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KR-20260066098-A - Stable GLP-1 analogs for the treatment of human diseases and disorders

KR20260066098AKR 20260066098 AKR20260066098 AKR 20260066098AKR-20260066098-A

Abstract

The disclosures described herein provide enzymatically stable and potent GLP-1 analogs (i.e., derivatives) for the treatment of metabolic diseases or disorders in subjects. In some embodiments, the GLP-1 analog is a derivatized GLP-1 peptide, and the derivatized peptide has a difference of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids from any one of GLP-1, GLP-1(7-39), GLP-1(7-36), or GLP-1(7-37). In certain embodiments, the GLP-1 analog comprises at least one lysine substituent. The GLP-1 analogs described herein demonstrate potent receptor binding and an extended plasma half-life. Pharmaceutical compositions of GLP-1 analogs for the treatment of metabolic diseases or disorders, such as diabetes or obesity, in subjects are described herein.

Inventors

  • 바이 준카이
  • 장 구오칭
  • 장 풀리앙
  • 페닝턴 마이클
  • 싱 심라트

Assignees

  • 앰비오, 인코포레이티드

Dates

Publication Date
20260512
Application Date
20240905
Priority Date
20230906

Claims (20)

  1. As a GLP-1 analog: Xaa7-Xaa8-Xaa9-Xaa10-Xa11-Xaa12-Xaa13-Xaa14-Xaa15-Xaa16- Xaa17-Xaa18-Xaa19-Xaa20-Xaa21-Xaa22-Xaa23-Xaa24-Xaa25-Xaa26- Xaa27-Xaa28-Xaa29-Xaa30-Xaa31-Xaa32-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37 (SEQ ID NO: 1) During the meal Xaa7 is His or Tyr, and Xaa8 is Ala or Aib or Aib-ψ[CH 2 NH], and Xaa9 is Glu, and Xaa10 is Gly, and Xaa11 is Thr, and Xaa12 is Phe, and Xaa13 is Thr, and Xaa14 is Ser, and Xaa15 is Asp, and Xaa16 is Val, and Xaa17 is Ser, and Xaa18 is Ser, and Xaa19 is Tyr or Aib, Xaa20 is Leu, and Xaa21 is Glu, and Xaa22 is Gly, and Xaa23 is Gln, and Xaa24 is Ala, and Xaa25 is Ala, and Xaa26 is Lys, and Xaa27 is Glu, and Xaa28 is Phe, and Xaa29 is Ile, and Xaa30 is Ala, and Xaa31 is Trp, and Xaa32 is Leu, and Xaa33 is Val, and Xaa34 is Lys or Arg, and Xaa35 is Gly, and Xaa36 is Arg or DAP (L-2,3-diaminopropionic acid), and Xaa37 is a Gly, a GLP-1 analog.
  2. As a GLP-1 analog: Xaa7-Xaa8-Xaa9-Xaa10-Xa11-Xaa12-Xaa13-Xaa14-Xaa15-Xaa16- Xaa17-Xaa18-Xaa19-Xaa20-Xaa21-Xaa22-Xaa23-Xaa24-Xaa25-Xaa26- Xaa27-Xaa28-Xaa29-Xaa30-Xaa31-Xaa32-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37- Xaa38-Xaa39-Xaa40-Xaa41-Xaa42-Xaa43-Xaa44(Sequence No. 2) During the meal Xaa7 is His or Tyr, and Xaa8 is Ala or Aib or Aib-ψ[CH 2 NH], and Xaa9 is Glu, and Xaa10 is Gly, and Xaa11 is Thr, and Xaa12 is Phe, and Xaa13 is Thr, and Xaa14 is Ser, and Xaa15 is Asp, and Xaa16 is Val, and Xaa17 is Ser, and Xaa18 is Ser, and Xaa19 is Tyr or Aib, Xaa20 is Leu or Aib, Xaa21 is Glu, and Xaa22 is Gly, and Xaa23 is Gln, and Xaa24 is Ala, and Xaa25 is Ala, and Xaa26 is Lys, and Xaa27 is Glu, and Xaa28 is Phe, and Xaa29 is Ile, and Xaa30 is Ala, and Xaa31 is Trp, and Xaa32 is Leu, and Xaa33 is Val, and Xaa34 is Lys or Arg or Gly, and Xaa35 is Gly, and Xaa36 is Arg or DAP (L-2,3-diaminopropionic acid) or Pro, and Xaa37 is Gly or Ser, and Xaa38 is Ser, and Xaa39 is Gly, and Xaa40 is Ala, and Xaa41 is Pro, and Xaa42 is Pro, and Xaa43 is Pro, and Xaa44 is a Ser, a GLP-1 analog.
