Anti-IL-17 antibodies
The present invention relates to the field of medicine, and specifically to the field of monoclonal antibodies against human IL-17. More specifically, the invention relates to monoclonal antibodies/antagonists of IL-17A, which bind with high affinity to an IL-17 epitope, wherein the antibodies contain amino acid substitutions in hypervariable regions of heavy and light chains. The antibodies according to this invention can be chimeric, humanized or human antibodies or antigen-binding fragments thereof, and can be used as a medicinal agent for treating autoimmune and inflammatory disorders and disorders of cell proliferation and development. The invention also relates to methods for producing said antibodies.
1. An isolated monoclonal antibody or fragment thereof that specifically binds to human IL-17A, and comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the antibody or fragment thereof comprises:
a) HCDR1, HCDR2 and HCDR3 of the VH comprising the amino acid sequences of SEQ ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 9, respectively; and LCDR1, LCDR2 and LCDR3 of the VL comprising the amino acid sequences of SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, respectively; or
b) a variant of a), comprising one amino acid substitution selected from the group consisting of:
the fifth amino acid of SEQ ID NO: 7 is D, K, L, P, T or M;
the sixth amino acid of SEQ ID NO: 7 is F;
the seventh amino acid of SEQ ID NO: 7 is G, N, S, T, V or M;
the eighth amino acid of SEQ ID NO: 7 is I;
the ninth amino acid of SEQ ID NO: 7 is G, N or T;
the first amino acid of SEQ ID NO: 8 is G, I, L, M or S;
the third amino acid of SEQ ID NO: 8 is D;
the fourth amino acid of SEQ ID NO: 8 is M;
the fifth amino acid of SEQ ID NO: 8 is L, R or V;
the sixth amino acid of SEQ ID NO: 8 is L;
the eighth amino acid of SEQ ID NO: 8 is T, L, R or W;
the ninth amino acid of SEQ ID NO: 8 is T or Y;
the tenth amino acid of SEQ ID NO: 8 is S, L, R or W;
the eleventh amino acid of SEQ ID NO: 8 is T, L or K;
the third amino acid of SEQ ID NO: 9 is R, A, I or N;
the fourth amino acid of SEQ ID NO: 9 is E, L, S, T, V or M;
the sixth amino acid of SEQ ID NO: 9 is F or V;
the seventh amino acid of SEQ ID NO: 9 is S;
the eighth amino acid of SEQ ID NO: 9 is A, F, L, P or Y;
the ninth amino acid of SEQ ID NO: 9 is F, H, I, S, W or M;
the tenth amino acid of SEQ ID NO: 9 is A, I, N, R, S or V;
the fifth amino acid of SEQ ID NO: 10 is N or R;
the sixth amino acid of SEQ ID NO: 10 is S or T;
the seventh amino acid of SEQ ID NO: 10 is L or R;
the eighth amino acid of SEQ ID NO: 10 is V;
the ninth amino acid of SEQ ID NO: 10 is Y, L, S, T or V;
the tenth amino acid of SEQ ID NO: 10 is L or V;
the eleventh amino acid of SEQ ID NO: 10 is S, P or R;
the twelfth amino acid of SEQ ID NO: 10 is W, A or L;
the first amino acid of SEQ ID NO: 11 is E, L or M;
the second amino acid of SEQ ID NO: 11 is S or L;
the third amino acid of SEQ ID NO: 11 is G;
the fourth amino acid of SEQ ID NO: 11 is I, K, L, M, R or W;
the second amino acid of SEQ ID NO: 12 is A;
the third amino acid of SEQ ID NO: 12 is G or T;
the fourth amino acid of SEQ ID NO: 12 is F, A or I;
the fifth amino acid of SEQ ID NO: 12 is R;
the sixth amino acid of SEQ ID NO: 12 is S;
the seventh amino acid of SEQ ID NO: 12 is F;
the eighth amino acid of SEQ ID NO: 12 is H; and
the tenth amino acid of SEQ ID NO: 12 is I, L or W.
2. The isolated monoclonal antibody or fragment thereof according to claim 1 , wherein:
LCDR1 comprises the amino acid sequence of SEQ ID NO: 10;
LCDR2 comprises the amino acid sequence of SEQ ID NO: 11; and
LCDR3 comprises the amino acid sequence of SEQ ID NO: 12.
3. The isolated monoclonal antibody or fragment thereof according to claim 1 , wherein:
a) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 13; and
b) the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 14.
4. The isolated monoclonal antibody or fragment thereof according to claim 1 , wherein the heavy chain of the isolated monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 15.
5. The isolated monoclonal antibody or fragment thereof according to claim 1 , wherein the light chain of the isolated monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 16.
6. The isolated monoclonal antibody or fragment thereof according to claim 1 , wherein said fragment is selected from F(ab′)2, F(ab)2, Fab′, Fab, Fv and scFv.
7. The isolated monoclonal antibody or fragment thereof according to claim 6 , wherein said fragment is produced by mammalian, yeast or bacterial cells.
8. The isolated monoclonal antibody or fragment thereof according to claim 1 , wherein the CDRs of the light chain variable region and of the heavy chain variable region are from a non-human source.
