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 - 52 . (canceled)
53 . An isolated anti-IL-6 antibody or antigen binding fragment thereof comprising:
a) a heavy chain variable (VH) domain comprising a VH CDR1 comprising the sequence of GYX 1 LX 2 NYLIE (SEQ ID NO:45), a VH CDR2 comprising the sequence of VX 3 TPGX 4 GTIN (SEQ ID NO:46), 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
wherein one or more of the following: X 1 is not A, X 2 is not S, X 3 is not I and X 4 is not S, and wherein X 1 , X 2 , X 3 , and X 4 are not simultaneously V, T, P and G, respectively.
54 . The isolated anti-IL-6 antibody or antigen binding fragment of claim 53 , one of the following: X 1 is not A, X 2 is not S, X 3 is not I, X 4 is not S.
55 . The isolated anti-IL-6 antibody or antigen binding fragment of claim 53 , wherein two of the following: X 1 is not A, X 2 is not S, X 3 is not I and X 4 is not S.
56 . The isolated anti-IL-6 antibody or antigen binding fragment of claim 53 , three of the following: X 1 is not A, X 2 is not S, X 3 is not I and X 4 is not S.
57 . The isolated anti-IL-6 antibody or antigen binding fragment of claim 53 , wherein X 1 is not A, X 2 is not S, X 3 is not I, and X 4 is not S.
58 . The isolated anti-IL-6 antibody or antigen binding fragment of claim 53 , wherein X 1 is A, X 3 is I, and X 4 is S.
59 . The isolated anti-IL-6 antibody or antigen binding fragment of claim 53 , wherein X 1 is A, X 2 is S, and X 4 is S.
60 . The isolated anti-IL-6 antibody or antigen binding fragment of claim 53 , wherein X 1 is A, X 2 is S, and X 3 is I.
61 . The isolated anti-IL-6 antibody or antigen binding fragment of claim 53 , wherein X 2 is S, X 3 is I, and X 4 is S.
62 . The antibody or antigen binding fragment of claim 53 , wherein X 1 is conservative substitution for V.
63 . The antibody or antigen binding fragment of claim 53 , wherein X 2 is a conservative substitution for P.
64 . The antibody or antigen binding fragment of claim 53 , wherein X 3 a conservative substitution for T.
65 . The antibody or antigen binding fragment of claim 53 , wherein X 4 a conservative substitution for G.
66 . The isolated antibody or antigen binding fragment of claim 53 , wherein the VH domain comprises, excluding the CDRs, an amino acid sequence that is at least 90% identical to SEQ ID NO:37.
67 . The isolated antibody or antigen binding fragment of claim 53 , wherein the VL domain comprises an amino acid sequence that is at least 90% identical to SEQ ID NO:38.
68 . The isolated antibody or antigen binding fragment of claim 53 , wherein the VL domain comprises amino acids 1-111 of SEQ ID NO:38.
69 . The isolated antibody or antigen binding fragment of claim 53 , wherein the VH domain comprises, excluding the CDRs, SEQ ID NO:37 and the VL domain comprises, excluding the CDRs, amino acids 1-111 of SEQ ID NO:38.
70 . The isolated antibody or antigen binding fragment of claim 53 , comprising a heavy chain comprising the VH domain, wherein the heavy chain 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.
71 . The isolated antibody or antigen binding fragment of claim 53 , comprising a heavy chain comprising the VH domain, wherein the heavy chain, excluding the CDRs, comprises SEQ ID NO:41 or SEQ ID NO:47.
72 . The isolated antibody or antigen binding fragment of claim 53 , comprising a light chain comprising the VL domain, wherein the a light chain comprises SEQ ID NO:42.
73 . The isolated antibody or antigen binding fragment of claim 53 , -comprising (a) a heavy chain that comprises the VH domain, wherein the heavy chain, excluding the CDRs, comprises amino acids 1-225 of SEQ ID NO:39 or comprises SEQ ID NO:54 and (b) a light chain comprising the VL domain, wherein the light chain comprises SEQ ID NO:42.
74 . An isolated antibody or antigen binding fragment of claim 53 , further comprising a heavy chain comprising the VH domain, wherein the heavy chain, excluding the CDRs, comprises SEQ ID NO:41 comprising 0, 1, 2 3 or 4 mutations at positions selected from I254, H311, I254, and H346.
75 . The isolated antibody or antigen binding fragment of claim 74 , wherein the mutation at position I254 are selected from I254A and I254R.
76 . The isolated antibody or antigen binding fragment of claim 74 , wherein the mutation at position H311 are selected from H311A, H311E and H311N.
77 . The isolated antibody or antigen binding fragment of claim 74 , wherein the mutation at position D313 is D313T.
78 . The isolated antibody or antigen binding fragment of claim 74 , wherein the mutation at position H436 is H436A.
79 . The isolated antibody or antigen binding fragment of claim 53 , wherein the antibody is an IgG2 antibody.
80 . The antibody or antigen binding fragment of claim 53 , wherein the antibody or antigen binding fragment is an IgG2-A isoform or an IgG2-AB isoform, but not an IgG2-B isoform.
81 . A pharmaceutical composition comprising the antibody or antigen binding fragment of claim 53 and a pharmaceutically acceptable carrier.