amount” or “pharmaceutically effective amount” means the GIP derivative, pharmaceutically acceptable salt, solvate, or Refers to the amount or dose of a combination thereof.
- An effective amount can be readily determined by the attending physician of ordinary skill in the art by using known techniques or by observing the results obtained under similar circumstances. When determining an effective amount for a patient, the mammalian species; his size, age and general health; the specific disease or disorder involved; degree or severity of involvement of the disease or disorder; individual patient response; the particular compound being administered; mode of administration; the bioavailability characteristics of the agent being administered; selected dosing regimen; use of concomitant medications; and other relevant circumstances are considered by the attending physician.
- “Individual” refers to a subject in need of treatment for a disease, and more specifically refers to mammals such as human or non-human primates, mice, rats, dogs, cats, horses and cattle. .
- administration is meant introducing a substance into a patient by any suitable method.
- the route of administration may be any general route that can reach the patient's in vivo target.
- the administration may be, for example, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, or rectal administration, but is not limited thereto.
- the dosage may be prescribed in various ways depending on factors such as formulation method, administration mode, age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and response sensitivity of the patient, and those skilled in the art will appreciate such factors
- the dosage can be appropriately adjusted taking these factors into account.
- the number of administration may be once a day or twice or more within the range of clinically acceptable side effects, and may be administered to one or two or more sites for the administration site, and total daily or at intervals of 2 to 5 days.
- the number of days of administration may range from 1 to 30 days per treatment. If necessary, the same treatment can be repeated after a titration period.
- the same dose as that of humans per kg or, for example, the above dose is converted by the volume ratio (for example, the average value) of the target animal and the human organ (heart, etc.) One dose can be administered.
- an effective amount of the GIP derivative, a pharmaceutically acceptable salt thereof, a solvate thereof, or a conjugate thereof may be administered simultaneously, separately, or sequentially with an effective amount of one or more other active ingredients.
- the one or more other active ingredients may be one or more other agents for treating lung disease, but are not limited thereto.
- Another aspect provides the use of the GIP derivative, a pharmaceutically acceptable salt thereof, a solvate thereof, or the conjugate for use in the manufacture of a medicament for the prevention or treatment of lung disease.
- the GIP derivative, a pharmaceutically acceptable salt thereof, a solvate thereof, the conjugate, and a lung disease are as described above.
- the GIP derivative according to an aspect, or a long-acting conjugate thereof suppresses inflammation of the lung, improves pulmonary fibrosis by inhibiting epithelial-mesenchymal transition of alveolar epithelial cells, and has an effect of improving emphysema, so prevention of lung diseases such as COPD or for therapeutic purposes.
- FIG. 1 is a diagram showing the results of preparing a GIP derivative (SEQ ID NOs: 11, 17, 21, and 24)-PEG-immunoglobulin Fc region conjugate and analyzing it by SDS-PAGE.
- 2A is a graph showing the relative expression levels of inflammation-related genes IL-6, IL-12, IL-1 ⁇ , and TNF- ⁇ after treatment with native GIP or long-acting GIP derivatives.
- 2B is a graph showing the concentrations (ng/mL) of inflammation-related cytokines IL-6, IL-12/23 p40, IL-1 ⁇ , and TNF- ⁇ after treatment with native GIP or long-acting GIP derivatives.
- 3A is a graph showing the relative expression levels of inflammation-related genes IL-6, IL-12, and TNF- ⁇ after treatment with native GIP or long-acting GIP derivatives.
- 3B is a graph showing the relative expression levels of EMT markers fibronectin, Col1 ⁇ 1, and Col3 ⁇ 1 after treatment with native GIP or long-acting GIP derivatives.
- 5A is a graph showing lung weights 3 weeks after administration of a normal mouse control group, an excipient control group, a group administered with roflumilast, and a group administered with a long-acting GIP derivative.
