Anti-IL-6 antibodies for the treatment of arthritis
View Patent ↗The present invention is directed to therapeutic methods using IL-6 antagonists such as anti-IL-6 antibodies and fragments thereof having binding specificity for IL-6 to prevent or treat rheumatoid arthritis.
1. A method of treating rheumatoid arthritis comprising intravenously or subcutaneously administering a therapeutically effective dosage of an anti-interleukin-6 (anti-IL-6) antibody or antibody fragment having the variable light (V L ) CDRs in SEQ ID NO:4, 5 and 6 and the variable heavy (V H ) CDRs in SEQ ID NO:7, 8 or 120 and 9 to a patient in need thereof, wherein said antibody or antibody fragment comprises a variable light chain polypeptide comprising a polypeptide having at least 98% identity to SEQ ID NO: 709 and a variable heavy chain polypeptide comprising a polypeptide having at least 98% identity to SEQ ID NO: 657, and further comprising an Fc region, which Fc region contains one or more mutations that reduce or eliminate glycosylation of the anti-IL-6 antibody or antibody fragment.
2. The method of claim 1 , wherein said anti-IL-6 antibody or antibody fragment contains an anti-IL-6 antibody or antibody fragment having the variable light (V L ) CDRs in SEQ ID NO:4, 5 and 6 and the variable heavy (V H ) CDRs in SEQ ID NO:7, 8 and 9.
3. The method of claim 1 , wherein said anti-IL-6 antibody or antibody fragment contains the variable light (V L ) CDRs in SEQ ID NO: 4, 5 and 6 and the variable heavy (V H ) CDRs in SEQ ID NO:7, 120 and 9.
4. The method claim 1 wherein said antibody or antibody fragment containing said CDRs comprises a variable light chain polypeptide comprising a polypeptide having at least 99% identity to SEQ ID NO: 709.
5. The method claim 1 wherein said antibody or antibody fragment containing said CDRs comprises a variable light chain polypeptide comprising a polypeptide identical to SEQ ID NO: 709.
6. The method claim 1 wherein said antibody or antibody fragment containing said CDRs comprises a variable heavy chain polypeptide comprising a polypeptide having at least 99% identity to SEQ ID NO: 657.
7. The method claim 1 wherein said antibody or antibody fragment containing said CDRs comprises a variable heavy chain polypeptide comprising a polypeptide identical to SEQ ID NO: 657.
8. The method claim 1 wherein said antibody or antibody fragment containing said CDRs comprises a variable light chain polypeptide comprising a polypeptide having at least 99% identity to SEQ ID NO: 709 and a variable heavy chain polypeptide comprising a polypeptide having at least 99% identity to SEQ ID NO: 657.
9. The method of claim 8 , wherein said anti-IL-6 antibody or antibody fragment containing said CDRs comprises the IgG1 constant light chain sequence contained in SEQ ID NO: 586 and the constant heavy chain sequence contained in SEQ ID NO: 588.
10. The method claim 1 wherein said antibody or antibody fragment containing said CDRs comprises a variable light chain polypeptide comprising a polypeptide identical to SEQ ID NO: 709 and a variable heavy chain polypeptide comprising a polypeptide identical to SEQ ID NO: 657.
11. The method of claim 10 , wherein said anti-IL-6 antibody or antibody fragment containing said CDRs comprises the IgG1 constant light chain sequence contained in SEQ ID NO: 586 and the constant heavy chain sequence contained in SEQ ID NO: 588.
12. The method of claim 10 , wherein said IL-6 antibody or antibody fragment containing said CDRs is administered at least twice.
13. The method of claim 12 , wherein the patient receives at least a first dosage and a second dosage, and said second dosage is about eight weeks subsequent to said first dosage.
14. The method of claim 10 , wherein the patient is administered said anti-IL-6 antibody or antibody fragment containing said CDRs every 8 weeks or 2 months.
15. The method of claim 10 wherein said patient has previously received or is concurrently receiving methotrexate.
16. The method of claim 15 , wherein the dosage of said methotrexate is at least 10 mg/week.
17. The method of claim 15 , wherein said patient continues to receive methotrexate for at least 8 weeks after administration of said anti-IL-6 antibody or antibody fragment containing said CDRs.
