Anti-il-6 antibodies, compositions, methods and uses

• US 7,560,112 B2
• Filed: 04/28/2006
• Issued: 07/14/2009
• Est. Priority Date: 04/29/2005
• Status: Expired

• Current Assignee: Janssen Biotech, Inc. (Johnson & Johnson)
• Original Assignee: Applied Molecular Evolution, Inc. (Eli Lilly and Company), Centocor Ortho Biotech Incorporated (Johnson & Johnson)
• Inventors: Marquis, David Matthew, Knight, David M., Wu, Sheng-Jiun, Yang, Jing, Vasserot, Alain Philippe, Chen, Yan, Smith, Eric Michael, Stojanovic-Susulic, Vedrana, Song, Xiao-Yu R., Gardner, Debra, Shealy, David J., Liang, Bailin, Tam, Susan H., Lark, Michael W., Sweet, Raymond W.
• Primary Examiner(s): MERTZ, PREMA MARIA
• Application Number:
  US11/413,561
• Publication Number:
  US 20060257407A1
• Time in Patent Office: 1,173 Days
• Field of Search: None
• US Class Current: 424/139.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/54 characterised by the route of administration
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• 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 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• 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 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 3/04 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 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• 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 5/50 : for increasing or potentiating the activity of insulin
• 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 9/10 : 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 16/248 : IL-6
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/33 : Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/34 : Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/567 : Framework region [FR]
• CPC Class Codes: C07K 2317/73 : Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• 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

Abstract

An anti-IL-6 antibody, including isolated nucleic acids that encode at least one anti-IL-6 antibody, vectors, host cells, transgenic animals or plants, and methods of making and using thereof have applications in diagnostic and/or therapeutic compositions, methods and devices.

Claims

1. An isolated IL-6 antibody, comprising a light chain variable region amino acid sequence of SEQ ID NO:

97 and/or a heavy chain variable region amino acid sequence of SEQ ID NO;

99.

7. The IL-6 antibody according to any one of claims 1-4, wherein said antibody down regulates an activity of IL-6 polypeptide consisting of the amino acid sequence set forth in SEQ ID NO:

115, wherein said activity is selected from the group consisting of binding of IL-6 to soluble gp80 (sIL-6R), IL-6-induced monocyte chemoattractant protein-1 (MCP-1) production, IL-6 and IL-1β

-induced serum amyloid A (SAA) production, IL-6 dependent STAT3 phosphorylation, and a decrease in protein kinase B (Akt), insulin recentor (IR), and IR-1 phosphorylation on sub-confluent HepG2 cells.

8. A composition comprising the IL-6 antibody according to any one of claims 1-4 and at least one pharmaceutically acceptable carrier or diluent.

9. The composition of claim 8, further comprising at least one compound or polypeptide selected from a detectable label or reporter, a TNF antagonist, an anti-infective drug, a cardiovascular (CV) system drug, a central nervous system (CNS) drug, an autonomic nervous system (ANS) drug, a respiratory tract drug, a gastrointestinal (GI) tract drug, a hormonal drug, a drug for fluid or electrolyte balance, a hematologic drug, an antineoplastic, an immunomodulation drug, an opthalmic, otic or nasal drug, a topical drug, a nutritional drug, a cytokine, and a cytokine antagonist.

10. An anti-idiotype antibody or fragment that specifically binds the IL-6 antibody according to any one of claims 1-4.

11. An IL-6 antibody produced by a method comprising providing an isolated recombinant non-human host cell capable of expressing in recoverable amounts said antibody, transforming the host cell with a nucleic acid encoding the IL-6 antibody according to any one of claims 1-4 and recovering said antibody.

14. The IL-6 antibody according to any one of claims 1-4, wherein said antibody has a human constant region.

2. An isolated IL-6 antibody, comprising a light chain variable region amino acid sequence of SEQ ID NO:

97 and a heavy chain variable region amino acid sequence of SEQ ID NO;

99.

6. The IL-6 antibody according to any one of claims 2-4, wherein said antibody binds IL-6 with at least one affinity selected from at least 10⁻

9 M, at least 10<sup>−

10</sup> M, at least 10<sup>−

11</sup> M, and at least 10<sup>−

12</sup> M, at least 10<sup>−

13</sup> M, at least 10<sup>−

14</sup> M, and at least 10<sup>−

15</sup> M, as determined by surface plasmon resonance or the Kinexa method.