- 5B is a graph showing the relative expression levels of the inflammatory cytokines IL-1 ⁇ , IL-6, IL-12 and TNF- ⁇ in the lung tissue in the normal mouse control group, the excipient control group, the roflumilast administration group and the long-acting GIP derivative administration group. .
- GIP derivatives exhibiting activity on human GIP receptors were prepared and their sequences are shown in Table 1 below.
- Aib amino acid denoted by Aib in the sequence shown in Table 1 is Aib (aminoisobutyric acid), which is a non-natural amino acid.
- the GIP derivative peptide is used as a GIP derivative having an amidated C-terminus if necessary.
- Example 1 In order to measure the activity of the GIP derivative prepared in Example 1, a method for measuring the cell activity in vitro using a GIP receptor-transformed cell line was used.
- the cell line was transformed to express each human GIP receptor gene in CHO (chinese hamster ovary), and is suitable for measuring the activity of GIP.
- human GIP was serially diluted from 16 nM to 0.000015 nM by 4 times, and the GIP derivative prepared in Example 1 was diluted from 16 nM to 4 times each. Serial dilutions to 0.000015 nM.
- the culture medium was removed from the cultured CHO cells expressing the human GIP receptor, 5 ⁇ l of each serially diluted substance was added to the cells, and 5 ⁇ l of a buffer containing cAMP antibody was added thereto, followed by room temperature for 15 minutes. cultured in Then, 10 ⁇ l of a detection mix containing cell lysis buffer was added to lyse the cells, followed by reaction at room temperature for 90 minutes. The cell lysate after the reaction was completed was applied to the LANCE cAMP kit (PerkinElmer, USA) to calculate the EC 50 value through the accumulated cAMP, and then compared with each other.
- LANCE cAMP kit PerkinElmer, USA
- Relative titers of human GIP receptors compared to human GIP are shown in Table 2 below.
- a long-acting conjugate including the GIP derivative prepared in Example 1 was prepared. Specifically, the GIP derivatives of SEQ ID NOs: 11, 17, 21 and 24 were linked to the immunoglobulin Fc region via PEG, a non-peptidic polymer, respectively.
- the specific manufacturing process of the long-acting conjugate was as follows, and the same process was repeated to prepare the GIP derivative conjugates of SEQ ID NOs: 11, 17, 21 and 24.
- the molar ratio of the single pegylated immunoglobulin Fc region to the GIP derivative (SEQ ID NOs: 11, 17, 21 and 24) is 1:1 to 3, total protein At a concentration of 0.1 to 0.5 mg/ml, the reaction was carried out in a buffer containing isopropanol at 4 to 8° C. for about 14 to 18 hours.
- the reaction solution was purified by using a Source 15ISO (GE Healthcare Life Science, USA) column, in which GIP derivatives (SEQ ID NOs: 11, 17, 21 and 24) were covalently linked by PEG to the immunoglobulin Fc region, respectively.
- Example 3 In order to measure the activity of the long-acting GIP conjugate prepared in Example 3, in the same manner as in Example 2, a method of measuring cell activity in vitro using a GIP receptor-transformed cell line was used.
- 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, 5 ⁇ l of each serially diluted substance was added to the cells, and 5 ⁇ l of a buffer containing cAMP antibody was added thereto, followed by room temperature for 15 minutes.
- Relative titers of human GIP receptors compared to human GIP are shown in Table 3 below.
- the GIP derivative of the present invention possesses the activity of native GIP, and especially when it is prepared as a long-acting conjugate, it exhibits an activity equal to or higher than that of native GIP and has an increased half-life, so it has excellent properties as a drug. indicates
- a human monocyte/macrophage cell line THP-1 cell line
- Macrophages are known to induce the progression of inflammation by secreting cytokines and chemokines at the initial stage of infection and mobilizing other immune cells.
