NZ762962B2 - Long-acting conjugates of glp-2 derivatives - Google Patents
Long-acting conjugates of glp-2 derivatives Download PDFInfo
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- NZ762962B2 NZ762962B2 NZ762962A NZ76296218A NZ762962B2 NZ 762962 B2 NZ762962 B2 NZ 762962B2 NZ 762962 A NZ762962 A NZ 762962A NZ 76296218 A NZ76296218 A NZ 76296218A NZ 762962 B2 NZ762962 B2 NZ 762962B2
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- glp
- lysine
- derivative
- xaa
- asp
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- A61K47/50—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
- A61K47/51—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
- A61K47/62—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 a protein, peptide or polyamino acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- A61K47/50—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
- A61K47/51—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
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/605—Glucagons
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/53—Hinge
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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
Abstract
The present invention relates to a glucagon-like peptide-2 (GLP-2) derivative, a conjugate thereof and uses of both. In addition, the present invention relates to a method for preparing a GLP-2 derivative and a conjugate thereof. In particular, the invention provides GLP-2 (glucagon-like-peptide-2) analogues with variation at positions 1, 2, 30, 34 of GLP-2 that have increased half life in vivo.
Claims (24)
1. [Claim 1] A glucagon-like peptide-2 (GLP-2) conjugate, wherein a GLP-2 derivative and an immunoglobulin Fc region are each covalently linked via a non-peptidyl polymer at both termini of the non-peptidyl polymer, wherein the non-peptidyl polymer is selected from the group consisting of polyethylene glycol, polypropylene glycol, ethylene glycol-propylene glycol copolymer, polyoxyethylated polyol, polyvinyl alcohol, polysaccharide, dextran, polyvinyl ethyl ether, lipid polymer, chitin, hyaluronic acid, and a combination thereof, wherein the GLP-2 derivative comprises an amino acid sequence of the following General Formula 1: [General Formula 1] X X DGSFSDEMNTILDNLAARDFINWLIQTX ITDX (SEQ ID NO: 9), 1 2 30 34 wherein, in the above formula, X is imidazoacetyldeshistidine, desaminohistidine, ß- hydroxyimidazopropionyldeshistidine, N-dimethylhistidine, or ß- carboxyimidazopropionyldeshistidine; X is glycine; X is lysine; and X is absent, or lysine, arginine, glutamine, histidine, or 6-azido-lysine, X is histidine, imidazoacetyldeshistidine, desaminohistidine, ß- hydroxyimidazopropionyldeshistidine, N-dimethylhistidine, or ß- carboxyimidazopropionyldeshistidine; X is alanine, glycine, or 2-aminoisobutyric acid (Aib); X is arginine; and X is absent, or lysine, arginine, glutamine, histidine, 6-azido-lysine, or cysteine.
2. [Claim 2] The GLP-2 conjugate according to claim 1, wherein X is glycine, X is lysine, and MARKED-UP COPY X is lysine or 6-azido-lysine.
3. [Claim 3] The GLP-2 conjugate according to claim 1, wherein X is glycine, X is arginine, and X is lysine or cysteine.
4. [Claim 4] The GLP-2 conjugate according to claim 2 or 3, wherein (1) X is imidazoacetyldeshistidine, X is glycine, X is lysine, and X is lysine; 1 2 30 34 (2) X is imidazoacetyldeshistidine, X is glycine, X is arginine, and X is lysine; 1 2 30 34 (3) X is imidazoacetyldeshistidine, X is glycine, X is lysine, and X is 6-azido- 1 2 30 34 lysine; or (4) X is imidazoacetyldeshistidine, X is glycine, X is arginine, and X is cysteine. 1 2 30 34
5. [Claim 5] The GLP-2 conjugate according to any one of claims 1 to 4, wherein the GLP-2 derivative is an amino acid sequence selected from the group consisting of SEQ ID NOS: 3 to
6. [Claim 6] The GLP-2 conjugate according to any one of claims 1 to 5, wherein one end of the non-peptidyl polymer is conjugated to the immunoglobulin Fc region and the other end thereof is conjugated to the hydroxyl group, thiol group, amino group, or azide group of the GLP-2 derivative.
7. [Claim 7] The GLP-2 conjugate according to any one of claims 1 to 6, wherein the immunoglobulin Fc region is non-glycosylated.
8. [Claim 8] The GLP-2 conjugate according to any one of claims 1 to 7, wherein the immunoglobulin Fc region comprises a hinge region. MARKED-UP COPY
9. [Claim 9] The GLP-2 conjugate according to any one of claims 1 to 8, wherein the immunoglobulin Fc region is an IgG4 Fc region.
