# US 8,772,458 B2 · Crystalline anti-hTNFalpha antibodies

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- Number: US 8,772,458 B2
- Document ID: US8772458B2
- Status: Granted
- Kind: B2
- Application number: 13/774,706
- Filed: 2013-02-22
- Published: 2013-11-21
- Granted: 2014-07-08
- Earliest claimed: 2006-10-27
- Assignees: AbbVie Biotechnology Ltd.
- Applicants: AbbVie Biotechnology Ltd
- Inventors: Anette Koenigsdorfer; Stefan Gottschalk; Hans-Juergen Krause; Gerhard Winter; David W. Borhani; Wolfgang Fraunhofer
- Web page: https://patentgrep.com/patent/US8772458B2

## CPC

- C07K 16/241: {Tumor Necrosis Factors}
- A61K 9/50: Microcapsules {having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals (A61K9/2081 takes precedence; particles with a single coating comprising drug A61K9/167)}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 7/06: Antianaemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 11/08: Bronchodilators
- A61P 13/08: of the prostate
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/04: for non-specific disorders of the connective tissue
- A61P 19/06: Antigout agents, e.g. antihyperuricemic or uricosuric agents
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 19/10: for osteoporosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- 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
- A61P 27/02: Ophthalmic agents
- A61P 27/16: Otologicals
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 39/00: General protective or antinoxious agents
- C07K 2299/00: Coordinates from 3D structures of peptides, e.g. proteins or enzymes
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to a batch crystallization method for crystallizing an anti-hTNFalpha antibody which allows the production of said antibody on an industrial scale; antibody crystals as obtained according to said method; compositions containing said crystals as well as methods of use of said crystals and compositions.

## Claims

### Claim 1

A method for treating a TNFalpha-related disorder in a subject in need thereof, said method comprising the step of administering to the subject an effective amount of anti-hTNFalpha antibody crystals,
wherein the antibody is an isolated human IgG antibody comprising two heavy chains each with a molecular weight of about 50 kpa, 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, and
wherein the crystals have a needle-like morphology with a length 1 of about 2-500 μm and an 1/d ratio of about 3 to 30.

### Claim 2

A method for treating a TNFalpha-related disorder in a subject in need thereof, said method comprising the step of administering to the subject an effective amount of a pharmaceutical composition comprising:
(a) crystals of an isolated human IgG anti-hTNFalpha antibody, wherein the antibody comprises two heavy chains each with a molecular weight of about 50 kpa, 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, and wherein the crystals have a needle-like morphology with a length 1 of about 2-500 μm and an 1/d ratio of about 3 to 30, and
(b) a pharmaceutical excipient.

### Claim 3 (depends on 2)

The method according to claim 2, wherein the pharmaceutical composition is administered to the subject by parenteral route, oral route, or injection.

### Claim 4 (depends on 1, 2)

The method of claim 1 or 2, wherein said TNFalpha-related disorder is selected from the group consisting of an allergy, multiple sclerosis, autoimmune diabetes, autoimmune uveitis and nephrotic syndrome; an infectious disease, transplant rejection or graft-versus-host disease, malignancy, pulmonary disorder, cardiac disorder, inflammatory bone disorders, bone resorption disease, alcoholic hepatitis, viral hepatitis, fulminant hepatitis, coagulation disturbances, burns, reperfusion injury, keloid formation, scar tissue formation, pyrexia, periodontal disease, obesity and radiation toxicity; a pulmonary disorder, a coronary disorder, a metabolic disorder, anemia, pain, a hepatic disorder, a skin disorder, a nail disorder, or vasculitis, Behcet's disease, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), restenosis, diabetes, anemia, pain, a Crohn's disease-related disorder, a hepatitis C virus infection, age-related cachexia, Alzheimer's disease, brain edema, inflammatory brain injury, chronic fatigue syndrome, dermatomyositis, drug reactions, edema in and/or around the spinal cord, familial periodic fevers, Felty's syndrome, fibrosis, glomerulonephritides (e.g. post-streptococcal glomerulonephritis or IgA nephropathy), loosening of prostheses, microscopic polyangiitis, mixed connective tissue disorder, multiple myeloma, cancer and cachexia, multiple organ disorder, myelo dysplastic syndrome, orchitism osteolysis, pancreatitis, including acute, chronic, and pancreatic abscess, periodontal disease polymyositis, progressive renal failure, pseudogout, pyoderma gangrenosum, relapsing polychondritis, rheumatic heart disease, sarcoidosis, sclerosing cholangitis, stroke, thoracoabdominal aortic aneurysm repair (TAAA), TNF receptor associated periodic syndrome (TRAPS), symptoms related to Yellow Fever vaccination, an inflammatory disease associated with the ear, chronic ear inflammation, or pediatric ear inflammation, uveitis, sciatica, prostatitis, endometriosis, choroidal neovascularization, lupus, Sjogren's syndrome, and wet macular degeneration.

### Claim 5 (depends on 2)

The method of claim 2, wherein the pharmaceutical excipient embeds or encapsulates the crystals.

### Claim 6 (depends on 1, 2)

The method of claim 1 or 2, wherein the IgG antibody is selected from the group consisting of an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, and an IgG4 antibody.

### Claim 7 (depends on 1, 2)

The method of claim 1 or 2, wherein the antibody is an IgG1 antibody.

### Claim 8 (depends on 1, 2)

The method of claim 1 or 2, wherein the antibody is adalimumab.

### Claim 9 (depends on 2)

The method of claim 2, wherein the composition has an antibody concentration greater than about 1 mg/ml.

### Claim 10 (depends on 2)

The method of claim 2, wherein the composition has an antibody concentration greater than about 200 mg/ml.

### Claim 11 (depends on 1)

The method of claim 1, wherein the crystal is combined with a polymeric carrier or an oil or lipid carrier.

### Claim 12 (depends on 11)

The method of claim 11, 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, glycami-noglycans, sulfated polysaccharides, blends and copolymers thereof.

### Claim 13 (depends on 1, 2)

The method of claim 1 or 2, wherein said TNFalpha-related disorder is an autoimmune disease.

### Claim 14 (depends on 13)

The method of claim 13, wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and gouty arthritis.

### Claim 15 (depends on 1, 2)

The method of claim 1 or 2, wherein said TNFalpha-related disorder is an intestinal disorder.

### Claim 16 (depends on 1, 2)

The method of claim 1 or 2, wherein said TNFalpha-related disorder is a spondyloarthropathy.

### Claim 17 (depends on 1, 2)

The method of claim 1 or 2, wherein said TNFalpha-related disorder is rheumatoid arthritis.

### Claim 18 (depends on 1, 2)

The method of claim 1 or 2, wherein said TNFalpha-related disorder is psoriatic arthritis.

### Claim 19 (depends on 1, 2)

The method of claim 1 or 2, wherein said TNFalpha-related disorder is psoriasis.

### Claim 20 (depends on 19)

The method of claim 19, wherein the psoriasis is chronic plaque psoriasis.

### Claim 21 (depends on 1, 2)

The method of claim 1 or 2, wherein said TNFalpha-related disorder is juvenile rheumatoid arthritis (JRA).