12. The IL-6 antibody according to any one of claims 2-4, wherein said antibody has an EC₅₀ value of about 2.7 ×

10<sup>−

11</sup> M or less.

13. The antibody according to claim 12, wherein the EC₅₀ value is about 2.7×

10⁻

or less.

3. An isolated IL-6 antibody, comprising a complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO:

3, a CDRL2 amino acid sequence of SEQ ID NO;

21, a CDRL3 amino acid sequence of SEQ ID NO;

29, a complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO;

39, a CDRH2 amino acid sequence of SEQ ID NO;

59, and a CDRH3 amino acid sequence of SEQ ID NO;

89.

4. An isolated IL-6 antibody, comprising at least one light chain variable region and one heavy chain variable region, said light chain variable region comprising:

a complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO;

132 comprising the sequence S-X₁-X₂-X₃-X₄-V-X₅- Y-M-Y, wherein X₁ is A or G, X₂ is S or R, X₃ is H, I, S, or Y, X₄ is S or Y, and X₅ is S or F;

a CDRL2 amino acid sequence of SEQ ID NO;

133 comprising the sequence D-X₆-S-X₇-L-X₈-S, wherein X₆ is F, L, M, or T, X₇ is N or E, and X₈ is A or T; and

a CDRL3 amino acid sequence of SEQ ID NO;

134 comprising the sequence X₉-X₁₀-W-S-G-Y-P-Y-T, wherein X₉ is M, C, or S, and X₁₀ is Q or C;

said heavy chain variable region comprising;

a complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO;

135 comprising the sequence G-F-X₁₁-X₁₂-S-X₁₃-F-A-X₁₄-S, wherein X₁₁ is T or Q, X₁₂ is F, S, or T, X₁₃ is S or P, and X₁₄ is L or M;

a CDRH2 amino acid sequence of SEQ ID NO;

136 comprising the sequence K-X₁₅-S-X₁₆-G-G-S-X₁₇-X₁₈-Y-X₁₉-X₂₀- D-T-X₂₁-X₂₂-X₂₃, wherein X₁₅ is A or I, X₁₆ is S or P, X₁₇ is Y or W, X_{b 18} is T, E, or Y, X₁₉ is Y or F, X₂₀ is P, S, D, or F, X₂₁ is V or D, X₂₂ is T or A, and X₂₃ is G or P; and

a CDRH3 amino acid sequence of SEQ ID NO;

137 comprising the sequence Q-L-W-G-X₂₄-Y-A-L-D-X₂₅, wherein X₂₄ is S, Y, T, or N, and X₂₅ is Y, T, F, or I.

5. The isolated IL-6 antibody of claim 4, further comprising, interspersed between the complementarity determining regions, a human light chain framework region 1 (FRL1)of SEQ ID NO:

105, a FRL2 of SEQ ID NO;

106, a FRL3 of SEQ ID NO;

107, a FRL4 of SEQ ID NO;

108, a human heavy chain framework region 1 (FRH1) of SEQ ID NO;

109, a FRH2 of SEQ ID NO;

110, a FRH3 of SEQ ID NO;

111, and a FRH4 of SEQ ID NO;

112.

15. An isolated IL-6 antibody, comprising a light chain variable region amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:

98 and a heavy chain variable region amino acid sequence encoded by the nucleotide sequence of SEQ ID NO;

100.

16. An isolated IL-6 antibody, comprising a complementarity determining region light chain 1 (CDRL1) amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:

4, a CDRL2 amino acid sequence encoded by the nucleotide sequence of SEQ ID NO;

22, a CDRL3 amino acid sequence encoded by the nucleotide sequence of SEQ ID NO;

30, a complementarity determining region heavy chain 1 (CDRH1) amino acid sequence encoded by the nucleotide sequence of SEQ ID NO;

40, a CDRH2 amino acid sequence encoded by the nucleotide sequence of SEQ ID NO;

60, and a CDRH3 amino acid sequence encoded by the nucleotide sequence of SEQ ID NO;

90.