9. The isolated monoclonal antibody or fragment thereof according to claim 1 , wherein said isolated monoclonal antibody is an IgG1, IgG2, IgG3, IgG4, IgA or IgD.
10. The isolated monoclonal antibody or fragment thereof according to claim 9 , wherein said isolated monoclonal antibody is a human IgG1 further comprising amino acid modifications in Fc-region selected from: M252Y/S254T/T256E, N434W, N434A, N434F, H433K/N434F/Y436H, H433K/N434F/Y436H+M252Y/S254T/T256E, T307A/E380A/N434A, and T250Q/M428L.
11. A pharmaceutical composition comprising the isolated monoclonal antibody or fragment thereof according to claim 1 , in combination with one or several pharmaceutically suitable carriers, vehicles or diluents.
12. The pharmaceutical composition according to claim 11 , further comprising active pharmaceutical ingredients selected from TNF-α inhibitors or any other anti-IL-17A antibodies.
13. An isolated monoclonal antibody or fragment thereof that specifically binds to human IL-17A, and comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the antibody or fragment thereof comprises HCDR1, HCDR2 and HCDR3 of the VH comprising the amino acid sequences of SEQ ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 9, respectively; and, wherein LCDR1, LCDR2 and LCDR3 of the VL comprising the amino acid sequences of SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, respectively.
14. The isolated monoclonal antibody or fragment thereof according to claim 13 , wherein:
a) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 13; and
b) the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 14.
15. The isolated monoclonal antibody or fragment thereof according to claim 14 , wherein the VH comprises the amino acid sequence of SEQ ID NO: 13, and the VL comprises the amino acid sequence of SEQ ID NO: 14.
16. An isolated binding protein containing an antibody that specifically binds to human IL-17A, the antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the antibody comprises:
a) HCDR1, HCDR2 and HCDR3 of the VH comprising the amino acid sequences of SEQ ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 9, respectively; and LCDR1, LCDR2 and LCDR3 of the VL comprising the amino acid sequences of SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, respectively; or
b) a variant of a), comprising one amino acid substitution selected from the group consisting of:
the fifth amino acid of SEQ ID NO: 7 is D, K, L, P, T or M;
the sixth amino acid of SEQ ID NO: 7 is F;
the seventh amino acid of SEQ ID NO: 7 is G, N, S, T, V or M;
the eighth amino acid of SEQ ID NO: 7 is I;
the ninth amino acid of SEQ ID NO: 7 is G, N or T;
the first amino acid of SEQ ID NO: 8 is G, I, L, M or S;
the third amino acid of SEQ ID NO: 8 is D;
the fourth amino acid of SEQ ID NO: 8 is M;
the fifth amino acid of SEQ ID NO: 8 is L, R or V;
the sixth amino acid of SEQ ID NO: 8 is L;
the eighth amino acid of SEQ ID NO: 8 is T, L, R or W;
the ninth amino acid of SEQ ID NO: 8 is T or Y;
the tenth amino acid of SEQ ID NO: 8 is S, L, R or W;
the eleventh amino acid of SEQ ID NO: 8 is T, L or K;
the third amino acid of SEQ ID NO: 9 is R, A, I or N;
the fourth amino acid of SEQ ID NO: 9 is E, L, S, T, V or M;
the sixth amino acid of SEQ ID NO: 9 is F or V;
the seventh amino acid of SEQ ID NO: 9 is S;
the eighth amino acid of SEQ ID NO: 9 is A, F, L, P or Y;
the ninth amino acid of SEQ ID NO: 9 is F, H, I, S, W or M;
the tenth amino acid of SEQ ID NO: 9 is A, I, N, R, S or V;
the fifth amino acid of SEQ ID NO: 10 is N or R;
the sixth amino acid of SEQ ID NO: 10 is S or T;
the seventh amino acid of SEQ ID NO: 10 is L or R;
the eighth amino acid of SEQ ID NO: 10 is V;
the ninth amino acid of SEQ ID NO: 10 is Y, L, S, T or V;
the tenth amino acid of SEQ ID NO: 10 is L or V;
the eleventh amino acid of SEQ ID NO: 10 is S, P or R;
the twelfth amino acid of SEQ ID NO: 10 is W, A or L;
the first amino acid of SEQ ID NO: 11 is E, L or M;
the second amino acid of SEQ ID NO: 11 is S or L;
the third amino acid of SEQ ID NO: 11 is G;
the fourth amino acid of SEQ ID NO: 11 is I, K, L, M, R or W;
the second amino acid of SEQ ID NO: 12 is A;
the third amino acid of SEQ ID NO: 12 is G or T;
the fourth amino acid of SEQ ID NO: 12 is F, A or I;
the fifth amino acid of SEQ ID NO: 12 is R;
the sixth amino acid of SEQ ID NO: 12 is S;
the seventh amino acid of SEQ ID NO: 12 is F;
the eighth amino acid of SEQ ID NO: 12 is H; and
the tenth amino acid of SEQ ID NO: 12 is I, L or W.