WO2018004283A2 - 글루카곤 유도체, 이의 결합체, 및 이를 포함하는 조성물, 및 이의 치료적 용도 - Google Patents
글루카곤 유도체, 이의 결합체, 및 이를 포함하는 조성물, 및 이의 치료적 용도 Download PDFInfo
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- WO2018004283A2 WO2018004283A2 PCT/KR2017/006922 KR2017006922W WO2018004283A2 WO 2018004283 A2 WO2018004283 A2 WO 2018004283A2 KR 2017006922 W KR2017006922 W KR 2017006922W WO 2018004283 A2 WO2018004283 A2 WO 2018004283A2
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- cysteine
- peptide
- lysine
- valine
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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- 241001515965 unidentified phage Species 0.000 description 1
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Images
Classifications
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
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- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
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- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
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- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
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- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
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-
- 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
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- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/31—Fusion polypeptide fusions, other than Fc, for prolonged plasma life, e.g. albumin
Definitions
- Exendin-4 made from a lizard venom with approximately 50% amino acid homology with GLP-1, is also known to activate GLP-1 receptors to reduce hyperglycemia in diabetic patients ( J Biol Chem. 1992 Apr 15; 267 (11): 7402-5.). However, it has been reported that drugs for treating obesity, including GLP-1 or exendin-4, exhibit problems that cause side effects of vomiting and nausea.
- X21 is aspartic acid (D), glutamic acid (E), leucine (L), valine (V), or cysteine (C) or is absent;
- X16 is glutamic acid (E), serine (S) or cysteine (C);
- X7 is cysteine (C), threonine (T), or valine (V);
- X20 is glutamine (Q) or lysine (K);
- X14 is leucine (L) or cysteine (C);
- X16 is glutamic acid (E), serine (S) or cysteine (C);
- X27 is isoleucine (I) or methionine (M);
- X27 is methionine (M).
- X20 is glutamine (Q) or lysine (K);
- one specific form of the invention is X10 and X14, X12 and X16, X16 and X20, X17 and X21, X20 and X24, and X24 of Formula 1 or 2
- Each of the amino acids of at least one amino acid pair of the amino acid pair of X28 is substituted with glutamic acid or lysine capable of forming a ring.
- one specific form of the present invention is represented by Formula 1 or 2, X10 and X14, X12 and X16, X16 and X20, X17 and X21, X20 and X24, and X24 And at least one amino acid pair of the amino acid pair of X28 to form a ring (eg, a lactam ring) between each amino acid.
- a ring eg, a lactam ring
- immunoglobulin Fc region is a non-glycosylated Fc region derived from human IgG4.
- X12 is lysine (K) or cysteine (C);
- X24 is valine (V) or glutamine (Q);
- the covalent bond between the peptide moiety and the biocompatible material moiety is characterized in that they are linked to each other via a linker.
- the insulin secreting peptide is GLP-1, exendin-3, exendin-4, agonists, derivatives, fragments thereof, It is characterized in that it is selected from the group consisting of variants and combinations thereof.
- the method further comprises administering a compound or substance having therapeutic activity against one or more metabolic syndrome.
- X13 is tyrosine or cysteine
- X16 is glutamic acid, serine or cysteine
- X18 is arginine, or cysteine
- X7 is cysteine, threonine, or valine
- X10 is tyrosine or cysteine
- X29 is threonine
- X14 is leucine or cysteine
- X16 is glutamic acid, serine or cysteine
- X17 is aspartic acid, glutamic acid, lysine, arginine, serine, cysteine, or valine;
- X18 is aspartic acid, glutamic acid, arginine, or cysteine;
- X24 is valine or glutamine
- X1 is tyrosine
- X18 is arginine
- the peptide according to the present invention may be unmodified N-terminus and / or C-terminus, but in order to protect from protein cleavage enzymes in vivo and increase stability, the N-terminus and / or C-terminus thereof, etc.
- This chemically modified or protected by an organic group, or modified form by addition of amino acids in the peptide terminal is also included in the scope of the peptide according to the present invention.
- the terminal of the peptide according to the present invention has a carboxyl group, but is not particularly limited thereto.
- pharmaceutically acceptable means a substance that can be effectively used for a desired use without causing excessive toxicity, irritation, or allergic reactions within the scope of medical judgment.
- non-peptidyl linker may be selected from the group consisting of fatty acids, saccharides, polymers, low molecular weight compounds, nucleotides, and combinations thereof.