18. The method of claim 10 , wherein the patient exhibits methotrexate resistance at the time of administration of said anti-IL-6 antibody or antibody fragment containing said CDRs.
19. The method of claim 10 , wherein said anti-IL-6 antibody or antibody fragment containing said CDRs is administered subcutaneously.
20. The method of claim 10 , wherein said anti-IL-6 antibody or antibody fragment containing said CDRs is administered intravenously.
21. The method of claim 10 , wherein said anti-IL-6 antibody or antibody fragment containing said CDRs is contained in a composition that comprises said anti-IL6 antibody or antibody fragment, about 5 mM Histidine base, about 5 mM Histidine HC! to make final pH 6, 250 mM sorbitol, and 0.015% (w/w) Polysorbate 80.
22. The method of claim 10 , wherein said anti-IL-6 antibody or antibody fragment containing said CDRs is contained in a composition comprising about 25 mM Histidine base, Phosphoric acid q.s. to pH 6, and about 250 mM sorbitol.
23. The method claim 10 , wherein the administered dosage of said anti-IL-6 antibody or antibody fragment containing said CDRs is at least about 50 or 100 mg.
24. The method of claim 10 , wherein the administered dosage of said anti-IL-6 antibody or antibody fragment is about 80 mg.
25. The method of claim 10 , wherein the administered dosage of said anti-IL-6 antibody or antibody fragment is about 160 mg.
26. The method of claim 10 , wherein the administered dosage of said anti-IL-6 antibody or antibody fragment is about 320 mg.
27. The method of claim 10 , wherein at least one anti-inflammatory agent, analgesic agent, or disease-modifying antirheumatic drug (DMARD) is additionally administered to said patient.
28. The method of claim 27 , wherein said anti-inflammatory agent is selected from the group consisting of steroids, Cortisone, Glucocorticoids, prednisone, prednisolone, Hydrocortisone (Cortisol), Cortisone acetate, Methylprednisolone, Dexamethasone, Betamethasone, Triamcinolone, Beclometasone, and Fludrocortisone acetate, non-steroidal anti-inflammatory drug (NSAIDs), ibuprofen, naproxen, meloxicam, etodolac, nabumetone, sulindac, tolementin, choline magnesium salicylate, diclofenac, dif1usinal, indomethicin, Ketoprofen, Oxaprozin, piroxicam, and nimesulide, Salicylates, Aspirin (acetylsalicylic acid), Dif1unisal, Salsalate, p-amino phenol derivatives, Paracetamol, phenacetin, Propionic acid derivatives, Ibuprofen, Naproxen, Fenoprofen, Ketoprofen, Flurbiprofen, Oxaprozin, Loxoprofen, Acetic acid derivatives, Indomethacin, Sulindac, Etodolac, Ketorolac, Diclofenac, Nabumetone, Enolic acid (Oxicam) derivatives, Piroxicam, Meloxicam, Tenoxicam, Droxicam, Lomoxicam, Isoxicam, Fenamic acid derivatives (Fenamates), Mefenamic acid, Meclofenamic acid, Flufenamic acid, Tolfenamic acid, Selective COX-2 inhibitors (Coxibs), Celecoxib, Rofecoxib, Valdecoxib, Parecoxib, Lumiracoxib, Etoricoxib, Firocoxib, Sulphonanilides, Nimesulide, and Licofelone.
29. The method of claim 27 , wherein said DMARD is selected from the group consisting of mycophenolate mofetil (CellCept), calcineurin inhibitors, cyclosporine, sirolimus, everolimus, oral retinoids, azathioprine, fumeric acid esters, D-penicillamine, cyclophosphamide, immunoadsorption column, Prosorba(r) column, a gold salt, auranofin, sodium aurothiomalate (Myocrisin), hydroxychloroquine, chloroquine, leflunomide, methotrexate (MTX), minocycline, sulfasalazine (SSZ), tumor necrosis factor alpha (TNFalpha) blockers, etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi>>, Interleukin 1 (IL-I) blockers, e.g., anakinra (Kineret), monoclonal antibodies against B cells, rituximab (Rituxan>>, T cell co stimulation blockers, abatacept (Orencia), Interleukin 6 (IL-6) blockers, tocilizumab, RoActemra, and Actemra.