- the THP-1 cell line was based on RPMI 1640 in a medium supplemented with 10% FBS (fetal bovine serum), 100 ⁇ g/mL streptomycin, 100 U/mL penicillin, and 0.05 mM ⁇ -mercaptoethanol, 37 It was cultured at °C, 5% carbon dioxide conditions. An inflammatory response was induced by adding LPS (Lipopolysaccharide) to the cell line at 1 ⁇ g/mL, and the effect on the inflammatory response by LPS when treated with native GIP and long-acting GIP derivatives was confirmed at the mRNA level.
- LPS Lipopolysaccharide
- the native GIP was diluted to a concentration of 10 ⁇ M, and the long-acting GIP derivative was diluted to a concentration of 1 or 10 ⁇ M.
- the long-acting GIP derivative the long-acting GIP conjugate (SEQ ID NO: 17) prepared in Example 3 was used.
- the treated THP-1 cell line was isolated from RNA using the RNeasy Mini Kit (Qiagen, U.S.), and cDNA was synthesized using the iScriptTM cDNA Synthesis Kit (Bio-rad, U.S.). The expression level of inflammation-related genes was checked for the synthesized cDNA using the QuantStudio 6 Flex Real-Time PCR System (Applied Biosystems, U.S.). Delta Delta Ct method was used, and beta-actin was used as a housekeeping gene. IL-6, IL-12, IL-1 ⁇ , and TNF- ⁇ were identified as inflammation-related genes.
- 2A is a graph showing the relative expression levels of inflammation-related genes IL-6, IL-12, IL-1 ⁇ , and TNF- ⁇ after treatment with native GIP or long-acting GIP derivatives.
- PMA Phorbol 12-myristate 13-acetate
- 2B is a graph showing the concentrations (ng/mL) of the inflammation-related cytokines IL-6, IL-12/23 p40, IL-1 ⁇ , and TNF- ⁇ after treatment with native GIP or long-acting GIP derivatives.
- Example 6 Improvement of inflammation and fibrosis of long-acting GIP conjugates in-vitro Effect check
- the human alveolar epithelial cell A549 cell line was used to confirm the effect of the long-acting GIP derivative for improving inflammation and fibrosis on COPD in-vitro .
- the purpose of this study was to determine the effect on epithelial mesenchymal transition (EMT) of alveolar epithelial cells, which is known to be important in the pulmonary fibrosis process.
- EMT epithelial mesenchymal transition
- the A549 cell line was cultured in a medium supplemented with 10% fetal bovine serum (FBS), 100 ⁇ g/mL streptomycin, and 100 U/mL penicillin based on F-12K at 37° C. and 5% carbon dioxide. Cell lines were sequentially treated with TGF- ⁇ 1 and LPS to induce inflammatory responses and EMT.
- the native GIP was diluted to a concentration of 10 ⁇ M
- the long-acting GIP derivative was diluted to a concentration of 1 or 10 ⁇ M.
- the long-acting GIP conjugate (SEQ ID NO: 17) prepared in Example 3 was used as the long-acting GIP derivative.
- 3A is a graph showing the relative expression levels of inflammation-related genes IL-6, IL-12, and TNF- ⁇ after treatment with native GIP or long-acting GIP derivatives.
- 3B is a graph showing the relative expression levels of EMT markers fibronectin, Col1 ⁇ 1, and Col3 ⁇ 1 after treatment with native GIP or long-acting GIP derivatives.
- EMT markers increased when TGF- ⁇ and LPS were treated, but these also decreased again when treated with native GIP and long-acting GIP derivatives.
- the long-acting GIP derivative can improve chronic bronchitis and pulmonary fibrosis by inhibiting inflammation and epithelial-mesenchymal transition (EMT) of alveolar epithelial cells.
- EMT epithelial-mesenchymal transition
- COPD animal model mice administered ELA 0.2U/mouse to C57BL/6 mice were treated with excipient control group, long-acting GIP derivative (3.16 mg/kg, Q2D, subcutaneous) group.