Abstract
Description
서열번호 | 펩타이드 서열 | 고리 형성 여부 | pI | In vitro 활성(서열번호 1에 대한 상대적 활성,%) |
서열번호: 1 | HSQGTFTSDYSKYLDSRRAQDFVQWLMNT | - | 6.8 | 100 |
서열번호: 2 | HSQGTFTSDYSKYLDCDRAQDFVQWLMNT | - | 4.56 | 0.6 |
서열번호: 3 | HSQGTFTSDYSKYLDCERAQDFVQWLMNT | - | 4.66 | 6.1 |
서열번호: 4 | HSQGTFTSDYSKYLDSCDAQDFVQWLMNT | - | 4.13 | < 0.1 |
서열번호: 5 | HSQGTFTSDYSKYLDSCEAQDFVQWLMNT | - | 4.22 | 0.3 |
서열번호: 6 | HSQGTFTSDYSKYLDSCEADDFVQWLMNT | - | 4.03 | < 0.1 |
서열번호: 7 | YSQGTFTSDYSKYLDSCEADDFVQWLMNT | - | 3.71 | < 0.1 |
서열번호: 8 | YXQGTFTSDYSKYLDSCDAQDFVQWLINT | - | 3.77 | < 0.1 |
서열번호: 9 | YXQGTFTSDYSKYLDSCDAQDFVVWLINT | - | 3.77 | < 0.1 |
서열번호: 10 | YXQGTFTSDYSKYLDSCDADDFVVWLINT | - | 3.66 | < 0.1 |
서열번호: 11 | YXQGTFTSDYSKYLDEKCAKEFVQWLMNT | - | 4.78 | 4.6 |
서열번호: 12 | YXQGTFTSDYSKYLD E KRA K EFVQWLMNTC | 고리 형성 | 6.20 | 56.3 |
서열번호: 13 | YXQGTFTSDYSCYLDSRRAQDFVQWLMNT | - | 4.43 | 5.2 |
서열번호: 14 | YXQGTFTSDYSKYLDCKRAKEFVQWLMNT | - | 8.12 | 18.1 |
서열번호: 15 | YXQGTFTSDYSKYLCEKRAQDFVVWLMNT | - | 6.11 | 1.1 |
서열번호: 16 | YXQGTFTSDYSKYLDCRRAQVFVQWLMRT | - | 9.11 | 4.2 |
서열번호: 17 | YXQGTFTSDYSKYLDCVRAQDFVQWLMRT | - | 6.03 | 23.2 |
서열번호: 18 | YXQGTFTSDYSKYLDSRRACDFRLWLMNT | - | 8.15 | < 0.1 |
서열번호: 19 | YXQGTFTSDYSKYLC E KRA K EFVQWLMNT | 고리 형성 | 8.12 | 12.1 |
서열번호: 20 | YXQGTFTSDYSKYLD E CRA K EFVQWLMNT | 고리 형성 | 4.78 | 299.7 |
서열번호: 21 | YXQGTFTSDYSKYLD E KCA K EFVQWLMNT | 고리 형성 | 4.78 | 57.8 |
서열번호: 22 | YXQGTFTSDYSKYLD E KRC K EFVQWLMNT | 고리 형성 | 6.20 | 147.8 |
서열번호: 23 | YXQGTFTSDYSKYCD E KRA K EFVQWLMNT | 고리 형성 | 6.20 | 76.8 |
서열번호: 24 | YXQGTFTSDYSKCLD E KRA K EFVQWLMNT | 고리 형성 | 6.21 | 58.0 |
서열번호: 25 | YXQGTFTSDYSKYLD E KRA K CFVQWLMNT | 고리 형성 | 8.12 | 46.9 |
서열번호: 26 | WXQGTFTSDYSKYLD E CRA K DFVQWLMNT | 고리 형성 | 4.68 | 1.0 |
서열번호: 27 | YXQGTFVSDYSKYLD E CRA K DFVQWLMNT | 고리 형성 | 4.68 | 93.6 |
서열번호: 28 | WXQGTFVSDYSKYLD E CRA K DFVQWLMNT | 고리 형성 | 4.68 | < 0.1 |
서열번호: 29 | YXQGTFTSDYSKCLD E RRA K DFVQWLMNT | 고리 형성 | 6.15 | 61.3 |
서열번호: 30 | WXQGTFTSDYSKCLD E RRA K DFVQWLMNT | 고리 형성 | 4.44 | 0.3 |
서열번호: 31 | YXQGTFTSDYSKYLDC K RAK E FVQWLMNT | 고리 형성 | 8.12 | 6.3 |
서열번호: 32 | -SQGTFTSDYSKYLD E CRA K EFVQWLMNT | 고리 형성 | 4.78 | 0.7 |
서열번호: 33 | YXQGTFTSDYSKYLDSRRAQDFVQWLMNT | - | 6.04 | 108.2 |
서열번호: 34 | WXQGTFTSDYSKYCD E RRA K EFVQWLMNT | 고리 형성 | 6.21 | 0.2 |
서열번호: 35 | YXQGTFTSDYSKYCD E RRA K EFVQWLMNT | 고리 형성 | 6.2 | 17.7 |
서열번호: 36 | YXQGTFTSDCSKYLD E RRA K EFVQWLMNT | 고리 형성 | 6.21 | 9.9 |
서열번호: 37 | YXQGTFTSDYSKYLD E RRA K EFVQWLMNTC | 고리 형성 | 6.21 | 225.5 |
서열번호: 38 | YXQGTFCSDYSKYLD E RRA K EFVQWLMNT | 고리 형성 | 6.15 | 167.3 |
서열번호: 39 | YXQGTFVSDCSKYLD E RRA K DFVQWLMNT | 고리 형성 | 6.15 | 3.7 |