10. [Claim 10] A GLP-2 derivative comprising an amino acid sequence of the following General Formula 1: [General Formula 1] X1X2DGSFSDEMNTILDNLAARDFINWLIQTX30ITDX34 (SEQ ID NO: 9), wherein, in the above formula, X1 is imidazoacetyldeshistidine, desaminohistidine, ß- hydroxyimidazopropionyldeshistidine, N-dimethylhistidine, or ß- carboxyimidazopropionyldeshistidine; X2 is glycine; X30 is lysine; and X34 is absent, or lysine, arginine, glutamine, histidine, or 6-azido-lysine, X is histidine, imidazoacetyldeshistidine, desaminohistidine, ß- hydroxyimidazopropionyldeshistidine, N-dimethylhistidine, or ß- carboxyimidazopropionyldeshistidine; X is alanine, glycine, or 2-aminoisobutyric acid (Aib); X is arginine; and X is absent, or lysine, arginine, glutamine, histidine, 6-azido-lysine, or cysteine.
11. [Claim 11] The GLP-2 derivative according to claim 10, wherein X is glycine, X is lysine, and X is lysine or 6-azido-lysine.
12. [Claim 12] The GLP-2 derivative according to claim 10, wherein X is glycine, X is arginine and X is lysine or cysteine. MARKED-UP COPY
13. [Claim 13] The GLP-2 derivative according to claim 10, wherein (1) X is imidazoacetyldeshistidine, X is glycine, X is lysine, and X is lysine; 1 2 30 34 (2) X is imidazoacetyldeshistidine, X is glycine, X is arginine, and X is lysine; 1 2 30 34 (3) X is imidazoacetyldeshistidine, X is glycine, X is lysine, and X is 6-azido- 1 2 30 34 lysine; or (4) X is imidazoacetyldeshistidine, X is glycine, X is arginine, and X is cysteine. 1 2 30 34
14. [Claim 14] An isolated nucleic acid encoding the GLP-2 derivative according to any one of claims 10 to 13.
15. [Claim 15] A recombinant expression vector comprising the nucleic acid according to claim 14.
16. [Claim 16] An isolated transformant comprising the recombinant expression vector according to claim 15.
17. [Claim 17] A method for preparing the GLP-2 derivative according to any one of claims 10 to 13, comprising: a) culturing a transformant comprising a nucleic acid encoding the GLP-2 derivative according to any one of claims 10 to 13 to express the GLP-2 derivative; and b) isolating and purifying the expressed GLP-2 derivative.
18. [Claim 18] A method for preparing a GLP-2 conjugate, comprising: (a) preparing a complex by reacting a non-peptidyl polymer having two or more terminal reactive groups with any one of the GLP-2 derivative according to any one of claims 10 to 13 and an immunoglobulin Fc region such that the complex has the GLP-2 derivative or the immunoglobulin Fc region attached to one terminal end of the non-peptidyl polymer, and a reactive group at the other terminal end; and MARKED-UP COPY (b) preparing a conjugate by reacting the complex prepared in Step (a) with one of the immunoglobulin Fc region and the GLP-2 derivative not attached to the complex such that the GLP-2 derivative and the immunoglobulin Fc region are linked via a non-peptidyl polymer.
19. [Claim 19] The method according to claim 18, wherein the non-peptidyl polymer comprises one or more reactive groups selected from the group consisting of an aldehyde group, a propionaldehyde group, a butyraldehyde group, a maleimide group, and a succinimide derivative.
20. [Claim 20] The method according to claim 19, wherein the succinimide derivative is succinimidyl carboxymethyl, succinimidyl valerate, succinimidyl methylbutanoate, succinimidyl methylpropionate, succinimidyl butanoate, succinimidyl propionate, N-hydroxysuccinimide, or succinimidyl carbonate.
21. [Claim 21] A pharmaceutical composition for preventing or treating one or more diseases selected from intestinal disease, intestinal injury, and gastrosia, comprising the GLP-2 conjugate according to any one of claims 1 to 9 or the GLP-2 derivative according to any one of claims 10 to 13.
22. [Claim 22] Use of the GLP-2 conjugate according to any one of claims 1 to 9 or the GLP-2 derivative according to any one of claims 10 to 13 in the manufacture of a medicament to prevent or treat one or more diseases selected from intestinal disease, intestinal injury, and gastrosia.
