WO2006065975B1 - Methods of treating ankylosing spondylitis using anti-tnf antibodies and peptides of human tumor necrosis factor - Google Patents

Methods of treating ankylosing spondylitis using anti-tnf antibodies and peptides of human tumor necrosis factor

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Publication number
WO2006065975B1
WO2006065975B1 PCT/US2005/045388 US2005045388W WO2006065975B1 WO 2006065975 B1 WO2006065975 B1 WO 2006065975B1 US 2005045388 W US2005045388 W US 2005045388W WO 2006065975 B1 WO2006065975 B1 WO 2006065975B1
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WIPO (PCT)
Prior art keywords
human
antibody
tnf
antigen
tnfα
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Application number
PCT/US2005/045388
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French (fr)
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WO2006065975A3 (en
WO2006065975A2 (en
WO2006065975A8 (en
Inventor
Junming Le
Jan T Vilcek
Peter E Daddona
John Ghrayeb
David M Knight
Scott A Siegel
David Shealey
Original Assignee
Centocor Inc
Univ New York
Junming Le
Jan T Vilcek
Peter E Daddona
John Ghrayeb
David M Knight
Scott A Siegel
David Shealey
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Application filed by Centocor Inc, Univ New York, Junming Le, Jan T Vilcek, Peter E Daddona, John Ghrayeb, David M Knight, Scott A Siegel, David Shealey filed Critical Centocor Inc
Priority to US11/792,734 priority Critical patent/US20090041762A1/en
Publication of WO2006065975A2 publication Critical patent/WO2006065975A2/en
Publication of WO2006065975A3 publication Critical patent/WO2006065975A3/en
Publication of WO2006065975B1 publication Critical patent/WO2006065975B1/en
Publication of WO2006065975A8 publication Critical patent/WO2006065975A8/en
Priority to US12/885,406 priority patent/US20110195063A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/241—Tumor Necrosis Factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A90/00—Technologies having an indirect contribution to adaptation to climate change
    • Y02A90/10—Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Abstract

Anti-TNF antibodies, fragments and regions thereof which are specific for human tumor necrosis factor-α (TNFα) and are useful in vivo diagnosis and therapy of a number of TNFα-mediated pathologies and conditions, including ankylosing spondylitis, as well as polynucleotides coding for murine and chimeric antibodies, methods of producing the antibody, methods of use of the anti-TNF antibody, or fragment, region or derivative thereof, in immunoassays and immunotherapeutic approaches are provided.

Claims

AMENDED CLAIMS received by the International Bureau on 23 June 2006 (23.06.2006)What is claimed is:
1. A method of treating ankylosing spondylitis in a human in need thereof, comprising administering to the human an effective TNF-inhibiting amount of an anti-TNF chimeric antibody or antigen-binding fragment thereof for a sufficient period of time to treat the ankylosing spondylitis, wherein said anti-TNF chimeric antibody competitively inhibits binding of TNF to monoclonal antibody cA2.
2. A method of treating ankylosing spondylitis in a human in need thereof, comprising administering to the human an effective TNF-inhibiting amount of chimeric anti-TNF antibody cA2 for a sufficient period of time to treat the ankylosing spondylitis.
3. A method for treating ankylosing spondylitis in a human in need thereof, comprising administering to the human at least one monoclonal antibody cA2, or a TNF binding fragment thereof for a sufficient period of time to treat the ankylosing spondylitis.
4. A method of treating ankylosing spondylitis in a human in need thereof, comprising administering to the human an effective TNF-inhibiting amount of an anti-TNF chimeric antibody for a sufficient period of time to treat the ankylosing spondylitis, wherein said anti-TNF chimeric antibody comprises an IgGl constant region and competitively inhibits binding of TNF to monoclonal antibody cA2.
5. A method of treating ankylosing spondylitis in a human in need thereof, comprising administering to the human an effective TNF-inhibiting amount of an anti-TNF chimeric antibody for a sufficient period of time to treat the ankylosing spondylitis, wherein said anti-TNF chimeric antibody comprises a 197 non-human variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NO.:3 and SEQ ID NO.:5.
6. A method of treating ankylosing spondylitis in a human in need thereof, comprising administering to the human an effective TNF-inhibiting amount of an anti-TNF chimeric antibody for a sufficient period of time to treat the ankylosing spondylitis, wherein said anti-TNF chimeric antibody comprises an IgGl human constant region and a non-human variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NO.: 3 and SEQ ID NO.:5.