서열번호: 40 | YXQGTFVSDYSKYLD E RRA K DFVQWLMNTC | 고리 형성 | 6.15 | 40.8 |
서열번호: 41 | YXQGTFCSDYSKYLD E RRA K DFVQWLMNT | 고리 형성 | 6.03 | 45.2 |
서열번호: 42 | YXQGTFCSDYSKYLDSRRAQDFVQWLMNT | - | 6.03 | 37.9 |
서열번호: 43 | YXQGTFTSDCSKYLDSRRAQDFVQWLMNT | - | 6.03 | 1.6 |
서열번호: 44 | YXQGTFTSDYSKYLDSRRAQDFVQWLMNTC | - | 6.21 | 75.4 |
Claims (58)
- 하기 일반식 1의 아미노산 서열을 포함하는 펩타이드를 포함하는, 선천성 고인슐린증의 예방 또는 치료용 약학적 조성물:X1-X2-QGTF-X7-SD-X10-S-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-F-X23-X24-W-L-X27-X28-X29-X30 (일반식 1, 서열번호: 45)상기 식에서,X1은 히스티딘(H), 데스아미노-히스티딜(desamino-histidyl), 디메틸-히스티딜(N-dimethyl-histidyl), 베타-히드록시 이미다조프로피오닐(beta-hydroxy imidazopropionyl), 4-이미다조아세틸(4-imidazoacetyl), 베타-카르복시 이미다조프로피오닐(beta-carboxy imidazopropionyl), 트립토판(W), 또는 티로신(Y)이거나, 부존재하고;X2는 알파-메틸-글루탐산(α-methyl-glutamic acid), Aib(aminoisobutyric acid), D-알라닌, 글리신(G), Sar(N-methylglycine), 세린(S) 또는 D-세린이며;X7은 트레오닌(T), 발린(V) 또는 시스테인(C)이고;X10은 티로신(Y) 또는 시스테인(C)이고;X12는 리신(K) 또는 시스테인(C)이고;X13은 티로신(Y) 또는 시스테인(C)이고;X14는 류신(L) 또는 시스테인(C)이고;X15는 아스파르트산(D), 글루탐산(E) 또는 시스테인(C)이고;X16은 글루탐산(E), 아스파르트산(D), 세린(S), 알파-메틸-글루탐산, 또는 시스테인(C)이거나, 부존재하며;X17은 아스파르트산(D), 글루타민(Q), 글루탐산(E), 리신(K), 아르기닌(R), 세린(S), 시스테인(C), 또는 발린(V)이거나, 부존재하며;X18은 알라닌(A), 아스파르트산(D), 글루탐산(E), 아르기닌(R), 발린(V), 또는 시스테인(C)이거나, 부존재하며;X19는 알라닌(A), 아르기닌(R), 세린(S), 발린(V), 또는 시스테인(C)이거나, 부존재하며;X20은 리신(K), 히스티딘(H), 글루타민(Q), 아스파르트산(D), 아르기닌 (R), 알파-메틸-글루탐산, 또는 시스테인(C)이거나, 부존재하며;X21은 아스파르트산(D), 글루탐산(E), 류신(L), 발린(V), 또는 시스테인(C)이거나, 부존재하며;X23은 이소류신(I), 발린(V), 또는 아르기닌(R)이거나, 부존재하며;X24는 발린(V), 아르기닌(R), 알라닌(A), 시스테인(C), 글루탐산(E), 리신(K), 글루타민(Q), 알파-메틸-글루탐산, 또는 류신(L)이거나, 부존재하며;X27는 이소류신(I), 발린(V), 알라닌(A), 리신(K), 메티오닌(M), 글루타민(Q), 또는 아르기닌(R)이거나, 부존재하며;X28은 글루타민(Q), 리신(K), 아스파라긴(N), 또는 아르기닌(R)이거나, 부존재하며;X29는 리신(K), 알라닌(A), 글리신(G), 또는 트레오닌(T)이거나, 부존재하며;X30은 시스테인(C)이거나, 부존재함(단, 상기 일반식 1의 아미노산 서열이 서열번호: 1과 동일한 경우는 제외함).
- 제1항에 있어서,상기 일반식 1에서,X1이 히스티딘(H), 트립토판(W), 또는 티로신(Y)이거나, 부존재하고;X2가 세린(S) 또는 Aib(aminoisobutyric acid)이며;X7은 트레오닌(T), 발린(V) 또는 시스테인(C)이고;X10은 티로신(Y) 또는 시스테인(C)이고;X12는 리신(K) 또는 시스테인(C)이고;X13은 티로신(Y) 또는 시스테인(C)이고;X14는 류신(L) 또는 시스테인(C)이고;X15는 아스파르트산(D), 또는 시스테인(C)이고;X16은 글루탐산(E), 세린(S) 또는 시스테인(C)이며;X17은 아스파르트산(D), 글루탐산(E), 리신(K), 아르기닌(R), 세린(S), 시스테인(C), 또는 발린(V) 이고;X18은 아스파르트산(D), 글루탐산(E), 아르기닌(R), 또는 시스테인(C)이며;X19는 알라닌(A), 또는 시스테인(C)이고;X20은 글루타민(Q), 아스파르트산(D), 리신(K), 또는 시스테인(C)이며;X21은 아스파르트산(D), 글루탐산(E), 류신(L), 발린(V), 또는 시스테인(C)이고;X23은 이소류신(I), 발린(V) 또는 아르기닌(R)이며;X24는 발린(V), 아르기닌(R), 알라닌(A), 글루탐산(E), 리신(K), 글루타민(Q), 또는 류신(L)이고;X27는 이소류신(I), 발린(V), 알라닌(A), 메티오닌(M), 글루타민(Q) 또는 아르기닌(R)이며;X28은 글루타민(Q), 리신(K), 아스파라긴(N) 또는 아르기닌(R)이고;X29는 트레오닌(T)이며;X30은 시스테인(C)이거나, 부존재하는,약학적 조성물.
