Crystalline anti-human IL-12 antibodies

• US 8,168,760 B2
• Filed: 03/27/2008
• Issued: 05/01/2012
• Est. Priority Date: 03/29/2007
• Status: Expired due to Fees

• Current Assignee: Abbvie Incorporated
• Original Assignee: Abbott Laboratories
• Inventors: Borhani, David W., Fraunhofer, Wolfgang, Krause, Hans-Juergen, Koenigsdorfer, Anette, Winter, Gerhard, Gottschalk, Stefan
• Primary Examiner(s): NOAKES, SUZANNE MARIE
• Application Number:
  US12/079,434
• Publication Number:
  US 20080292642A1
• Time in Patent Office: 1,496 Days
• Field of Search: None
• US Class Current: 530/388.15
• CPC Class Codes: A61K 39/39591 Stabilisation, fragmentation
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• 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 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/14 : for RNA viruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 33/00 : Antiparasitic agents
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/16 : for decreasing, blocking or antagonising the activity of the thyroid hormones
• CPC Class Codes: A61P 5/38 : of the suprarenal hormones
• CPC Class Codes: A61P 5/40 : Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07K 16/244 : Interleukins [IL]
• CPC Class Codes: C07K 2299/00 : Coordinates from 3D structures of peptides, e.g. proteins or enzymes
• CPC Class Codes: C30B 7/00 : Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions from molten solvents C30B9/00; by normal or gradient freezing C30B11/00; under a protective fluid C30B27/00
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention relates to batch crystallization methods for crystallizing an anti-hIL-12 antibody that allows the production of the antibody on an industrial scale, antibody crystals obtained according to the methods, compositions containing the crystals, and methods of using the crystals and the compositions.

Claims

1. A crystal of an intact ABT-874 antibody, wherein said crystal has a length of about 2-500 μ

m.

2. The crystal according to claim 1, wherein the crystal has a sword-like morphology.

3. The crystal of claim 1, wherein the crystal has a needle morphology and an 1/d ratio of about 1 to 100.

4. The crystal of claim 1, wherein the crystal has a needle morphology with a length of about 100-300 μ

m and an 1/d ratio of about 1 to 3.

5. The crystal of claim 1, wherein the crystal is obtainable by a batch crystallization method.

6. The crystal of claim 1, wherein the crystal is obtainable by a vapor diffusion crystallization method.

7. The crystal according to claim 1, obtainable by a crystallization method comprising the steps of:

(a) providing an aqueous crystallization mixture having an aqueous solution of the antibody in admixture with at least one polyalkylene glycol as crystallization agent; and

(b) incubating the aqueous crystallization mixture until crystals of the antibody are formed.

8. The crystal according to claim 7, wherein the pH of the aqueous crystallization mixture is in the range of about pH 4 to about 6.5.

9. The crystal according to claim 7, wherein the aqueous crystallization mixture comprises a buffer.

10. The crystal according to claim 9, wherein the buffer comprises an acetate buffer.

11. The crystal according to claim 10, wherein the buffer comprises sodium acetate.

12. The crystal according to any one of claims 9-11, wherein the buffer concentration in the aqueous crystallization mixture is up to about 0.5 M.

13. The crystal according to any one of claims 7 or 8-11, wherein the polyalkylene glycol has an average molecular weight in the range of about 400 to about 10,000.

14. The crystal according to claim 13, wherein the polyalkylene glycol is polyethylene glycol.

15. The crystal according to any one of claims 7 or 8-11, wherein the polyalkylene glycol concentration in the crystallization mixture is in the range of about 5 to 30% (w/v).

16. The crystal according to claim 15, wherein the polyalkylene glycol is polyethylene glycol.

17. The crystal according to any one of claims 7 or 8-11, wherein at least one of the following additional crystallization conditions are met:

a) incubation is performed for between about 1 hour to about 250 days;

b) incubation is performed at a temperature between about 4°

C. and about 37°

C.; and

c) the antibody concentration is in the range of about 0.5 to about 280 mg/ml.

18. The crystal according to claim 7, wherein the crystallization method further comprises the step of drying the crystals.

19. The crystal according to any one of claims 7 or 8-11, further comprising the step of exchanging the crystallization mother liquor with an artificial mother liquor.

20. The crystal according to any one of claims 7 or 8-11, wherein the batch volume is in the range of about 1 ml to about 20,000 liters.

21. The crystal according to claim 1 for use in medicine.

22. A pharmaceutical composition comprising:

(a) the crystal according to claim 1, and (b) at least one pharmaceutical excipient;

wherein the composition is provided as a solid, a semisolid or a liquid formulation, each formulation containing the antibody in crystalline form.