7. The method of Claim 5 wherein the non-human variable region comprises a polypeptide encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NO.:2 and SEQ ID NO.:4.
8. The method of Claim 6 wherein the non-human variable region comprises a polypeptide encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NO.:2 and SEQ ID NO.:4.
9. A method of treating ankylosing spondylitis in a human in need thereof, comprising administering to the human an effective TNF-inhibiting amount of an anti-TNF chimeric antibody for a sufficient period of time to treat the ankylosing spondylitis, wherein said anti-TNF chimeric antibody has epitopic specificity identical to monoclonal antibody cA2.
10. The method of Claim 1, further comprising administering to the human an effective amount of a therapeutic agent selected from the group consisting of: an antirheumatic, a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anethetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteriod, an anabolic steroid, a diabetes related agent, a mineral, a nutritional, a thyroid agent, a vitamin, a calcium related hormone, an 198 antidiarrheal, an antitussive, an antiemetic, an antiulcer, a laxative, an anticoagulant, an erythropoietin, a filgrastim, a sargramostim, an immunization, an immunoglobulin, an immunosuppressive, a growth hormone, a hormone replacement drug, an estrogen receptor modulator, a mydriatic, a cycloplegic, an alkylating agent, an antimetabolite, a mitotic inhibitor, a radiopharmaceutical, an antidepressant, an antimanic agent, an antipsychotic, an anxiolytic, a hypnotic, a sympathomimetic, a stimulant, donepezil, tacrine, an asthma medication, a beta agonist, an inhaled steroid, a leukotriene inhibitor, a methylxanthine, a cromolyn, an epinephrine, an epinephrine analog, dornase alpha, a cytokine and a cytokine antagonist.
11. The method of Claim 10, wherein the cytotoxic drug is selected from the group consisting of: daunorubicin, doxorubicin, methotrexate and Mitomycin C.
12. The method of Claim 1, further comprising administering to the human an effective amount of a disease-modifying anti-rheumatic drug.
13. The method of Claim 12, wherein the disease-modifying anti-rheumatic drug is selected from the group consisting of: auranofin, azathioprine, chloroquine, D- penicillamine, gold sodium thiomalate hydroxychloroquine and Myocrisin.
14. The method of Claim 1 , further comprising administering to the human an effective amount of an anti-inflammatory agent.
15. The method of Claim 14, wherein the anti-inflammatory agent is selected from the group consisting of: pentasa, mesalazine, asacol, codeine phosphate, benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin, aspirin and ibuprofen. 199
16. The method of Claim 1 , further comprising administering to the human an effective amount of methotrexate.
17. The method of Claim 10, wherein the therapeutic agent is a pain control agent.
18. The method of Claim 17, wherein the pain control agent is selected from the group consisting of: paracetamol and dextropropoxyphene.
19. The method of Claim 1, further comprising administering to the human an effective amount of at least one therapeutic agent selected from the group consisting of: at least one antibiotic and at least one steroid.
20. The method of Claim 1, wherein said anti-TNF chimeric antibody is a humanized antibody and is produced recombinantly.
21. A method of producing a human anti-TNF chimeric antibody of Claim 1 , wherein said human anti-TNF chimeric antibody or antigen-binding fragment thereof is produced by chemical synthesis.
22. A method of producing a human anti-TNF chimeric antibody of Claim 1, wherein said human anti-TNF chimeric antibody or antigen-binding fragment thereof is produced by using a hybridoma.
23. A method of producing a human anti-TNF chimeric antibody of Claim 1 , wherein said human anti-TNF chimeric antibody or antigen-binding fragment thereof is not produced by using B lymphocytes.
24. A method of producing a human anti-TNF chimeric antibody of Claim 1, wherein said human anti-TNF chimeric antibody or antigen-binding fragment thereof is produced by using phage display. 200
25. A method of producing a human anti-TNF chimeric antibody of Claim 1 , wherein said human anti-TNF chimeric antibody or antigen-binding fragment thereof is produced by using a transgenic animal.
26. A method of treating ankylosing spondylitis in a human in need thereof, comprising administering to the human a single or divided 0.1 - 100 mg/kg dose of an anti-TNF chimeric antibody for a sufficient period of time to treat the ankylosing spondylitis, wherein said anti-TNF chimeric antibody competitively inhibits binding of TNF to monoclonal antibody cA2.