- 제1항에 있어서,상기 일반식 1에서X1이 히스티딘(H), 트립토판(W), 또는 티로신(Y)이고;X2가 세린(S) 또는 Aib(aminoisobutyric acid)이며;X7은 시스테인(C), 트레오닌(T), 또는 발린(V)이고;X10은 티로신(Y) 또는 시스테인(C)이며;X12는 리신(K) 또는 시스테인(C)이고;X13은 티로신(Y) 또는 시스테인(C)이며;X14는 류신(L) 또는 시스테인(C)이고;X15는 아스파르트산(D), 또는 시스테인(C)이며;X16은 글루탐산(E), 세린(S) 또는 시스테인(C)이고;X17은 글루탐산(E), 리신(K), 아르기닌(R), 시스테인(C), 또는 발린(V)이며;X18은 아르기닌(R), 또는 시스테인(C)이고;X19는 알라닌(A), 또는 시스테인(C)이며;X20은 글루타민(Q) 또는 리신(K)이고;X21은 아스파르트산(D), 글루탐산(E), 발린(V), 또는 시스테인(C)이며;X23은 발린(V)이고;X24는 발린(V) 또는 글루타민(Q)이며;X27는 메티오닌(M)이고;X28은 아스파라긴(N) 또는 아르기닌(R)이며;X29는 트레오닌(T)이고;X30은 시스테인(C)이거나, 부존재하는,약학적 조성물.
- 제1항에 있어서,상기 일반식 1에서X1이 티로신(Y)이고;X2가 Aib(aminoisobutyric acid)이며;X7은 시스테인(C), 트레오닌(T), 또는 발린(V)이고;X10은 티로신(Y) 또는 시스테인(C)이며;X12는 리신(K)이고;X13은 티로신(Y) 또는 시스테인(C)이며;X14는 류신(L) 또는 시스테인(C)이고;X15는 아스파르트산(D), 또는 시스테인(C)이며;X16은 글루탐산(E), 세린(S) 또는 시스테인(C)이고;X17은 리신(K), 아르기닌(R), 시스테인(C), 또는 발린(V)이며;X18은 아르기닌(R), 또는 시스테인(C)이고;X19는 알라닌(A), 또는 시스테인(C)이며;X20은 글루타민(Q) 또는 리신(K)이고;X21은 아스파르트산(D), 글루탐산(E), 또는 시스테인(C)이며;X23은 발린(V)이고;X24는 글루타민(Q)이며;X27는 메티오닌(M)이고;X28은 아스파라긴(N) 또는 아르기닌(R)이며;X29는 트레오닌(T)이고;X30은 시스테인(C)이거나, 부존재하는,약학적 조성물.
- 제1항에 있어서,상기 일반식 1에서X1이 히스티딘(H), 트립토판(W), 또는 티로신(Y)이거나, 부존재하고;X2가 세린(S) 또는 Aib(aminoisobutyric acid)이며;X7은 트레오닌(T), 발린(V) 또는 시스테인(C)이고;X10은 티로신(Y) 또는 시스테인(C)이며;X12는 리신(K) 또는 시스테인(C)이고;X13은 티로신(Y) 또는 시스테인(C)이며;X14는 류신(L) 또는 시스테인(C)이고;X15는 아스파르트산(D), 또는 시스테인(C)이며;X16은 글루탐산(E), 세린(S) 또는 시스테인(C)이고;X17은 아스파르트산(D), 글루탐산(E), 리신(K), 아르기닌(R), 세린(S), 시스테인(C), 또는 발린(V) 이며;X18은 아스파르트산(D), 글루탐산(E), 아르기닌(R), 또는 시스테인(C)이고;X19는 알라닌(A), 또는 시스테인(C)이며;X20은 글루타민(Q), 아스파르트산(D), 또는 리신(K)이고;X21은 아스파르트산(D), 또는 글루탐산(E)이며;X23은 발린(V)이고;X24는 발린(V) 또는 글루타민(Q)이며;X27는 이소류신(I) 또는 메티오닌(M)이고;X28은 아스파라긴(N) 또는 아르기닌(R)이며;X29는 트레오닌(T)이고;X30은 시스테인(C)이거나, 부존재하는,약학적 조성물.
- 제1항에 있어서,상기 일반식 1에서X1이 티로신(Y)이고;X2가 Aib(aminoisobutyric acid)이며;X7은 트레오닌(T)이고;X10은 티로신(Y)이며;X12는 리신(K)이고;X13은 티로신(Y)이며;X14는 류신(L)이고;X15는 아스파르트산(D), 또는 시스테인(C)이며;X16은 글루탐산(E), 세린(S) 또는 시스테인(C)이고;X17은 리신(K) 또는 아르기닌(R)이며;X18은 아르기닌(R)이고;X19는 알라닌(A)이며;X20은 글루타민(Q), 시스테인(C), 또는 리신(K)이고;X21은 아스파르트산(D), 시스테인(C), 발린(V) 또는 글루탐산(E)이며;X23은 발린(V) 또는 아르기닌(R)이고;X24는 글루타민(Q) 또는 류신(L)이며;X27는 메티오닌(M)이고;X28은 아스파라긴(N) 또는 아르기닌(R)이며;X29는 트레오닌(T)이고;X30은 부존재하는,약학적 조성물.
