Highly concentrated stabilized IgM solution

• US 8,920,797 B2
• Filed: 07/24/2009
• Issued: 12/30/2014
• Est. Priority Date: 10/09/2003
• Status: Active Grant

• Current Assignee: Chugai Seiyaku Kabushiki Kaisha (Roche Holding AG)
• Original Assignee: Chugai Seiyaku Kabushiki Kaisha (Roche Holding AG)
• Inventors: Igawa, Tomoyuki, Sekimori, Yasuo
• Primary Examiner(s): WEN, SHARON X
• Application Number:
  US12/509,075
• Publication Number:
  US 20090285802A1
• Time in Patent Office: 1,985 Days
• Field of Search: None
• US Class Current: 424/130.1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/7016 Disaccharides, e.g. lactose, lactulose lactobionic acid A61K31/7032
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 39/39591 Stabilisation, fragmentation
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• 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 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0095 Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: C07K 16/3084 against tumour-associated gangliosides
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype

Abstract

The present inventors discovered that stable and highly concentrated IgM solutions can be prepared by using, as an additive, a compound comprising a polyvalent cationic ion, such as magnesium chloride or arginine hydrochloride, to suppress IgM aggregation in solutions.

Claims

1. An aqueous solution of IgM comprising at least 1 mg/mL IgM, citrate buffer, and a polyvalent cation that is Mg++ or arginine ion, wherein the polyvalent cation is present at a concentration that suppresses by at least 10% the increase of water-soluble IgM aggregates produced during storage of the solution at a temperature selected from 4°

C., 25°

C., and 40°

C., compared to the increase of water-soluble IgM aggregates seen with the same solution without the polyvalent cation.

2. The solution of claim 1, wherein the polyvalent cation is Mg++.

3. The solution of claim 1, wherein the polyvalent cation is arginine ion.

4. The solution of claim 1, wherein the degree of suppression is at least 30%.

5. The solution of claim 1, wherein the degree of suppression is at least 50%.

6. The solution of claim 1, wherein the degree of suppression is at least 80%.

7. The solution of claim 1, wherein the IgM concentration is 1-200 mg/mL.

8. The solution of claim 1, wherein the concentration of IgM in the solution is higher than 10 mg/mL.

9. The solution of claim 1, wherein the concentration of IgM in the solution is 20 mg/mL or more.

10. The solution of claim 1, wherein the concentration of IgM in the solution is 25 mg/mL or more.

11. The solution of claim 1, wherein the concentration of IgM in the solution is 40 mg/mL or more.

12. The solution of claim 1, wherein the concentration of IgM in the solution is 50 mg/mL or more.

13. The solution of claim 1, wherein the concentration of the polyvalent cation in the solution is 1 mM to 1000 mM.

14. The solution of claim 1, wherein the concentration of the polyvalent cation in the solution is 10 mM to 500 mM.

15. The solution of claim 1, wherein the concentration of the polyvalent cation in the solution is 50 mM to 200 mM.

16. The solution of claim 1, wherein the pH of the solution is 5 to 8.

17. The solution of claim 1, wherein the solution does not comprise proteins other than IgM.

18. A method for preparing the solution of claim 1, the method comprising adding the polyvalent cation to a first solution comprising the IgM to form a second solution comprising the IgM at 1 mg/mL or more, citrate buffer, and the polyvalent cation.

19. The method of claim 18, wherein the concentration of the IgM in the second solution is 20 mg/mL or more.

20. The method of claim 18, further comprising storing the second solution at 4°

C. to 25°

C. for at least one month.

21. The method of claim 18, further comprising freezing or lyophilizing the second solution.