30. The method of claim 27 , wherein said DMARD is not an antibody.
31. The method of claim 10 , wherein the efficacy of said administration is determined by detecting at least one of the following: (i) improved DAS-28 scores, (ii) improved EULAR scores, (iii) improved LDAS scores (iv) improved ACR scores, (v) an increase in serum albumin, (vi) a decrease in CRP, (vii) improvement in one or more SF36 domain scores, (viii) an improvement in SF-6D score, wherein said efficacy is measured relative to said patient's baseline prior to administration of said antibody or antibody fragment, relative untreated patients, relative to patients receiving a placebo or control formulation, or relative to age/gender norms.
32. The method of claim 1 , wherein said anti-IL-6 antibody containing said CDRs contains variable heavy and light sequences identical to those contained in SEQ ID NO:18 and SEQ ID NO:20.
33. The method of claim 32 , wherein said anti-IL-6 antibody or antibody fragment containing said CDRs comprises the IgG1 constant light chain sequence contained in SEQ ID NO: 586 and the constant heavy chain sequence contained in SEQ ID NO: 588.
34. The method of claim 1 , wherein said anti-IL-6 antibody or fragment containing said CDRs comprises variable heavy and light chain sequences which are identical to the variable heavy and light sequences contained in SEQ ID NO: 19 and SEQ ID NO: 20.
35. The method of claim 34 , wherein said anti-IL-6 antibody or antibody fragment containing said CDRs comprises the IgG1 constant light chain sequence contained in SEQ ID NO: 586 and the constant heavy chain sequence contained in SEQ ID NO: 588.
36. The method of claim 1 , wherein said anti-IL-6 antibody or antibody fragment containing said CDRs comprises the IgG1 constant light chain sequence contained in SEQ ID NO: 586 and the constant heavy chain sequence contained in SEQ ID NO: 588.
37. The method of claim 1 , wherein said IL-6 antibody or antibody fragment containing said CDRs is administered at least twice.
38. The method of claim 37 , wherein the patient receives at least a first dosage and a second dosage, and said second dosage is about eight weeks subsequent to said first dosage.
39. The method of claim 1 , wherein the patient is administered said anti-IL-6 antibody or antibody fragment containing said CDRs every 8 weeks or 2 months.
40. The method of claim 1 , wherein said patient has previously received or is concurrently receiving methotrexate.
41. The method of claim 40 , wherein the dosage of said methotrexate is at least 10 mg/week.
42. The method of claim 40 , wherein said patient continues to receive methotrexate for at least 8 weeks after administration of said anti-IL-6 antibody or antibody fragment containing said CDRs.
43. The method of claim 1 , wherein the patient exhibits methotrexate resistance at the time of administration of said anti-IL-6 antibody or antibody fragment containing said CDRs.
44. The method of claim 1 , wherein said anti-IL-6 antibody or antibody fragment containing said CDRs is administered subcutaneously.
45. The method of claim 1 , wherein said anti-IL-6 antibody or antibody fragment containing said CDRs is administered intravenously.
46. The method of claim 1 , wherein said anti-IL-6 antibody or antibody fragment containing said CDRs is contained in a composition that comprises said anti-IL6 antibody or antibody fragment, about 5 mM Histidine base, about 5 mM Histidine HCl to make final pH 6, 250 mM sorbitol, and 0.015% (w/w) Polysorbate 80.
47. The method of claim 1 , wherein said anti-IL-6 antibody or antibody fragment containing said CDRs is contained in a composition comprising about 25 mM Histidine base, Phosphoric acid q.s. to pH 6, and about 250 mM sorbitol.
48. The method claim 1 , wherein the administered dosage of said anti-IL-6 antibody or antibody fragment containing said CDRs is at least about 50 or 100 mg.
49. The method of claim 1 , wherein the administered dosage of said anti-IL-6 antibody or antibody fragment is about 80 mg.
50. The method of claim 1 , wherein the administered dosage of said anti-IL-6 antibody or antibody fragment is about 160 mg.
51. The method of claim 1 , wherein the administered dosage of said anti-IL-6 antibody or antibody fragment is about 320 mg.
