NZ730054B2 - Compositions and methods of use for treating metabolic disorders - Google Patents
Compositions and methods of use for treating metabolic disorders Download PDFInfo
- Publication number
- NZ730054B2 NZ730054B2 NZ730054A NZ73005415A NZ730054B2 NZ 730054 B2 NZ730054 B2 NZ 730054B2 NZ 730054 A NZ730054 A NZ 730054A NZ 73005415 A NZ73005415 A NZ 73005415A NZ 730054 B2 NZ730054 B2 NZ 730054B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- sequence
- polypeptide
- complex
- terminus
- amino acid
- Prior art date
Links
- 208000030159 metabolic disease Diseases 0.000 title abstract 2
- 239000000203 mixture Substances 0.000 title abstract 2
- 101000893549 Homo sapiens Growth/differentiation factor 15 Proteins 0.000 claims abstract 10
- 229920001184 polypeptide Polymers 0.000 claims 18
- 108090000765 processed proteins & peptides Proteins 0.000 claims 18
- 102000004196 processed proteins & peptides Human genes 0.000 claims 18
- 102100040896 Growth/differentiation factor 15 Human genes 0.000 claims 9
- 239000000833 heterodimer Substances 0.000 claims 8
- 238000006467 substitution reaction Methods 0.000 claims 7
- 125000003275 alpha amino acid group Chemical group 0.000 claims 6
- 229940024606 amino acid Drugs 0.000 claims 4
- 150000001413 amino acids Chemical class 0.000 claims 4
- 125000001433 C-terminal amino-acid group Chemical group 0.000 claims 1
- 229960000310 isoleucine Drugs 0.000 claims 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims 1
- 125000000741 isoleucyl group Chemical group [H]N([H])C(C(C([H])([H])[H])C([H])([H])C([H])([H])[H])C(=O)O* 0.000 claims 1
- 230000037396 body weight Effects 0.000 abstract 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
- 208000018914 glucose metabolism disease Diseases 0.000 abstract 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- 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
- A61K47/68—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
- 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
- A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
- C07K14/475—Growth factors; Growth regulators
- C07K14/495—Transforming growth factor [TGF]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
-
- 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
-
- 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
- C07K2317/526—CH3 domain
-
- 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
complex comprising a GDF15 polypeptide is described. Methods of treating individuals with a metabolism disorder, such as, glucose metabolism disorder and/or a body weight disorder, and compositions associated therewith, are provided.
Claims (12)
1. A complex comprising a first heterodimer and a second heterodimer, each of the first heterodimer and second heterodimer comprising: a first polypeptide and a second polypeptide, wherein: the first polypeptide comprises from N-terminus to C-terminus a human IgG Fc sequence comprising a first hinge region and a first CH3 sequence comprising at least one engineered protuberance comprising at least one substitution of the corresponding amino acid in a human IgG 1 Fc sequence, wherein the substitution is selected from the group consisting of Q347W/Y, T366W/Y, and T394W/Y, according to EU numbering; the second polypeptide comprises from N-terminus to C-terminus a human IgG Fc sequence comprising a second hinge region and a second CH3 sequence comprising at least one engineered cavity comprising at least one substitution of the corresponding amino acid in a human IgG 1 Fc sequence, wherein the substitution is selected from the group consisting of T366S, L368A, T394S, F405T/V/A, and Y407T/V/A, according to EU numbering; wherein the first polypeptide dimerizes with the second polypeptide via positioning of the protuberance of the first polypeptide into the cavity of the second polypeptide, wherein either the C-terminus of the first polypeptide or the C-terminus of the second polypeptide is conjugated to the N-terminus of a GDF15 mutein via a linker, wherein the GDF15 mutein comprises a contiguous amino acid sequence at least 98 amino acids long and at least 95% identical to the amino acid sequence of SEQ ID NO:1, wherein the C-terminal amino acid of the GDF15 mutein corresponds to Isoleucine at position 112 in SEQ ID NO:1, and the contiguous amino acid sequence does not comprise the first two amino acids present at the N-terminus of SEQ ID NO:1, and wherein the GDF15 mutein comprises a D5T substitution relative to the amino acid sequence of SEQ ID NO:1, and wherein the GDF15 mutein in the first heterodimer dimerizes with the GDF15 mutein in the second heterodimer thereby forming the complex comprising the first heterodimer and second heterodimer.
2. The complex of claim 1, wherein the first polypeptide comprises from N-terminus to C-terminus: the human IgG Fc sequence comprising the first hinge region and the first CH3 sequence comprising at least one engineered protuberance; the linker, and the GDF15 mutein; and the second polypeptide comprises from N-terminus to C-terminus: the human IgG Fc sequence comprising the second hinge region and the second CH3 sequence comprising at least one engineered cavity.
3. The complex of claim 1 or 2, wherein the IgG Fc of the first polypeptide is an IgG1 Fc.
4. The complex of any one of the preceding claims, wherein the IgG Fc of the second polypeptide is an IgG1 Fc.
5. The complex of any one of the preceding claims, wherein the first polypeptide comprises the substitution T366W.
6. The complex of any one of the preceding claims, wherein the second polypeptide comprises the substitutions T366S, L368A, and Y407V.
7. The complex of any one of the preceding claims, wherein the first polypeptide further comprises a first CH2 sequence.
8. The complex of any one of the preceding claims, wherein the second polypeptide further comprises a second CH2 sequence.
9. The complex of any one of the preceding claims, wherein the GDF15 mutein comprises the amino acid sequence of SEQ ID NO:129.
10. The complex of any one of the preceding claims, wherein the GDF15 mutein consists of the amino acid sequence of SEQ ID NO:129.
11. The complex of any one of claims 1 to 10, wherein the linker comprises the sequence Glycine-Glycine-Glycine-Glycine-Ser ((G4 ) ), wherein n=2-5.
12. The complex of any one of claims 1 to 10, wherein the linker comprises the sequence (G S) or (G S) . 4 3 4 5
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201462073737P | 2014-10-31 | 2014-10-31 | |
| US201562244604P | 2015-10-21 | 2015-10-21 | |
| PCT/US2015/058111 WO2016069921A1 (en) | 2014-10-31 | 2015-10-29 | Compositions and methods of use for treating metabolic disorders |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ730054A NZ730054A (en) | 2023-11-24 |
| NZ730054B2 true NZ730054B2 (en) | 2024-02-27 |
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