23. A pharmaceutical composition comprising:

(a) the crystal according to claim 1, and (b) at least one pharmaceutical excipient, which embeds or encapsulates the crystals.

24. The composition of claim 22 or 23, wherein the composition has an antibody concentration greater than about 1 mg/ml.

25. The composition of claim 24, wherein the composition has an antibody concentration greater than about 200 mg/ml.

26. The composition according to claim 22 and 23, wherein the composition comprises at least one carrier selected from the group consisting of a polymeric biodegradable carrier, a polymeric non-biodegradable carrier, an oil carrier, and a lipid carrier.

27. The composition according to claim 26, wherein the polymeric carrier is a polymer selected from one or more of the group consisting of:

poly (acrylic acid), poly (cyanoacrylates), poly (amino acids), poly (anhydrides), poly (depsipeptide), poly (esters), poly (lactic acid), poly (lactic-co-glycolic acid) or PLGA, poly (β

-hydroxybutryate), poly (caprolactone), poly (dioxanone);

poly (ethylene glycol), poly (hydroxypropyl)methacrylamide, poly[(organo) phosphazene, poly (ortho esters), poly (vinyl alcohol), poly (vinylpyrrolidone), maleic anhydride alkyl vinyl ether copolymers, pluronic polyols, albumin, alginate, cellulose and cellulose derivatives, collagen, fibrin, gelatin, hyaluronic acid, oligosaccharides, glycaminoglycans, sulfated polysaccharides, blends and copolymers thereof.

28. An injectable liquid composition comprising the crystal according to claim 1 and having an antibody concentration in the range of about 10 to about 400 mg/ml.

29. A crystal slurry composition comprising the crystal according to claim 1, having an antibody concentration greater than about 100 mg/ml.

30. A batch crystallization method for crystallizing an ABT-874 antibody to form crystals having a length of about 2-500 μ

m, the method comprising the steps of;

(a) providing an aqueous crystallization mixture having an aqueous solution of the antibody in admixture with at least one polyalkylene glycol having an average molecular weight in the range of about 400 to about 10,000 as crystallization agent, wherein the antibody concentration is in the range of about 0.5 to about 280 mg/ml; and

(b) incubating the aqueous crystallization mixture at a pH of about 4 to about 6.5 and at a temperature of about 4°

C. to about 37°

C. until crystals of the antibody having a length of about 2-500 μ

m are formed.

31. The crystallization method according to claim 30, wherein the aqueous crystallization mixture comprises a buffer.

32. The crystallization method according to claim 31, wherein the buffer comprises an acetate buffer.

33. The crystallization method according to claim 32, wherein the buffer comprises sodium acetate.

34. The crystallization method according to any one of claims 31 to 33, wherein the buffer concentration in the aqueous crystallization mixture is up to about 0.5 M.

35. The crystallization method according to claim 30, wherein the polyalkylene glycol is polyethylene glycol.

36. The crystallization method according to claim 30, wherein the polyalkylene glycol concentration in the crystallization mixture is in the range of about 5 to 30% (w/v).

37. The crystallization method according to any one of claims 30 or 31-33, wherein incubation is performed for between about 1 hour to about 250 days.

38. The crystallization method according to claim 30, further comprising the step of drying the crystals.

39. The crystallization method according to any one of claims 30 or 31-33, further comprising the step of exchanging the crystallization mother liquor with an artificial mother liquor.

40. The crystallization method according to any one of claims 30 or 31-33, wherein the batch volume is in the range of about 1 ml to about 20,000 liters.

41. The crystallization method according to any one of claims 30 or 31-33, further comprising the step of extending the yield of the crystals by adding additional polyalkylene glycol.

42. The method according to claim 41, wherein the polyalkylene glycol is polyethylene glycol.

43. The method according to claim 41, wherein the polyalkylene glycol is added continuously.

44. The crystallization method according to any one of claims 30 or 31-33, further comprising the step of seeding the reaction with ABT-874.

45. A batch crystallization method for crystallizing an IgG anti-human IL-12 antibody, the method comprising the steps of:

(a) providing an aqueous crystallization mixture having an aqueous solution of the antibody in admixture with at least one polyalkylene glycol having an average molecular weight in the range of about 400 to about 10,000 as crystallization agent, wherein the antibody concentration is in the range of about 0.5 to about 280 mg/ml; and

(b) incubating the aqueous crystallization mixture at a pH of about 4 to about 6.5 and at a temperature of about 4°

C. to about 37°

C. until crystals of the antibody are formed,

wherein the antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO;

2 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO;

1.