27. The method of Claim 26, wherein the single or divided dose of anti-TNF chimeric antibody is selected from the group consisting of: a 0.1 - 1 mg/kg dose, a 1.0 - 5 mg/kg dose, a 5 - 10 mg/kg dose and a 10 - 20 mg/kg dose.
28. The method of Claim 1, wherein the anti-TNF chimeric antibody is administered to the human by means of parenteral administration.
29. The method of Claim 1, wherein the anti-TNF chimeric antibody is administered to the human by means of subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, or transspon means.
30. The method of Claim 1, wherein the anti-TNF chimeric antibody is administered to the human via the lung.
31. The method of Claim 1 , wherein the anti-TNF chimeric antibody is administered to the human orally. 201
32. The method of Claim 1 , wherein the anti-TNF chimeric antibody is of immunoglobulin class IgGl, IgG27 IgG3, IgG4 or IgM.
33. The method of Claim 1 , wherein the anti-TNF chimeric antibody is a fragment selected from the group consisting of Fab, Fab', F(ab')2 and Fv.
34. A method of treating ankylosing spondylitis in a human in need thereof comprising administering to the human an initial 5mg/kg dose of an anti- TNF chimeric antibody, followed by another 5mg/kg dose of said anti-TNF chimeric antibody at two weeks, six weeks and every six weeks thereafter for a sufficient period of time to treat the ankylosing spondylitis, wherein said anti-TNF chimeric antibody competitively inhibits binding of TNF to monoclonal antibody cA2.
35. A method of treating ankylosing spondylitis in a human in need thereof, comprising administering to the human an effective TNFα-inhibitiag amount of an anti-TNFtf antibody or antigen-binding fragment thereof for a sufficient period of time to treat the ankylosing spondylitis, said antibody comprising a human constant region, wherein said anti-TNFα antibody or antigen bonding fragment (i) competitively inhibits binding of A2 (ATCC Accession No. PTA-7045) to human TNFα and (ii) binds to a neutralizing epitope of human TNFα with an affinity of at least 1 x 10s liter/mole, measured as an association constant (Ka), as determined by Scatchard analysis.
36. The method of Claim 35, wherein the antibody or antigen-binding fragment comprises a human constant region and a human variable region.
37. The method of Claim 35, which comprises at least one human light chain and at least one human heavy chain. 202
38. The method of Claim 37, wherein the light chain comprises all antigen- binding regions of the light chain of A2 (ATCC Accession No. PTA-7045).
39. The method of Claim 37, wherein the heavy chain comprises all antigen- binding regions of the heavy chain of A2 (ATCC Accession No. PTA-7045).
40. The method of Claim 37, wherein the light chain comprises all antigen- binding regions of the light chain of A2 (ATCC Accession No. PTA-7045) and the heavy chain comprises all antigen-binding regions of the heavy chain of A2 (ATCC Accession No. PTA-7045).
41. A method of treating ankylosing spondylitis in a human in need thereof, comprising administering to ihe human an effective TNFα-inhibiting amount of an anti-TNFα antibody or antigen-binding fragment thereof for a sufficient period of time to treat the ankylosing spondylitis, said antibody comprising a human constant region, wherein said antibody or antigen-binding fragment (i) comprises the antigen-binding regions of A2 (ATCC Accession No. PTA- 7045), and (ϋ) binds to a neutralising epitope of human TNF-α with an affinity of at least 1 x 10 liter/mole, measured as an association constant (Ka), as determined by Scatchard analysis.
42. A method of treating ankylosing spondylitis in a human in need thereof, comprising administering to comprising administering to the human a single or divided 0.1 - 100 mg/kg dose of an anti-TNFα antibody or antigen-binding fragment thereof for a sufficient period of time to treat the ankylosing spondylitis, said antibody comprising a human constant region, wherein said antibody or antigen-binding fragment (i) comprises the antigen-binding regions of A2 (ATCC Accession No. PTA-7045), and (ii) binds to a neutralizing epitope of human TNF-α with an affinity of at least 1 x 10s liter/mole, measured as an association constant (Ka), as determined by Scatchard analysis. 203
43. The method of Claim 42, wherein the single or divided dose of anti-TNFα antibody or antigen-binding fragment is selected from the group consisting of: a 0.1 - 1 mg/kg dose, a 1.0 - 5 mg/kg dose, a 5 - 10 mg/kg dose and a 10 - 20 mg/kg dose.
44. The method of Claim 35, wherein the anti-TNFα antibody or antigen-binding fragment is administered to the human by means of parenteral administration.