- 제1항에 있어서, 상기 펩타이드는 하기 일반식 2의 아미노산 서열을 포함하는 펩타이드인, 약학적 조성물:Y-Aib-QGTF-X7-SD-X10-S-X12-Y-L-X15-X16-X17-R-A-X20-X21-F-V-X24-W-L-M-N-T-X30 (일반식 2, 서열번호: 46)상기 일반식 2에서X7은 트레오닌(T), 발린(V) 또는 시스테인(C)이고;X10은 티로신(Y) 또는 시스테인(C)이고;X12는 리신(K) 또는 시스테인(C)이고;X15는 아스파르트산(D), 또는 시스테인(C)이고;X16은 글루탐산(E) 또는 세린(S)이며;X17은 리신(K) 또는 아르기닌(R)이고;X20은 글루타민(Q) 또는 리신(K)이며;X21은 아스파르트산(D), 또는 글루탐산(E)이고;X24는 발린(V) 또는 글루타민(Q)이고;X30은 시스테인(C)이거나, 부존재함.
- 제1항에 있어서, 상기 펩타이드는 천연형 글루카곤의 pI인 6.8과 상이한 pI를 가지는, 약학적 조성물.
- 제1항에 있어서, 일반식 1의 X10과 X14, X12와 X16, X16과 X20, X17과 X21, X20과 X24, 및 X24와 X28의 아미노산 쌍 중 적어도 하나의 아미노산 쌍의 아미노산 각각이 고리를 형성할 수 있는 글루탐산 또는 리신으로 치환된, 약학적 조성물.
- 제9항에 있어서,X12와 X16의 아미노산 쌍, X16과 X20의 아미노산 쌍, 또는 X17과 X21의 아미노산 쌍의 아미노산 각각이 고리를 형성할 수 있는 글루탐산 또는 리신으로 치환된, 약학적 조성물.
- 제1항에 있어서, 상기 일반식 1에서, X10과 X14, X12와 X16, X16과 X20, X17과 X21, X20과 X24, 및 X24와 X28의 아미노산 쌍 중 적어도 하나의 아미노산 쌍에서 각각의 아미노산 간에 고리를 형성하는, 약학적 조성물.
- 제1항에 있어서, 상기 펩타이드의 C-말단이 아미드화된, 약학적 조성물.
- 제1항에 있어서, 상기 펩타이드의 C-말단은 변형되지 않은, 약학적 조성물.
- 제1항에 있어서, 상기 펩타이드는 글루카곤 수용체를 활성화시킬 수 있는 천연형 글루카곤의 유도체인, 약학적 조성물.
- 제1항에 있어서, 상기 펩타이드는 서열번호: 2 내지 44로 이루어진 군에서 선택된 아미노산 서열을 포함하는 약학적 조성물.
- 제7항에 있어서, 상기 펩타이드는 서열번호: 12, 13, 15 및 36 내지 44로 이루어진 군에서 선택된 아미노산 서열을 포함하는 약학적 조성물.
- 제1항에 있어서, 상기 펩타이드는 서열번호: 37의 아미노산 서열을 포함하는 약학적 조성물.
- 제1항 내지 제17항 중 어느 한 항에 있어서, 상기 펩타이드는 일반식 1의 아미노산 서열을 포함하는 펩타이드 부위에 생체적합성 물질부가 결합되어 있는 지속형 결합체의 형태인 약학적 조성물.
- 제18항에 있어서, 상기 생체적합성 물질부는 고분자 중합체, 지방산, 콜레스테롤, 알부민 및 이의 단편, 알부민 결합물질, 특정 아미노산 서열의 반복단위의 중합체, 항체, 항체 단편, FcRn 결합물질, 생체 내 결합조직 혹은 그 유도체, 뉴클레오타이드, 파이브로넥틴, 트랜스페린(Transferrin), 당류, 헤파린, 및 엘라스틴으로 이루어진 군에서 선택되는 약학적 조성물.
- 제19항에 있어서, 상기 고분자 중합체는 폴리에틸렌 글리콜, 폴리프로필렌 글리콜, 에틸렌 글리콜-프로필렌 글리콜 공중합체, 폴리옥시에틸화폴리올, 폴리비닐알콜, 다당류, 덱스트란, 폴리비닐에틸에테르, 생분해성 고분자, 지질 중합체, 키틴, 히알루론산, 올리고뉴클레오타이드 및 이들의 조합으로 이루어진 군으로부터 선택되는 약학적 조성물.
- 제19항에 있어서, 상기 FcRn 결합 물질은 면역글로불린 Fc 영역을 포함하는 폴리펩타이드인 약학적 조성물.
- 제18항에 있어서, 상기 펩타이드 부위와 생체적합성 물질부는 링커를 통해 서로 연결된 약학적 조성물.
- 제22항에 있어서, 상기 링커는 펩타이드, 지방산, 당류, 고분자 중합체, 저분자 화합물, 뉴클레오타이드 및 이들의 조합으로 이루어진 군으로부터 선택되는 약학적 조성물.
- 제23항에 있어서, 상기 고분자 중합체는 폴리에틸렌 글리콜, 폴리프로필렌 글리콜, 에틸렌 글리콜-프로필렌 글리콜 공중합체, 폴리옥시에틸화폴리올, 폴리비닐알콜, 다당류, 덱스트란, 폴리비닐에틸에테르, 생분해성 고분자, 지질 중합체, 키틴, 히알루론산, 올리고뉴클레오타이드 및 이들의 조합으로 이루어진 군으로부터 선택되는, 약학적 조성물.
- 제22항에 있어서, 상기 링커는 폴리에틸렌 글리콜인 약학적 조성물.
- 제21항에 있어서, 상기 면역글로불린 Fc 영역은 비당쇄화된 약학적 조성물.
