IL-6 antibodies
Improved IL-6 antibodies are provided. Uses of the antibodies in the treatment of IL-6-related diseases, e.g., ocular diseases such as diabetic macular edema, are disclosed.
1. An isolated antibody or antigen binding fragment thereof comprising:
a) a heavy chain variable (VH) domain comprising a VH CDR1 comprising the sequence of SEQ ID NO:31, a VH CDR2 comprising the sequence of SEQ ID NO:32, and a VH CDR3 comprising the sequence of SEQ ID NO:33, and
b) a light chain variable (VL) domain comprising a VL CDR1 comprising the sequence of SEQ ID NO:34, a VL CDR2 comprising the sequence of SEQ ID NO:35, and a VL CDR3 comprising the sequence of SEQ ID NO:36.
2. The isolated antibody or antigen binding fragment of claim 1 , wherein the VH domain comprises an amino acid sequence that is at least 90% identical to SEQ ID NO:37.
3. The isolated antibody or antigen binding fragment of claim 1 , wherein the VH domain comprises an amino acid sequence that is at least 90% identical to SEQ ID NO:39, SEQ ID NO:41, or SEQ ID NO:54.
4. The isolated antibody or antigen binding fragment of claim 1 , wherein the VL domain comprises an amino acid sequence that is at least 90% identical to SEQ ID NO:38.
5. The isolated antibody or antigen binding fragment of claim 1 , wherein the VL domain comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 42.
6. The isolated antibody or antigen binding fragment of claim 1 , wherein the VH domain comprises SEQ ID NO:37 and the VL domain comprises SEQ ID NO:38.
7. The isolated antibody or antigen binding fragment of claim 1 , wherein the VH domain comprises SEQ ID NO:41 and the VL domain comprises SEQ ID NO:42.
8. The isolated antibody or antigen binding fragment of claim 1 , wherein the VH domain comprises SEQ ID NO:39 or SEQ ID NO:54 and the VL domain comprises SEQ ID NO:42.
9. An isolated antibody or antigen binding fragment of claim 1 , further comprising a heavy chain comprising the VH domain, wherein the heavy chain comprises SEQ ID NO:47.
10. An isolated antibody or antigen binding fragment of claim 1 , further comprising a heavy chain comprising the VH CDR1, the VH CDR2 and the VH CDR3, wherein the heavy chain comprises SEQ ID NO:41 comprising 0, 1, 2 3 or 4 mutations at positions selected from 1254, H311, 1254, and H346.
11. The isolated antibody or antigen binding fragment of claim 10 , wherein the mutation at position 1254 are selected from I254 Å and I254R.
12. The isolated antibody or antigen binding fragment of claim 10 , wherein the mutation at position H311 are selected from H311A, H331E and H311N.
13. The isolated antibody or antigen binding fragment of claim 10 , wherein the mutation at position D313 is D313T.
14. The isolated antibody or antigen binding fragment of claim 10 , wherein the mutation at position H436 is H436A.
15. The isolated antibody or antigen binding fragment of claim 1 , further comprising a light chain comprising the VL domain, wherein the light chain comprises SEQ ID NO:42.
16. An isolated antibody or antigen binding fragment comprising a heavy chain sequence comprising SEQ ID NO: 47 and a light chain sequence comprising SEQ ID NO:42.
17. The isolated antibody or antigen binding fragment of claim 1 , wherein the antibody is an IgG2 antibody.
18. The antibody or antigen binding fragment of claim 17 , wherein the antibody or antigen binding fragment is an IgG2-A isoform or an IgG2-A/B isoform, but not an IgG2-B isoform.
19. A pharmaceutical composition comprising the antibody or antigen binding fragment of claim 1 and a pharmaceutically acceptable carrier.
20. A method of treating an IL-6 associated disease, the method comprising administering to a subject a therapeutically effective amount of an IL-6 antibody or antigen binding fragment of claim 1 , wherein the IL-6 associated disease is an ocular disease characterized by an elevated level of IL-6 in the vitreous.
21. The method of claim 20 , wherein the IL-6 associated disease is diabetic macular edema (DME), diabetic retinopathy, uveitis, dry eye (e.g., dry eye disease or dry eye syndrome), age-related macular degeneration (AMD), proliferative diabetic retinopathy (PDR), retinal vein occlusion (RVO), neuromyelitis optica (NMO), corneal transplant, corneal abrasion, or physical injury to the eye.
22. The method of claim 21 , wherein the antibody or antigen binding fragment is delivered to the vitreous of the subject's eye.
23. The method of claim 22 , wherein the IL-6 associated disease is diabetic macular edema.