23. [Claim 23] The pharmaceutical composition according to claim 21 or the use of claim 22, wherein the intestinal disease is short-bowel syndrome, hypersensitive intestinal disease, inflammatory intestinal disease, Crohn’s disease, colonitis, colitis, pancreatitis, ileitis, mucositis, or intestine atrophy. MARKED-UP COPY
24. [Claim 24] The pharmaceutical composition according to claim 21 or the use of claim 22, wherein the gastrosia is stomach cramps, gastritis, gastric ulcer, duodenitis, or duodenal ulcer. OPA18231_Sequence List.txt <110> HANMI PHARM. CO., LTD. <120> Long-acting conjugates of GLP-2 derivatives <130> OPA18231 <150> KR 100126577 <151> 201728 <160> 9 <170> KoPatentIn 3.0 <210> 1 <211> 33 <212> PRT <213> Homo sapiens <400> 1 His Ala Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn 1 5 10 15 Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr 20 25 30 <210> 2 <211> 34 <212> PRT <213> Artificial Sequence <220> <223> GLP-2 derivative <220> <221> MISC_FEATURE <222> (1) <223> Xaa is imidazoacetyldeshistidine <400> 2 Xaa Gly Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn 1 5 10 15 Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr 20 25 30 Asp Cys Page 1 OPA18231_Sequence List.txt <210> 3 <211> 34 <212> PRT <213> Artificial Sequence <220> <223> GLP-2 derivative <220> <221> MISC_FEATURE <222> (1) <223> Xaa is imidazoacetyldeshistidine <400> 3 Xaa Gly Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn 1 5 10 15 Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr 20 25 30 Asp Lys <210> 4 <211> 34 <212> PRT <213> Artificial Sequence <220> <223> GLP-2 derivative <220> <221> MISC_FEATURE <222> (1) <223> Xaa is imidazoacetyldeshistidine <400> 4 Xaa Gly Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn 1 5 10 15 Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Arg Ile Thr 20 25 30 Asp Lys Page 2 OPA18231_Sequence List.txt <210> 5 <211> 34 <212> PRT <213> Artificial Sequence <220> <223> GLP-2 derivative <220> <221> MISC_FEATURE <222> (1) <223> Xaa is imidazoacetyldeshistidine <220> <221> MISC_FEATURE <222> (34) <223> Xaa is 6-azidolysine <400> 5 Xaa Gly Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn 1 5 10 15 Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr 20 25 30 Asp Xaa <210> 6 <211> 34 <212> PRT <213> Artificial Sequence <220> <223> GLP-2 derivative <220> <221> MISC_FEATURE <222> (1) <223> Xaa is imidazoacetyldeshistidine <400> 6 Xaa Gly Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn Page 3 OPA18231_Sequence List.txt 1 5 10 15 Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Arg Ile Thr 20 25 30 Asp Cys <210> 7 <211> 34 <212> PRT <213> Artificial Sequence <220> <223> GLP-2 derivative <220> <221> MISC_FEATURE <222> (1) <223> Xaa is imidazoacetyldeshistidine <220> <221> MISC_FEATURE <222> (2) <223> Xaa is Aib(2-aminoisobutyric acid) <400> 7 Xaa Xaa Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn 1 5 10 15 Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr 20 25 30 Asp Cys <210> 8 <211> 34 <212> PRT <213> Artificial Sequence <220> <223> GLP-2 derivative <220> <221> MISC_FEATURE Page 4 OPA18231_Sequence List.txt <222> (2) <223> Xaa is Aib(2-aminoisobutyric acid) <400> 8 His Xaa Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn 1 5 10 15 Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Lys Ile Thr 20 25 30 Asp Cys <210> 9 <211> 34 <212> PRT <213> Artificial Sequence <220> <223> GLP-2 derivative <220> <221> MISC_FEATURE <222> (1) <223> Xaa = Histidine, imidazoacetyldeshistidine, desaminohistidine, beta-hydroxyimidazopropionyldeshistidine, N-dimethylhistidine, or beta-carboxyimidazopropionyldeshistidine <220> <221> MISC_FEATURE <222> (2) <223> Xaa is Alanine, Glycine, or Aib(2-aminoisobutyric acid) <220> <221> MISC_FEATURE <222> (30) <223> Xaa is Lysine, or Arginine <220> <221> MISC_FEATURE <222> (34) <223> Xaa is absent, Lysine, Arginine, Glutamine, Histidine, 6-azidolysine, or Cysteine <400> 9 Page 5 OPA18231_Sequence List.txt Xaa Xaa Asp Gly Ser Phe Ser Asp Glu Met Asn Thr Ile Leu Asp Asn 1 5 10 15 Leu Ala Ala Arg Asp Phe Ile Asn Trp Leu Ile Gln Thr Xaa Ile Thr 20 25 30 Asp Xaa Page 6 [
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR20170126577 | 2017-09-28 | ||
| PCT/KR2018/011586 WO2019066586A1 (en) | 2017-09-28 | 2018-09-28 | Long-acting conjugate of glucagon-like peptide-2 (glp-2) derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ762962A NZ762962A (en) | 2024-07-05 |
| NZ762962B2 true NZ762962B2 (en) | 2024-10-08 |
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