- 제21항에 있어서, 상기 면역글로불린 Fc 영역은 (a) CH1 도메인, CH2 도메인, CH3 도메인 및 CH4 도메인; (b) CH1 도메인 및 CH2 도메인; (c) CH1 도메인 및 CH3 도메인; (d) CH2 도메인 및 CH3 도메인; (e) CH1 도메인, CH2 도메인, CH3 도메인 및 CH4 도메인 중 1개 또는 2개 이상의 도메인과 면역글로불린 힌지 영역 또는 힌지 영역의 일부와의 조합; 및 (f) 중쇄 불변영역 각 도메인과 경쇄 불변영역의 이량체로 구성된 군으로부터 선택되는 것인 약학적 조성물.
- 제21항에 있어서, 상기 면역글로불린 Fc 영역을 포함하는 폴리펩타이드는 이량체 형태(dimeric form)인 약학적 조성물.
- 제21항에 있어서, 상기 면역글로불린 Fc 영역은 이황화 결합을 형성할 수 있는 부위가 제거되거나, 천연형 Fc에서 N-말단의 일부 아미노산이 제거되거나, 천연형 Fc의 N-말단에 메티오닌 잔기가 부가되거나, 보체결합부위가 제거되거나 또는 ADCC(antibody dependent cell mediated cytotoxicity) 부위가 제거된, 천연형 Fc의 유도체인 약학적 조성물.
- 제21항에 있어서, 상기 면역글로불린 Fc 영역은 IgG, IgA, IgD, IgE 및 IgM로 구성되는 군으로부터 선택되는 면역글로불린에서 유래된 Fc 영역인 것인 약학적 조성물.
- 제30항에 있어서, 상기 면역글로불린 Fc 영역은 IgG4 Fc 영역인 것인 약학적 조성물.
- 제21항에 있어서, 상기 면역글로불린 Fc 영역은 인간 IgG4 유래의 비-당쇄화된 Fc 영역인 것인 약학적 조성물.
- 제22항에 있어서, 상기 링커는 상기 일반식 1의 아미노산 서열을 포함하는 펩타이드의 시스테인 잔기에 연결되는 약학적 조성물.
- 제22항에 있어서, 상기 지속형 결합체의 상기 링커는 한쪽 말단이 생체적합성 물질부의 아민기 또는 티올기와, 상기 링커의 다른 말단이 일반식 1의 아미노산 서열을 포함하는 펩타이드 부위의 아민기 또는 티올기에 각각 반응하여 형성된 공유결합으로 상기 펩타이드 부위와 상기 생체적합성 물질부에 각각 연결되어 있는 약학적 조성물.
- 하기 일반식 2의 아미노산 서열을 포함하는 분리된 펩타이드:Y-Aib-QGTF-X7-SD-X10-S-X12-Y-L-X15-X16-X17-R-A-X20-X21-F-V-X24-W-L-M-N-T-X30 (일반식 2, 서열번호: 46)상기 일반식 2에서X7은 트레오닌(T), 발린(V) 또는 시스테인(C)이고;X10은 티로신(Y) 또는 시스테인(C)이고;X12는 리신(K) 또는 시스테인(C)이고;X15는 아스파르트산(D), 또는 시스테인(C)이고;X16은 글루탐산(E) 또는 세린(S)이며;X17은 리신(K) 또는 아르기닌(R)이고;X20은 글루타민(Q) 또는 리신(K)이며;X21은 아스파르트산(D), 또는 글루탐산(E)이고;X24는 발린(V) 또는 글루타민(Q)이고;X30은 시스테인(C)이거나, 부존재하며;단, 상기 일반식 2의 아미노산 서열을 포함하는 분리된 펩타이드 중에서 서열번호: 19, 33, 49, 및 50에 해당하는 펩타이드는 제외됨.
- 제35항에 있어서, 상기 펩타이드는 일반식 2의 X16이 글루탐산이고, X20은 리신이며, X16과 X20의 측쇄가 락탐 고리를 형성하고 있는 펩타이드.
- 제35항에 있어서, 상기 일반식 2의 아미노산 서열을 포함하는 펩타이드의 C-말단이 아미드화된 펩타이드.
- 제35항에 있어서, 상기 펩타이드의 C-말단은 변형되지 않은, 펩타이드.
- 제35항에 있어서, 상기 펩타이드는 서열번호: 12, 13, 15 및 36 내지 44로 이루어진 군에서 선택된 아미노산 서열을 포함하는 펩타이드.
- 펩타이드 부위 및 상기 펩타이드 부위에 공유결합으로 연결된 생체적합성 물질부를 포함하는 분리된 결합체로서, 상기 펩타이드 부위는 하기 일반식 2의 아미노산 서열과 동일한 서열이거나 이를 포함하는 서열인 분리된 결합체:Y-Aib-QGTF-X7-SD-X10-S-X12-Y-L-X15-X16-X17-R-A-X20-X21-F-V-X24-W-L-M-N-T-X30 (일반식 2, 서열번호: 46)상기 일반식 2에서X7은 트레오닌(T), 발린(V) 또는 시스테인(C)이고;X10은 티로신(Y) 또는 시스테인(C)이고;X12는 리신(K) 또는 시스테인(C)이고;X15는 아스파르트산(D), 또는 시스테인(C)이고;X16은 글루탐산(E) 또는 세린(S)이며;X17은 리신(K) 또는 아르기닌(R)이고;X20은 글루타민(Q) 또는 리신(K)이며;X21은 아스파르트산(D), 또는 글루탐산(E)이고;X24는 발린(V) 또는 글루타민(Q)이고;X30은 시스테인(C)이거나, 부존재함.