- excipient control group long-acting GIP derivative (3.16 mg/kg, Q2D, subcutaneous) group.
- the long-acting GIP derivative the long-acting GIP conjugate (SEQ ID NO: 17) prepared in Example 3 was used.
- the lung tissue of each mouse was taken as an autopsy, and the degree of emphysema of the lung tissue was evaluated through H&E staining.
- the lung weight was measured, and the degree of change in the expression of inflammatory cytokines in the lung tissue following administration of an excipient, a long-acting GIP derivative, or roflumilast was confirmed through qPCR to evaluate the effect on inflammation.
- 5A is a graph showing lung weights 3 weeks after administration of a normal mouse control group, an excipient control group, a group administered with roflumilast, and a group administered with a long-acting GIP derivative.
- 5B is a graph showing the relative expression levels of the inflammatory cytokines IL-1 ⁇ , IL-6, IL-12 and TNF- ⁇ in the lung tissue in the normal mouse control group, the excipient control group, the roflumilast administration group and the long-acting GIP derivative administration group. .
- the degree of inflammation can be indirectly confirmed through the weight of the lung.
- the lung weight was significantly reduced compared to the excipient control group and roflumilast.
- the gene expression of inflammatory cytokines in the lung tissue showed a tendency to significantly decrease in the group administered with the long-acting GIP derivative compared to the control group.
- the long-acting GIP derivative exerts an anti-inflammatory effect by acting on macrophages and inhibiting the inflammation-related cytokines IL-6, IL-12/23 p40, IL-1 ⁇ , and TNF- ⁇ , and inflammation of alveolar epithelial cells. It was confirmed that pulmonary fibrosis can be improved by inhibiting related genes IL-6, IL-12, and TNF- ⁇ to exhibit an anti-inflammatory effect, and by inhibiting epithelial-mesenchymal transition (EMT) of alveolar epithelial cells. In addition, it was confirmed that the long-acting GIP derivative can improve lung inflammation and emphysema even in vivo .
- EMT epithelial-mesenchymal transition
- the long-acting GIP derivative can be used as a treatment for lung diseases such as pneumonia, alveolitis, asthma, pulmonary fibrosis, emphysema, chronic bronchitis, COPD, and COVID-19.
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Abstract
Description
서열번호 | 아미노산 서열 |
1 | YAibEGT FISDY SIAMD AIAQQ DFVNW LLAQK PSSGA PPPSC |