52. The method of claim 1 , wherein at least one anti-inflammatory agent, analgesic agent, or disease-modifying antirheumatic drug (DMARD) is additionally administered to said patient.
53. The method of claim 52 , wherein said anti-inflammatory agent is selected from the group consisting of steroids, Cortisone, Glucocorticoids, prednisone, prednisolone, Hydrocortisone (Cortisol), Cortisone acetate, Methylprednisolone, Dexamethasone, Betamethasone, Triamcinolone, Beclometasone, and Fludrocortisone acetate, non-steroidal anti-inflammatory drug (NSAIDs), ibuprofen, naproxen, meloxicam, etodolac, nabumetone, sulindac, tolementin, choline magnesium salicylate, diclofenac, diflusinal, indomethicin, Ketoprofen, Oxaprozin, piroxicam, and nimesulide, Salicylates, Aspirin (acetylsalicylic acid), Diflunisal, Salsalate, p-amino phenol derivatives, Paracetamol, phenacetin, Propionic acid derivatives, Ibuprofen, Naproxen, Fenoprofen, Ketoprofen, Flurbiprofen, Oxaprozin, Loxoprofen, Acetic acid derivatives, Indomethacin, Sulindac, Etodolac, Ketorolac, Diclofenac, Nabumetone, Enolic acid (Oxicam) derivatives, Piroxicam, Meloxicam, Tenoxicam, Droxicam, Lomoxicam, Isoxicam, Fenamic acid derivatives (Fenamates), Mefenamic acid, Meclofenamic acid, Flufenamic acid, Tolfenamic acid, Selective COX-2 inhibitors (Coxibs), Celecoxib, Rofecoxib, Valdecoxib, Parecoxib, Lumiracoxib, Etoricoxib, Firocoxib, Sulphonanilides, Nimesulide, and Licofelone.
54. The method of claim 52 , wherein said analgesic agent is selected from the group consisting of NSAIDs, COX-2 inhibitors, Celecoxib, Rofecoxib, Valdecoxib, Parecoxib, Lumiracoxib, Etoricoxib, Firocoxib, acetaminophen, opiates, Dextropropoxyphene, Codeine, Tramadol, Anileridine, Pethidine, Hydrocodone, Morphine, Oxycodone, Methadone, Diacetylmorphine, Hydromorphone, Oxymorphone, Levorphanol, Buprenorphine, Fentanyl, Sufentanyl, Etorphine, Carfentanil, dihydromorphine, dihydrocodeine, Thebaine, Papaverine, diproqualone, Flupirtine, Tricyclic antidepressants, and lidocaine.
55. The method of claim 1 , wherein the efficacy of said administration is determined by detecting at least one of the following: (i) improved DAS-28 scores, (ii) improved EULAR scores, (iii) improved LDAS scores (iv) improved ACR scores, (v) an increase in serum albumin, (vi) a decrease in CRP, (vii) improvement in one or more SF36 domain scores, (viii) an improvement in SF-6D score, wherein said efficacy is measured relative to said patient's baseline prior to administration of said antibody or antibody fragment, relative untreated patients, relative to patients receiving a placebo or control formulation, or relative to age/gender norms.
56. The method of treating rheumatoid arthritis of claim 1 , comprising administering a composition comprising at least about 10 mg/mL of said anti-IL-6 antibody or antibody fragment to a patient in need thereof.
57. The method of claim 56 , wherein said composition comprising at least about 20, 30, 40, 50, 60, 70, 80, or 100 mg/mL of said anti-IL-6 antibody or antibody fragment.
58. The method of claim 56 , wherein said composition is administered subcutaneously and comprises at least about 100 mg/mL of said anti-IL-6 antibody or antibody fragment.
59. The method of claim 56 , wherein said composition is administered intravenously and comprises at least about 10, 20, 30, or 40 mg/mL of said anti-IL-6 antibody or antibody fragment.
60. The method of claim 1 , wherein the Fc region which comprises one or more mutations that reduce or eliminate glycosylation is an IgG1 Fc region.
61. The method of claim 1 , wherein said intravenously or subcutaneously administered anti-IL-6 antibody or antibody fragment is aglycosylated or comprises at most 1-5 mannose residues.