Formulation of human antibodies for treating TNF-α associated disorders

• US 8,216,583 B2
• Filed: 08/15/2003
• Issued: 07/10/2012
• Est. Priority Date: 08/16/2002
• Status: Active Grant

• Current Assignee: AbbVie Biotechnology Ltd. (Puerto Rico) (Abbvie Incorporated)
• Original Assignee: Abbott Biotechnology Limited (Abbott Laboratories Incorporated)
• Inventors: Baust, Lisa, Dickes, Michael, Kruase, Hans-Juergen
• Primary Examiner(s): Bunner, Bridget E
• Application Number:
  US10/525,292
• Publication Number:
  US 20060153846A1
• Time in Patent Office: 3,252 Days
• Field of Search: None
• US Class Current: 424/158.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• 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 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• 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 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• 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 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• 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 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 : Antipsoriatics
• 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 19/08 : for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 25/02 : for peripheral neuropathies
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• 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 3/04 : Anorexiants; Antiobesity agents
• 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 31/12 : Antivirals
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 33/06 : Antimalarials
• 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 37/06 : 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 7/00 : Drugs for disorders of the blood or the extracellular fluid
• 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: C07K 16/241 : Tumor Necrosis Factors
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance
• 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

A liquid aqueous pharmaceutical formulation is described which has a high protein concentration, a pH of between about 4 and about 8, and enhanced stability.

Claims

1. A stable liquid aqueous pharmaceutical formulation comprising a human anti-Tumor Necrosis Factor alpha (TNFα

) antibody, or antigen-binding fragment thereof, at a concentration of between about 20 and about 150 mg/ml, a polyol, a surfactant, and a buffer system comprising citrate and phosphate,

wherein said formulation has a pH of about 4 to about 8, and

wherein the antibody, or antigen-binding portion thereof, comprises a light chain variable region comprising a complementary determining region (CDR) 1 domain comprising the amino acid sequence set forth in SEQ ID NO;

7;

a CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO;

5; and

a CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO;

3, or modified from SEQ ID NO;

3 by a single alanine substitution at position 1, 4, 5, 7, or 8, or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8, and/or 9; and

comprises a heavy chain variable region comprising a CDR 1 domain comprising the amino acid sequence set forth in SEQ ID NO;

8;

a CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO;

6; and

a CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO;

4, or modified from SEQ ID NO;

4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10, or 11, or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11, and/or 12.

2. The liquid aqueous pharmaceutical formulation of claim 1, wherein the antibody, or antigen-binding portion thereof, is the antibody D2E7, or antigen binding portion thereof.

3. The liquid aqueous pharmaceutical formulation of claim 1, wherein the antibody, or antigen binding portion thereof, comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

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

2.

4. The liquid aqueous pharmaceutical formulation of claim 1, comprising about 35-115 mg/ml of the antibody, or antigen-binding portion thereof.

5. The liquid aqueous pharmaceutical formulation of claim 1, comprising about 45-105 mg/ml of the antibody, or antigen-binding portion thereof.

6. The liquid aqueous pharmaceutical formulation of claim 1, wherein the pH is between about 4.5 to about 6.0.

7. The liquid aqueous pharmaceutical formulation of claim 1, wherein the polyol is a sugar alcohol.

8. The liquid aqueous pharmaceutical formulation of claim 7, wherein the sugar alcohol is mannitol.

9. The liquid aqueous pharmaceutical formulation of claim 1, wherein the surfactant is a polysorbate.

10. The liquid aqueous pharmaceutical formulation of claim 9, wherein the polysorbate is polysorbate 80.

11. A liquid aqueous pharmaceutical formulation comprising

(a) about 20 to about 150 mg/ml of a human anti-Tumor Necrosis Factor alpha (TNFα

) antibody, or antigen-binding portion thereof;

(b) 5-20 mg/ml of mannitol,

(c) 0.1-10 mg/ml of polysorbate-80, and

(d) a buffer system comprising citrate and phosphate, with a pH of 4 to 8,

wherein the antibody, or antigen-binding portion thereof, comprises a light chain variable region comprising a complementary determining region (CDR) 1 domain comprising the amino acid sequence set forth in SEQ ID NO;

7;

a CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO;

5; and

a CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO;

3, or modified from SEQ ID NO;

3 by a single alanine substitution at position 1, 4, 5, 7, or 8, or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8, and/or 9; and

comprises a heavy chain variable region comprising a CDR 1 domain comprising the amino acid sequence set forth in SEQ ID NO;

8;

a CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO;

6; and

a CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO;

4, or modified from SEQ ID NO;

4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10, or 11, or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11, and/or 12.

12. The liquid aqueous pharmaceutical formulation of claim 11, which comprises

(a) about 40 to about 100 mg/ml of antibody, or antigen-binding portion thereof,

(b) about 7.5 to about 15 mg/ml of mannitol, and

(c) about 0.5 to about 5 mg/ml of polysorbate 80.

13. The liquid aqueous pharmaceutical formulation of claim 11, wherein the antibody, or antigen-binding portion thereof, is the antibody D2E7 or an antigen binding portion thereof.

14. The liquid aqueous pharmaceutical formulation of claim 11, wherein the antibody, or antigen binding portion thereof, comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

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

2.

15. The liquid aqueous pharmaceutical formulation of claim 11, comprising about 35-115 mg/ml of the antibody, or antigen-binding portion thereof.

16. The liquid aqueous pharmaceutical formulation of claim 11, comprising about 45-105 mg/ml of the antibody, or antigen-binding portion thereof.

17. The liquid aqueous pharmaceutical formulation of claim 11, wherein the pH is between about 4.5 to about 6.0.

18. The liquid aqueous pharmaceutical formulation of claim 11, comprising 10 to 14 mg/ml of the mannitol.

19. The liquid aqueous pharmaceutical formulation of claim 11, comprising 0.5 to 5 mg/ml of the polysorbate 80.