  3. A GLP-1 analog according to claim 1 or 2, wherein the ε-amino group of Lys at position 26 is substituted with a substituent.
  4. A GLP-1 analog in paragraph 3, wherein the substituent is AEEA-AEEA-γ-Glu-(CH 2 ) m -OH, where m is 12, 14, 16, 18, 20, or 22.
  5. A GLP-1 analog that is resistant to enzymatic degradation in any one of claims 1 to 4.
  6. In claim 5, the resistance to enzymatic degradation is determined by comparing the enzymatic degradation rate of any one of the GLP derivatives of claims 1 to 5 with the enzymatic degradation rate of any one of natural GLP-1 (7-36), natural GLP-1 (7-37), natural GLP-1 (7-39), semaglutide, exenatide, lyxumia, dulaglutide, tyrzepatide, or liraglutide, of a GLP-1 analog.
  7. In claim 6, the degrading enzyme is a GLP-1 analog that is a protease or peptidase.
  8. In claim 7, the enzyme is dipeptidyl peptidase-4 (DPP-4), or neutral endopeptidase 24.11, or a GLP-1 analog that is a gastrointestinal enzyme.
  9. A GLP-1 analog according to any one of claims 1 to 8, wherein the binding affinity (IC 50 ) of the GLP-1 analog to the GLP-1 receptor is less than 10 nM.
  10. A GLP-1 analog according to any one of claims 1 to 9, wherein the binding affinity (IC 50 ) of the GLP-1 analog to the GLP-1 receptor is less than 5 nM.
  11. A GLP-1 analog according to any one of claims 1 to 10, wherein the binding affinity (IC 50 ) of the GLP-1 analog to the GLP-1 receptor is less than 1 nM.
  12. In any one of claims 1 to 11, the GLP-1 analog binding affinity is a GLP-1 analog measured by surface plasmon resonance.
  13. In any one of claims 1 to 11, the binding affinity of the GLP-1 analog is a GLP-1 analog measured using a recombinant cell line.
  14. In paragraph 13, the recombinant cell line is a GLP-1 analog expressing a GLP-1 receptor.
  15. In claim 14, the binding affinity (IC 50 ) of the GLP-1 analog to the GLP-1 receptor is determined by measuring luciferase activity.
  16. In any one of claims 1 to 15, the GLP-1 analog is a GLP-1 analog that exhibits an in vivo plasma elimination half-life of at least 1 hour, or 2 hours, or 4 hours, or 6 hours, or 8 hours, or 10 hours, or 24 hours, or 48 hours, or 72 hours, or 168 hours in humans.
  17. A pharmaceutical composition comprising a GLP-1 analog of any one of claims 1 to 16 and a pharmaceutically acceptable vehicle or carrier.
  18. A pharmaceutical composition according to claim 17, further comprising any one of an isotonic agent, an excipient, a preservative, and a buffer.
  19. A pharmaceutical composition according to claim 17 or 18, further comprising a surfactant.
  20. A pharmaceutical composition comprising, in any one of claims 17 to 19, an antidiabetic agent or an anti-obesity agent.

