Formulation of human antibodies for treating tnf-alpha associated disorders

• US 20060153846A1
• Filed: 08/15/2003
• Published: 07/13/2006
• Est. Priority Date: 08/16/2002
• Status: Active Grant

• Current Assignee: AbbVie Biotechnology Ltd. (Puerto Rico) (Abbvie Incorporated)
• Original Assignee: AbbVie Biotechnology Ltd. (Puerto Rico) (Abbvie Incorporated)
• Inventors: Krause, Hans-Juergen, Dickes, Michael, Baust, Lisa
• Granted Patent: US 8,216,583 B2
• Time in Patent Office: Days
• US Class Current: 424/145.100
• 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 pharmaceutical formulation selected from the group consisting of:

(a) a liquid aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody in a buffered solution, said formulation having a pH between about 4 and 8 and having a shelf life of at least 18 months;

(b) an aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody in a buffered solution, said formulation having a pH between about 4 and 8 and having a shelf life of at least 18 months in the liquid state;

(c) a liquid aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody in a buffered solution, said formulation having a pH between about 4 and 8 which maintains stability following at least 3 freeze/thaw cycles of the formulation; and

(d) a liquid aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody in a buffered solution, said formulation having a pH between 4 and 8 and having enhanced stability of at least 12 months at a temperature of 2-8°

C.

2. The formulation of claim 1, wherein the antibody is directed to TNFα

.

3. The formulation of claim 1, wherein the concentration of the antibody is between about 1-150 mg/ml.

4. The formulation of claim 1, wherein the concentration of the antibody is about 50 mg/ml.

5. The formulation of claim 1, which further is suitable for single use subcutaneous injection.

6. The formulation of claim 1, wherein the antibody is an human antibody, or an antigen-binding portion thereof, that dissociates from human TNFα

with a K_d of 1×

10<sup>−

8</sup> M or less and a K_off rate constant of 1×

10<sup>−

3</sup> s<sup>−

1</sup> or less, both determined by surface plasmon resonance, and neutralizes human TNFα

cytotoxicity in a standard in vitro L929 assay with an IC₅₀ of 1×

10<sup>−

7</sup> M or less.

7. The formulation of claim 6, wherein the antibody, or antigen-binding portion thereof, is a recombinant antibody, or antigen-binding portion thereof.

8. The formulation of claim 1, wherein the antibody is a human antibody, or antigen-binding portion, thereof with the following characteristics:

a) dissociates from human TNFα

with a K_off rate constant of 1×

10<sup>−

3</sup> s<sup>−

1</sup> or less, as determined by surface plasmon resonance;

b) has a light chain CDR3 domain comprising the amino acid sequence of 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;

c) has a heavy chain CDR3 domain comprising the amino acid sequence of 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.

9. The formulation of claim 1, wherein the antibody, or antigen-binding portion thereof, has 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.

10. The formulation of claim 1, wherein the antibody, or antigen-binding portion thereof, neutralizes the activity of human TNFα

, chimpanzee TNFα and

at least one additional primate TNFα

selected from the group consisting of baboon TNFα

, marmoset TNFα

, cynomolgus TNFα and

rhesus TNFα

.

11. The formulation of claim 1, wherein the antibody, or an antigen-binding portion thereof, also neutralizes the activity of mouse TNFα

and/or pig TNFα

.

12. The formulation of claim 1, wherein the antibody, or antigen-binding portion thereof, binds human TNFα

and is the antibody D2E7 or an antigen binding portion thereof.

13. An aqueous pharmaceutical composition comprising a polyol, a surfactant, and a buffer system comprising citrate and/or phosphate with a pH of about 4 to 8, in amounts sufficient to formulate an antibody for therapeutic use at a concentration of greater than about 45 mg/ml.

14. The composition of claim 13, wherein the polyol is mannitol and the surfactant is polysorbate 80.

15. The composition of claim 14, which contains 5-20 mg/ml of mannitol and 0.1-10 mg/ml of polysorbate 80.

16. The formulation of claim 13, which contains an antibody, or antigen-binding portion thereof, which binds human TNFα

and is the antibody D2E7 or an antigen binding portion thereof.

17. A liquid aqueous pharmaceutical formulation comprising

(a) 1-150 mg/ml of antibody,

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

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

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

18. The formulation of claim 17, wherein the pH is selected from the group consisting of between about 4.5 to about 6.0, between about 4.8 to about 5.5, and between about 5.0 to about 5.2.

19. The liquid aqueous pharmaceutical formulation of claim 17, which contains

(a) about 50 mg/ml of antibody,

(b) about 12 mg/ml of mannitol,

(c) about 1 mg/ml of Tween-80, and

(d) a buffer system comprising citrate and/or phosphate with a pH of about 4 to about 8.

20. The formulation of claim 17, wherein the buffer system comprises

(a) about 1.3 mg/ml of citric acid,

(b) about 0.3 mg/ml of sodium citrate,

(c) about 1.5 mg/ml of disodium phosphate dihydrate,

(d) about 0.9 mg/ml of sodium dihydrogen phosphate dihydrate, and

(e) about 6.2 mg/ml of sodium chloride.

21. The formulation of claim 19, wherein the antibody is directed to TNFα

.

22. The formulation of claim 19, wherein the antibody, or antigen-binding portion thereof, binds human TNFα

and is the antibody D2E7 or an antigen binding portion thereof.

23. The formulation of claim 22, which is administered to a subject suffering from a disorder in which TNFα

activity is detrimental such that TNFα

activity in the subject is inhibited.