- 제40항에 있어서, 상기 생체적합성 물질부는 고분자 중합체, 지방산, 콜레스테롤, 알부민 및 이의 단편, 알부민 결합물질, 특정 아미노산 서열의 반복단위의 중합체, 항체, 항체 단편, FcRn 결합물질, 생체 내 결합조직 혹은 그 유도체, 뉴클레오타이드, 파이브로넥틴, 트랜스페린(Transferrin), 당류, 헤파린, 및 엘라스틴으로 이루어진 군에서 선택되는 분리된 결합체.
- 제41항에 있어서, 상기 고분자 중합체는 폴리에틸렌 글리콜, 폴리프로필렌 글리콜, 에틸렌 글리콜-프로필렌 글리콜 공중합체, 폴리옥시에틸화폴리올, 폴리비닐알콜, 다당류, 덱스트란, 폴리비닐에틸에테르, 생분해성 고분자, 지질 중합체, 키틴, 히알루론산, 올리고뉴클레오타이드 및 이들의 조합으로 이루어진 군으로부터 선택되는 분리된 결합체.
- 제41항에 있어서, 상기 상기 FcRn 결합 물질은 면역글로불린 Fc 영역을 포함하는 폴리펩타이드인, 분리된 결합체.
- 제40항에 있어서, 상기 펩타이드 부위와 상기 생체적합성 물질부 사이의 공유결합은 링커를 통해 서로 연결된 분리된 결합체.
- 제44항에 있어서, 상기 링커는 펩타이드, 지방산, 당류, 고분자 중합체, 저분자 화합물, 뉴클레오타이드 및 이들의 조합으로 이루어진 군으로부터 선택되는 분리된 결합체.
- 제45항에 있어서, 상기 고분자 중합체는 폴리에틸렌 글리콜, 폴리프로필렌 글리콜, 에틸렌 글리콜-프로필렌 글리콜 공중합체, 폴리옥시에틸화폴리올, 폴리비닐알콜, 다당류, 덱스트란, 폴리비닐에틸에테르, 생분해성 고분자, 지질 중합체, 키틴, 히알루론산, 올리고뉴클레오타이드 및 이들의 조합으로 이루어진 군으로부터 선택되는 분리된 결합체.
- (i) 제35항 내지 제39항 중 어느 한 항의 분리된 펩타이드 또는 제40항 내지 제46항 중 어느 한 항의 분리된 결합체; 및 (ii) 약학적으로 허용되는 부형제를 포함하는, 저혈당의 예방 또는 치료용 약학적 조성물.
- (i) 제35항 내지 제39항 중 어느 한 항의 분리된 펩타이드 또는 제40항 내지 제46항 중 어느 한 항의 분리된 결합체; 및 (ii) 약학적으로 허용되는 부형제를 포함하는, 대사증후군의 예방 또는 치료용 약학적 조성물.
- 제48항에 있어서, 상기 조성물은 하나 이상의 대사증후군에 대한 치료적 활성을 가지는 화합물 또는 물질을 더 포함하는, 약학적 조성물.
- 제49항에 있어서, 상기 대사증후군에 대한 치료적 활성을 가지는 화합물 또는 물질은 인슐린 분비 펩타이드, GLP-1(glucagon like peptide-1) 수용체 아고니스트, 렙틴(Leptin) 수용체 아고니스트, DPP-IV(dipeptidyl peptidase-IV) 저해제, Y5 수용체 안타고니스트, MCH(Melanin-concentrating hormone) 수용체 안타고니스트, Y2/4 수용체 아고니스트, MC3/4(Melanocortin 3/4) 수용체 아고니스트, 위/췌장 리파아제(gastric/pancreatic lipase) 저해제, 5HT2c(5-hydroxytryptamine receptor 2C, G protein-coupled) 아고니스트, β3A 수용체 아고니스트, 아밀린(Amylin) 수용체 아고니스트, 그렐린(Ghrelin) 안타고니스트, 그렐린 수용체 안타고니스트, PPARα (peroxisome proliferator-activated receptor alpha) 아고니스트, PPARδ(peroxisome proliferator-activated receptor delta) 아고니스트, FXR(farnesoid X receptor) 아고니스트, 아세틸-CoA 카복실라제 억제제(acetyl-CoA carboxylase inhibitor), 펩타이드 YY, CCK(Cholecystokinin), 제닌(Xenin), 글리센틴(glicentin), 오베스타틴(obestatin), 세크레틴(secretin), 네스파틴(nesfatin), 인슐린(insuin), 및 GIP(glucose-dependent insulinotropic peptide)로 이루어진 군에서 선택되는, 약학적 조성물.
- 제47항에 있어서, 상기 대사증후군은 내당증 장애, 고콜레스테롤혈증, 이상지혈증, 비만, 당뇨, 고혈압, 비알코올지방간염 (nonalcoholic steatohepatitis, NASH), 이상지혈증에 의한 동맥경화, 죽상동맥경화증, 동맥경화증, 관상동맥 심질환(관동맥성 심장병), 및 뇌졸중으로 이루어진 군에서 선택된, 약학적 조성물.
