Stable pharmaceutical solution formulation of GLP-1R antibody fusion protein

• US 10,485,870 B2
• Filed: 02/03/2016
• Issued: 11/26/2019
• Est. Priority Date: 02/11/2015
• Status: Active Grant

• Current Assignee: Gmax Biopharm LLC
• Original Assignee: Gmax Biopharm LLC
• Inventors: Zhang, Cheng, Zhang, Hua, Fan, Kesuo, Guo, Yong, Jing, Shuqian
• Primary Examiner(s): Li, Ruixiang
• Application Number:
  US15/547,727
• Publication Number:
  US 20180000934A1
• Time in Patent Office: 1,392 Days
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 39/39591 Stabilisation, fragmentation
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 9/00 Medicinal preparations characterised by special physical form nuclear magnetic resonance contrast preparations or magnetic resonance imaging contrast preparations A61K49/18; preparations containing radioactive substances A61K51/12
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: C07K 14/00 Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
• CPC Class Codes: C07K 14/605 Glucagons
• CPC Class Codes: C07K 16/00 Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 16/2869 against hormone receptors for antibodies against neuromediator receptors C07K16/286

Abstract

Disclosed is a stable pharmaceutical solution formulation of a GLP-1R antibody fusion protein, comprising a therapeutically effective amount of the GLP-1R antibody fusion protein, an amino acid, a surfactant and a buffer system. The final concentration of the amino acid is 1-500 mM, the final concentration of the surfactant is 0.01%-0.5%, and the pH value of the stable solution formulation is from 5.0 to 8.0. The stable solution formulation of the present invention can be used in the treatment of diabetes, obesity and conditions associated therewith.

Claims

1. A stable pharmaceutical solution formulation of a GLP-1R antibody fusion protein, comprising the GLP-1R antibody fusion protein at a final concentration ranging from 0.1 mg/mL to 100 mg/mL, an amino acid at a final concentration ranging from 1 to 500 mM, a surfactant at a final concentration ranging from 0.01% to 0.5%;

and a citrate buffer at a final concentration ranging from 5 to 30 mM, wherein the stable solution formulation has a pH value ranging from 5.0 to 8.0;

wherein the GLP-1R antibody fusion protein comprises a light chain variable domain of SEQ ID NO;

1, SEQ ID NO;

2, SEQ ID NO;

3, SEQ ID NO;

4, SEQ ID NO;

5, or SEQ ID NO;

6; and

a heavy chain variable domain of SEQ ID NO;

7, SEQ ID NO;

8, or SEQ ID NO;

9; and

wherein the amino acid is arginine and the surfactant is a polyoxyethylene sorbitan monolaurate.

2. The stable solution formulation of claim 1, wherein the stable solution formulation is stable for at least 6 months at 25°

C.

3. The stable solution formulation of claim 1, wherein the final concentration of the amino acid is 80-200 mM, the final concentration of the surfactant is 0.01%-0.2%, and the pH of the stable solution formulation is from 5.5 to 7.0.

4. The stable solution formulation of claim 1, wherein the final concentration of the citrate buffer is 20 mM.

5. The stable solution formulation of claim 3, wherein the amino acid is L-arginine and the final concentration of L-arginine is 100-180 mM.

6. The stable solution formulation of claim 5, wherein the final concentration of L-arginine is 138 mM.

7. The stable solution formulation of claim 3, wherein the surfactant is TWEEN-80 and the final concentration of TWEEN-80 is 0.05%-0.15%.

8. The stable solution formulation of claim 7, wherein the final concentration of TWEEN-80 is 0.1%.

9. The stable solution formulation of claim 1, wherein the final concentration of the GLP-1R antibody fusion protein is 5 mg/mL-40 mg/mL.

10. The stable solution formulation of claim 1, wherein the GLP-1R antibody fusion protein comprises a light chain variable domain of SEQ ID NO:

3 or SEQ ID NO;

4 ; and

a heavy chain variable domain of SEQ ID NO;

8.

11. The stable solution formulation of claim 10, wherein the GLP-1R antibody fusion protein further comprises a light chain constant domain of SEQ ID NO:

10 or SEQ ID NO;

11, and a heavy chain constant domain of SEQ ID NO;

12.

12. The stable solution formulation of claim 1, wherein the final concentration of the GLP-1R antibody fusion protein is 5 mg/mL-40 mg/mL, the final concentration of L-arginine is 138 mM, the final concentration of TWEEN-80 is 0.1%, and the pH is between 6-7.

13. The stable solution formulation of claim 12, wherein the final concentration of the GLP-1R antibody fusion protein is 5 mg/mL.

14. The stable solution formulation of claim 12, wherein the final concentration of the GLP-1R antibody fusion protein is 10 mg/mL.

15. The stable solution formulation of claim 12, wherein the final concentration of the GLP-1R antibody fusion protein is 20 mg/mL.

16. The stable solution formulation of claim 12, wherein the final concentration of the GLP-1R antibody fusion protein is 30 mg/mL.

17. The stable solution formulation of claim 12, wherein the final concentration of the GLP-1R antibody fusion protein is 40 mg/mL.

18. The stable solution formulation of claim 12, wherein the pH is about 6.5.

19. The stable solution formulation of claim 1, wherein the stable solution formulation is stored in a sterile syringe.

20. The stable solution formulation of claim 1, wherein the GLP-1R antibody fusion protein comprises a light chain variable domain of SEQ ID NO:

3 and a heavy chain variable domain of SEQ ID NO;

8.

21. The stable solution formulation of claim 1, wherein the GLP-1R antibody fusion protein comprises a light chain variable domain of SEQ ID NO:

4 and a heavy chain variable domain of SEQ ID NO;

8.