45. The method of Claim 35, wherein the anή-TNFα antibody is administered io the human by at least one mode selected from parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracelebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intrareiinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, or transdermal.
46. The method of Claim 35, further comprising administering to the human an effective amount of a therapeutic agent selected from the group consisting of: radiotherapeutics, immunosuppressives, cytotoxic drugs, monoclonal antibodies, murine antibodies, chimeric antibodies, antibody fragments, antibody τegions, Vymphokines, cytokines, hemopoietic growth factors and immunoglobulins.
47. The method of Claim 35, further comprising administering to the human a disease-modifying anti-rheumatic drug.
4S. The method of Claim 47, wherein the disease-modifying anti-rheumatic drug is selected from the group consisting of: auranofin, a2atbioprine, chloroquine, D- penicillamine, gold sodium thiomalate hydroxychloroquine, Myocrisin and sulρhasala2ine. 204
49. The method of Claim 35, further comprising administering to the human an effective amount of an anti-inflammatory agent.
50. The method of Claim 49, wherein the anti-inflammatory agent is selected from the group consisting of: pentasa, mesalazine. asacol, codeine phosphate, benorylate, fenbufen, uaprosyn, diclofenac, etodolac and indomethacin, aspirin and ibuprofen.
51. The method of Claim 35, further comprising administering to the human an effective amount of meihoτrexate.
52. The method of Claim 35, further comprising administering to the human an effective amount of is a pain control agent.
53. The method of Claim 52, wherein the pain control agent is selected from the group consisting of: paracetamol and dextropropoxyphene.
54. The method of Claim 35, further comprising administering to the human an effective amount of at least one therapeutic agent selected from the group consisting of: at least one antibiotic and at least one steroid.
55. The method of Claim 35, wherein the anti-TMFα antibody or antigen-binding fragment is of immunoglobulin class IgGl7 IgG2, IgG3, lgG4 or IgM.
56. The method of Claim 35, wherein said fragment selected from the group consisting of Fab, Fab', F(ab')2 and Fv.
57. A method of treating ankylosing spondylitis in a human in need thereof, comprising administering to the human an effective TNFα-inhibiting amount of a composition comprising an anti-TNFα antibody or antigen-binding fragment thereof and a pharmaceutically acceptable carrier for a sufficient period of time to treat the ankylosing spondylitis, said antibody comprising a 205
human constant region, wherein said anti-TNFα antibody or antigen binding fragment (i) competitively inhibits binding of A2 (ATCC Accession No. PTA-7045) to human TNFα and (ii) binds to a neutralizing epitope of human TNFα with an affinity of at least I x I O8 liter/mole, measured as an association constant (Ka), as determined by Scatchard analysis.
58. The method of Claim 35, wherein said anti-TNFα antibody or antigen- binding fragment has specificity for a neutralizing epitope of human TNF-α.
59. The method of Claim 35, wherein said Scatchard analysis comprises labeling the anti-TNF-α antibody or antigen-binding fragment thereof and measuring direct binding of 125I labeled anti-TNF-α antibody or antigen-binding fragment thereof to immobilized rhTNFα, and wherein said antibodies are labelled to a specific activity of about 9.7 μCi/μg by the iodogen method.
60. A method of treating ankylosing spondylitis in a human in need thereof, comprising administering to the human an effective TNFα-inhibiting amount of an anti-TNFα antibody or antigen-binding fragment thereof for a sufficient period of time to treat the ankylosing spondylitis, said antibody comprising a human IgGl constant region, antibody or antigen-binding fragment (i) competitively inhibits binding of A2 (ATCC Accession No. PTA-7045) to human TNF-ct, and (ii) binds to a neutralizing epitope of human TNF-α with gg aann aafffifinniittyy ooff aatt lleeaasstt 1100 lliitteerr//mmoollee,, mmeeaassuuried as an association constant (Ka), as determined by Scatchard analysis.
61. The method of Claim 60, wherein the antibody or antigen-binding fragment comprises a human constant region and a human variable region.
62. The method of Claim 60, which comprises at least one human light chain and at least one human heavy chain. 206
63. The method of Claim 62, wherein the Ugbi chain comprises all antigen- binding regions of the light chain of A2 (ATCC Accession No. PTA-7045).
64. The antibody or antigen-binding fragment of Claim 62, wherein the heavy chain comprises all antigen-binding regions of the heavy chain of A2 (ATCC Accession No. PTA-7045).