2 | YAibEGT FISDY SIAMD AIAQQ DFVNW LLAGG PSSGA PPPSC |
3 | YAibEGT FISDY SIAibMD AIAQQ DFVNW LLAGG PSSGA PPPSC |
4 | YAibEGT FISDY SIYMD AIAQQ DFVNW LLAGG PSSGA PPPSC |
5 | YAibEGT FISDY SIQMD AIAQQ DFVNW LLAGG PSSGA PPPSC |
6 | YAibEGT FISDY SIYLD AIAQQ DFVNW LLAGG PSSGA PPPSC |
7 | YAibEGT FISDY SIYLD AQAQQ DFVNW LLAGG PSSGA PPPSC |
8 | YAibEGT FISDY SIYLD AQAAAib DFVNW LLAGG PSSGA PPPSC |
9 | YAibEGT FISDY SIYLD AQAAK DFVNW LLAGG PSSGA PPPSC |
10 | YAibEGT FISDY SIYLD AQAAK EFIAW LLAGG PSSGA PPPSC |
11 | YAibEGT FISDY SIAMD AIAQQ DFVNW LLAQK GKKND WKHNI TQC |
12 | YAibEGT FISDY SIYLD KQAAAib EFVNW LLAQK GKKND WKHNI TQC |
13 | YAibEGT FISDY SIYLD KQAAAib EFVNW LLAQK C |
14 | YAibEGT FISDY SIYLD AQAAAib EFVNW LLAQK C |
15 | YAibEGT FISDY SIAMD KIAQQ DFVNW LLAQK PSSGA PPPSC |
16 | YAibEGT FISDY SIAMD GIAQQ DFVNW LLAQK PSSGA PPPSC |
17 | YAibEGT FISDY SIALE KQAQQ DFVNW LLAGG PSSGA PPPSC |
18 | YAibEGT FISDY SIYLD KQAAQ EFVNW LLAQK PSSGA PPPSC |
19 | YAibEGT FISDY SIYLD KQAAAib EFVNW LLAibGH PSSGA PPPSC |
20 | YAibEGT FISDY SIYLD KQAAAib EFVNW LLAibGG PSSGA PPPSC |
21 | YAibEGT FISDY SIAibLD KQAAAib EFVNW LLAibGG PSSGA PPPSC |
22 | YAibEGT FISDY SIYLD KQAAAib EFVNW LLAGH PSSGA PPPSC |
23 | YAibEGT FISDY SIYLD KQAQK EFVNW LLAibGG PSSGA PPPSC |
24 | YAibEGT FISDY SIAibLD KQAAAib EFVNW LLAibGH PSSGA PPPSC |
25 | YAibEGT FISDY SIYLD KQAAAib EFVQW LIAibGG PSSGA PPPSC |
26 | YAibEGT FISDY SIYLD KQAAAib EFVQW LIAGH PSSGA PPPC |
서열번호 | 인간 GIP 수용체에서 인간 천연형 GIP 대비 GIP 유도체의 In vitro 활성 (%) |
1 | 49.3% |
2 | 13.9% |
3 | 15.6% |
4 | 10.5% |
5 | 12.1% |
6 | 17.4% |
7 | 19.6% |
8 | 1.9% |
9 | 2.0% |
10 | 13.9% |
11 | 121.9% |
12 | 49.2% |
13 | 31.1% |
14 | 17.4% |
15 | 31.1% |
16 | 11.3% |
17 | 111.4% |
18 | 13.6% |
19 | 66.7% |
20 | 75.3% |
21 | 122.7% |
22 | 71.6% |
23 | 87.6% |
24 | 183.0% |
25 | 78.3% |
26 | 66.7% |
서열번호 | 인간 GIP 수용체에서 인간 천연형 GIP 대비 지속형 GIP 결합체의 In vitro 활성 (%) |
11 | 84.8% |
17 | 153.2% |
21 | 148.5% |
24 | 123.3% |
Claims (10)
- 폐질환의 예방 또는 치료를 위한 약학적 조성물로서,약학적으로 허용되는 부형제와 서열번호 1 내지 26 중 어느 하나의 아미노산 서열을 포함하는 펩타이드를 약학적 유효량으로 포함하는 약학적 조성물.
- 청구항 1에 있어서, 상기 펩타이드는 지속형 결합체의 형태이고, 상기 지속형 결합체는 하기 화학식 1로 표시되는 약학적 조성물:[화학식 1]X - L - F단, 이때 X는 서열번호 1 내지 26 중 어느 하나의 아미노산 서열을 포함하는 펩타이드이고;L은 에틸렌글리콜 반복 단위를 함유하는 링커이며,F는 면역글로불린 Fc 영역이고,-는 X와 L 사이, L과 F 사이의 공유결합 연결을 나타낸다.
- 청구항 1 또는 청구항 2에 있어서, 상기 펩타이드는 그 C-말단이 아미드화된 약학적 조성물.
- 청구항 1 또는 청구항 2에 있어서, 상기 펩타이드는 서열번호 11, 17, 및 19 내지 26으로 구성된 군으로부터 선택된 아미노산 서열을 포함하는 약학적 조성물.
- 청구항 4에 있어서, 상기 펩타이드는 서열번호 11, 17, 21 및 24로 구성된 군으로부터 선택된 아미노산 서열을 포함하는 약학적 조성물.