- 제48항에 있어서, 상기 조성물은 (i) 서열번호: 37의 아미노산 서열을 포함하는 펩타이드 부위 및 이에 공유결합으로 연결된 생체적합성 물질부를 포함하는 결합체, 및 (ii) 엑센딘-4의 첫 번째 아미노산(히스티딘)의 알파 탄소가 제거된 이미다조아세틸 엑센딘-4 부위 및 이에 공유결합으로 연결된 생체적합성 물질을 포함하는 결합체를 모두 포함하는, 약학적 조성물.
- 제52항에 있어서, 상기 서열번호: 37의 아미노산 서열을 포함하는 펩타이드 부위 및 이미다조아세틸 엑센딘-4 부위는 각각의 생체적합성 물질부에 링커를 통해서 연결된, 약학적 조성물.
- 제1항 내지 제34항 중 어느 한 항의 약학적 조성물을 이를 필요로 하는 개체에게 투여하는 단계를 포함하는, 선천성 고인슐린증의 예방 또는 치료 방법.
- 제35항 내지 제39항 중 어느 한 항의 분리된 펩타이드 또는 제 40항 내지 제46항 중 어느 한 항의 분리된 결합체를 이를 필요로 하는 개체에 투여하는 단계를 포함하는, 저혈당의 예방 또는 치료 방법.
- 제35항 내지 제39항 중 어느 한 항의 분리된 펩타이드 또는 제 40항 내지 제46항 중 어느 한 항의 분리된 결합체를 이를 필요로 하는 개체에 투여하는 단계를 포함하는, 대사증후군의 예방 또는 치료 방법.
- 제56항에 있어서, 상기 방법은 하나 이상의 대사증후군에 대한 치료적 활성을 가지는 화합물 또는 물질을 투여하는 것을 더 포함하는, 방법.
- 제57항에 있어서, 상기 방법은 상기 분리된 펩타이드 또는 상기 분리된 결합체와 하나 이상의 대사증후군에 대한 치료적 활성을 가지는 화합물 또는 물질을 동시, 개별 또는 순차적으로 투여하는 방법.
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BR112018077457-0A BR112018077457A2 (pt) | 2016-06-29 | 2017-06-29 | composição farmacêutica para evitar ou tratar hiperinsulinismo congênito e seu método, hipoglicemia e seu método, síndrome metabólica e seu método e peptídeo isolado |
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CR20190161A CR20190161A (es) | 2016-12-29 | 2017-06-29 | Derivado de glucagon, conjugado del mismo, composición que comprende el mismo y uso terpéutico del mismo |
CA3029518A CA3029518A1 (en) | 2016-06-29 | 2017-06-29 | Glucagon derivative, conjugate thereof, composition comprising same, and therapeutic use thereof |
SG11201811697SA SG11201811697SA (en) | 2016-06-29 | 2017-06-29 | Glucagon derivative, conjugate thereof, composition comprising same and therapeutic use thereof |
IL263934A IL263934B2 (en) | 2016-06-29 | 2017-06-29 | A derivative of glucagon, its conjugate, a preparation containing it and its medical use |
MYPI2018002944A MY190855A (en) | 2016-06-29 | 2017-06-29 | Glucagon derivative, conjugate thereof, composition comprising same and therapeutic use thereof |
NZ750267A NZ750267A (en) | 2016-06-29 | 2017-06-29 | Glucagon derivative, conjugate thereof, composition comprising same and therapeutic use thereof |
MX2019000019A MX2019000019A (es) | 2016-06-29 | 2017-06-29 | Derivado de glucagon, conjugado del mismo, composicion que comprende el mismo y uso terapeutico del mismo. |
UAA201900200A UA126662C2 (uk) | 2016-06-29 | 2017-06-29 | Похідна глюкагону, її кон'югат, композиція, яка її містить, та її терапевтичне застосування |
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CN201780050664.0A CN109641035A (zh) | 2016-06-29 | 2017-06-29 | 胰高血糖素衍生物、其缀合物、包含其的组合物、和其治疗用途 |
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EA201990011A EA201990011A1 (ru) | 2017-06-02 | 2017-06-29 | Производное глюкагона, конъюгат на его основе, содержащая их композиция и их терапевтическое применение |
PH12018502742A PH12018502742A1 (en) | 2016-06-29 | 2018-12-21 | Glucagon derivative, conjugate thereof, composition comprising same and therapeutic use thereof |
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AU (1) | AU2017289014B2 (ko) |
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MX (1) | MX2019000019A (ko) |
MY (1) | MY190855A (ko) |
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PE (1) | PE20190355A1 (ko) |
PH (1) | PH12018502742A1 (ko) |
SG (1) | SG11201811697SA (ko) |
TN (1) | TN2018000452A1 (ko) |
TW (1) | TWI757305B (ko) |
UA (1) | UA126662C2 (ko) |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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EP3578204A4 (en) * | 2017-02-03 | 2021-01-06 | Hanmi Pharm. Co., Ltd. | BIOACTIVE SUBSTANCE CONJUGATE WITH ENHANCED DURABILITY AND ITS USE |
CN113365651A (zh) * | 2018-12-21 | 2021-09-07 | 韩美药品株式会社 | 包含胰岛素和胰高血糖素的药物组合物 |
EP3900734A4 (en) * | 2018-12-21 | 2022-10-12 | Hanmi Pharm. Co., Ltd. | PHARMACEUTICAL COMPOSITION WITH INSULIN AND GLUCAGON |
WO2022216129A1 (ko) | 2021-04-09 | 2022-10-13 | 한미약품 주식회사 | 글루카곤 유도체를 포함하는 만성 신장 질환 예방 또는 치료용 약학 조성물 |
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