65. The antibody or antigen-binding fragment of Claim 62, wherein the light chain comprises all antigen-binding regions of the light chain of A2 (ATCC Accession No. PTA-7045) and the heavy chain comprises all antigen-binding regions of the heavy chain of A2 (ATCC Accession No. PTA-7045).
66. A method of treating ankylosing spondylitis in a human in need thereof, comprising administering to the human an effective TNFα-mhibiting amount of an anti-TNFα antibody or antigen-binding fragment thereof for a sufficient period of time to treat the ankylosing spondylitis, said antibody comprising a human IgGl constant region, wherein said antibody or antigen-binding fragment (i) comprises the antigen-binding regions of A2 (ATCC Accession No. PTA-7045), and (ii) binds to a neutralizing epitope of human TNF-α with an affinity of at least I x 10 liter/mole, measured as an association constant (Ka), as determined by Scatchard analysis.
67. A method of treating ankylosing spondylitis in a human in need thereof, comprising administering to the human an effective TNFα-inhibiting amount of a light chain that specifically binds human TNFα and competitively inhibits binding of A2 (ATCC Accession No. PTA-7045) to human TNF-α, said light chain comprising a human tight chain constant region and a human light chain framework region, wherein said human light chain binds to a neutralizing epitope of human TNF-α with an affinity of at least 1 x 10* 207
liter/mole, measured as an association constant (Ka), as determined by Scatchard analysis,
68. A method of treating ankylosing spondylitis in a human m need thereof, comprising administering to the human an effective TNFα-inhibiting amount of a heavy chain that specifically binds human TNFα and competitively inhibits binding of A2 (ATCC Accession No. PTA-7045) to human TNF-α, said heavy chain comprising a human heavy chain constant region and a human heavy chain framework region, wherein said heavy chain binds to a neutralizing epitope of human TNF-α with an affinity of at least 1 x 10 liter/mole, measured as an association constant (Ka), as determined by Scaichard analysis.
69. A method of treating TNFα-mediated disease in a human in need thereof, comprising administering to the human an effective TNFa-inhibiting amount of an anti-TNFα antibody or antigen-binding fragment thereof for a sufficient period of time to treat the disease, said antibody comprising a human constant region, wherein said antibody or antigen-binding fragment (i) comprises the antigen-binding regions of A2 (ATCC Accession No. PTA- 7045), and (ιi) binds to a neutralizing epitope of human TNF-α with an g affinity of at least 1 x 10 liter/mole, measured as an association constant (Ka), as determined by Scatchard analysis, and wherein said disease is selected from the group consisting of thyroidosis, scleroderma, diabetes mellitus, Graves' disease, ulcerative colitis, atherosclerosis, and chronic inflammatory bowel disease.
70. Use of a pharmaceutical composition comprising an anti-TNFα antibody or antigen-binding fragment thereof, said antibody comprising a human constant region, wherein said anti-TNFα antibody or antigen binding fragment (i) competitively inhibits binding of A2 (ATCC Accession No. 208
PTA-7045) to human TNFα and (ii) binds to a neutralizing epitope of human TNFα with an affinity of at least 1 x 10s liter/mole, measured as an association constant (Ka), as determined by Scaτchard analysis, and a pharmaceutically acceptable carrier, for the manufacture of a medicament for the treatment of TNFα-raediated disease.
A formulation for treating TNFα-mediated disease comprising an anti-TNFα antibody or antigen-binding fragment thereof, said antibody comprising a human constant region, wherein said anti-TNFα antibody or antigen binding fragment (i) competitively inhibits binding of A2 (ATCC Accession No. PTA-7045) to human TNFα and (ii) binds to a neutralizing epitope of human TNFα in vivo with an affinity of at least 1 x 10s liter/mole, measured as an association constant (Ka), as determined by Scatchard analysis.
PCT/US2005/045388 2000-08-07 2005-12-13 Methods of treating ankylosing spondylitis using anti-tnf antibodies and peptides of human tumor necrosis factor WO2006065975A2 (en)

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US12/885,406 US20110195063A1 (en) 2000-08-07 2010-09-17 Methods of Treating Ankylosing Spondylitis Using Anti-TNF Antibodies and Peptides of Human Tumor Necrosis Factor

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US11/010,954 US20050249735A1 (en) 2000-08-07 2004-12-13 Methods of treating ankylosing spondylitis using anti-TNF antibodies and peptides of human tumor necrosis factor

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