- 청구항 2에 있어서, 상기 L 내의 에틸렌글리콜 반복 단위 부분의 화학식량은 1 내지 100 kDa 범위에 있는 약학적 조성물.
- 청구항 2에 있어서, 상기 F는 IgG Fc 영역인, 약학적 조성물.
- 청구항 1 또는 청구항 2에 있어서, 상기 약학적 조성물은 하기 중 어느 하나 이상의 효과를 갖는 것인, 약학적 조성물:(i) 폐의 염증 억제;(ii) 폐포상피세포의 상피간엽이행(EMT)의 억제; 및(iii) 폐기종의 개선.
- 청구항 1 또는 청구항 2에 있어서, 상기 폐질환은 간질성 폐질환, 진행성 섬유화 간질성 폐질환, 특발성 간질성 폐렴, 비특이성 간질성 폐렴, 폐섬유증, 간질성 폐섬유증, 특발성 폐섬유증, 폐포염, 폐렴, 폐기종, 기관지염, 천식, 폐섬유화증-폐기종 복합질환(Combined pulmonary fibrosis and emphysema, CPFE), 만성폐쇄성폐질환(COPD), 및 코로나바이러스감염증으로 구성된 군으로부터 선택된 하나 이상인 것인, 약학적 조성물.
- 청구항 9에 있어서, 상기 코로나바이러스감염증은 코로나바이러스감염증-19(COVID-19)인 것인, 약학적 조성물.
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CN202280010281.1A CN116847868A (zh) | 2021-01-29 | 2022-01-27 | 用于预防或治疗肺部疾病的包括gip衍生物或其长效共轭物的药学组合物 |
EP22746248.8A EP4342487A2 (en) | 2021-01-29 | 2022-01-27 | Pharmaceutical composition comprising gip derivative or long-acting conjugate thereof for preventing or treating pulmonary disease |
JP2023546299A JP2024505943A (ja) | 2021-01-29 | 2022-01-27 | Gip誘導体、またはその持続型結合体を含む肺疾患の予防用または治療用の薬学的組成物 |
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JP (1) | JP2024505943A (ko) |
KR (1) | KR20220110117A (ko) |
CN (1) | CN116847868A (ko) |
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Citations (2)
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WO1996032478A1 (en) | 1995-04-14 | 1996-10-17 | Genentech, Inc. | Altered polypeptides with increased half-life |
WO1997034631A1 (en) | 1996-03-18 | 1997-09-25 | Board Of Regents, The University Of Texas System | Immunoglobin-like domains with increased half lives |
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EA200400501A1 (ru) * | 2001-10-01 | 2005-06-30 | Эли Лилли Энд Компани | Способ снижения заболеваемости и смертности, связанных с критическими состояниями |
CN116063453A (zh) * | 2015-12-31 | 2023-05-05 | 韩美药品株式会社 | 胰高血糖素/glp-1/gip受体三重激动剂 |
CN110642935A (zh) * | 2019-09-25 | 2020-01-03 | 成都奥达生物科技有限公司 | 一种替瑞帕肽类似物 |
KR20200131784A (ko) * | 2020-11-04 | 2020-11-24 | (주)신테카바이오 | 제2형 중증급성호흡기증후군 코로나바이러스 감염 질환의 예방 또는 치료용 조성물 |
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WO1996032478A1 (en) | 1995-04-14 | 1996-10-17 | Genentech, Inc. | Altered polypeptides with increased half-life |
WO1997034631A1 (en) | 1996-03-18 | 1997-09-25 | Board Of Regents, The University Of Texas System | Immunoglobin-like domains with increased half lives |
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TW202245828A (zh) | 2022-12-01 |
WO2022164222A3 (ko) | 2022-09-15 |
EP4342487A2 (en) | 2024-03-27 |
CN116847868A (zh) | 2023-10-03 |
JP2024505943A (ja) | 2024-02-08 |
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