Description

Stable GLP-1 analogs for the treatment of human diseases and disorders Related applications This application claims the priority and benefit of international application PCT/CN2023/117248 filed on September 6, 2023. The entire contents of this application are incorporated herein by reference. Reference to the electronic sequence list The contents of the electronic sequence list (AMBO_001_001WO_SeqList_ST26.xml; size: 22,243 bytes; and creation date: August 21, 2024) are incorporated herein by reference in their entirety. GLP-1 is a product of proglucagon, a member of the peptide secretin-VIP family, and an important intestinal hormone that functions to regulate glucose metabolism and gastrointestinal secretion and metabolism. The amino acid sequence of GLP-1 was presented by Schmidt et al. ( Diabetologia 28 704-707 (1985). Human GLP-1 is a 37-amino acid residue peptide derived from preproglucagon, which is synthesized in L-cells at the terminal ileum, the pancreas, and the brain. The conversion of preproglucagon into GLP-1(7-36)amide, GLP-1(7-37), and GLP-2 primarily occurs in L-cells. GLP-1 is effective in stimulating insulin secretion in diabetic patients. Furthermore, unlike other insulin-stimulating hormones (with the exception of secretin), it potently inhibits glucagon secretion. GLP-1 has a prolonged blood glucose-lowering effect, particularly in diabetic patients. Because its insulin-stimulating and glucagon-stimulating actions depend on glucose, the blood glucose-lowering effect is autolimiting, and this hormone does not cause hypoglycemia regardless of the dose. These effects are maintained even in diabetic patients, and even in cases of poor metabolic control or secondary failure of sulfonylurea treatment, blood glucose levels can be completely normalized by administering a dose of GLP-1 slightly higher than the physiological dose. In addition to its effects on pancreatic islets, GLP-1 exerts potent effects on the gastrointestinal tract. GLP-1 administered at physiological doses strongly inhibits pentagastrin-induced and meal-induced gastric acid secretion. It also suppresses gastric emptying rate and pancreatic enzyme secretion. GLP-1 peptides maintain full activity even after subcutaneous administration, but are rapidly degraded primarily by dipeptidyl peptidase IV-like enzymes. The plasma half-life of GLP-1 in the human body is 2 minutes. The short half-life of GLP-1 and currently used analogs leads to an increase in the frequency of injections for patients. There is a particular need to reduce the frequency of injections for patients by extending the half-life through the development of GLP-1 analogs that enhance or maintain efficacy while increasing stability against enzymatic degradation. The disclosures described herein provide an enzymatically stable and potent GLP-1 analog (i.e., a derivative) for the treatment of a metabolic disease or disorder in a subject. In some embodiments, the GLP-1 analog is a derivatized GLP-1 peptide, and the derivatized peptide has a difference of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids from any one of GLP-1, GLP-1(7-39), GLP-1(7-36), and GLP-1(7-37). In some embodiments, the GLP-1 analog is a derivatized GLP-1 peptide, and the derivatized peptide has a difference of 10 or more amino acids from any one of GLP-1, GLP-1(7-39), GLP-1(7-36), and GLP-1(7-37). In certain embodiments, the GLP-1 analog comprises at least one lysine substituent. The GLP-1 analogs described herein demonstrate potent receptor binding affinity and an extended plasma half-life. The present invention describes a pharmaceutical composition of a GLP-1 analog for the treatment of metabolic diseases or disorders such as diabetes or obesity. Figure 1 shows the binding affinity of GLP-1R-like peptides measured by the luciferase reporter assay. Figures 2a and 2b illustrate the binding affinity of GLP-1R-like peptides measured by the luciferase reporter assay, with the margin of error indicated. Figure 2a shows the percentage of inhibition of GLP-1R-like peptides compared to semaglutide and liraglutide. Figure 2b shows the GLP-1R activation EC50 of the-like peptides compared to semaglutide and liraglutide. Figure 3 illustrates a GLP-1 analog. Figure 4 shows the natural GLP-1 (7-36) sequence. Figure 5 shows the sequence of Exendin-4. Figures 6a-6b Figure 6a illustrates the binding affinity of GLP-1R-like peptides measured by the Tag-Lite® receptor binding FRET assay in the absence of HSA. It shows the percentage of inhibition of GLP-1R-like peptides compared to semaglutide and liraglutide. Figure 6b is Compared to semaglutide and liraglutide It shows the GLP-1R activation IC50 of the analog peptide. Figures 7a-7b Figure 7a plots the binding affinity of GLP-1R-like peptides measured by the Tag-Lite® receptor binding FRET assay in the presence of 2% HSA. Figure 7b shows the percentage of inhibition of GLP-1R-like peptides compared to semaglutide and liraglutide. Compared to semaglutide and liragl