US2014178332A1PendingUtilityA1
IL-12/p40 BINDING PROTEINS
Est. expiryJun 30, 2025(expired)· nominal 20-yr term from priority
Inventors:Susan E. LacyEmma FungJonathan BelkRichard W. DixonMichael RoguskaPaul R. HintonShankar Kumar
A61P 37/06A61P 37/02A61P 9/10A61P 9/12A61P 5/00A61P 43/00A61P 7/06A61P 9/04A61P 9/02A61P 37/08A61P 3/10A61P 25/18A61P 31/18A61P 31/00A61P 25/32A61P 29/00A61P 33/00A61P 27/02A61P 31/12A61P 25/14A61P 31/14A61P 35/00A61P 25/04A61P 35/02A61P 25/24A61P 25/16A61P 31/10A61P 31/20A61P 31/04A61P 25/28A61K 45/06C07K 16/244C07K 2317/24A61P 13/12A61P 17/06A61P 17/14A61P 1/04A61P 19/02A61P 11/00A61P 15/00A61P 11/06A61P 17/00A61K 39/3955G01N 33/6869A61P 17/04A61P 17/02C07K 2317/76A61P 1/14C07K 2317/567C07K 2317/92A61P 1/16C07K 14/715
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Claims
Abstract
The present invention encompasses IL-12p40 binding proteins, particularly antibodies that bind human interleukin-12 (hIL-12) and/or human IL-23 (hIL-23). Specifically, the invention relates to antibodies that are chimeric, CDR grafted and humanized antibodies. Preferred antibodies have high affinity for hIL-12 and/or hIL-23 and neutralize h IL-12 and/or hIL-23 activity in vitro and in vivo. An antibody of the invention can be a full-length antibody or an antigen-binding portion thereof. Method of making and method of using the antibodies of the invention are also provided. The antibodies, or antibody portions, of the invention are useful for detecting hIL-12 and/or hIL-23 and for inhibiting hIL-12 and/or hIL-23 activity, e.g., in a human subject suffering from a disorder in which hIL-12 and/or hIL-23 activity is detrimental.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A method for treating a mammal comprising the step of administering to the mammal an effective amount of a binding protein comprising an antigen binding domain, said binding protein capable of binding a p40 subunit of IL-12, said antigen binding domain comprising six CDRs CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, as defined below:
CDR-H1:
(SEQ ID NO: 55)
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 ,
wherein;
X 1 is D, K, T, or S;
X 2 is Y, S, or T;
X 3 is Y, V, G, W, S, or F;
X 4 is I, or M;
X 5 is H, G, E, or V;
X 6 is V, or is not present; and
X 7 is S, or is not present;
CDR-H2:
(SEQ ID NO: 56)
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -
X 17 X 18 -X 19 -X 20 ,
wherein;
X 1 is H, D, G, W, S, Y or R;
X 2 is I, or F;
X 3 is Y, W, L, S, N, D or G;
X 4 is W, P, H, T, or S;
X 5 is D, G, E, A, or I;
X 6 is D, G, S, T, or N;
X 7 is D, G, S, or P;
X 8 is K, N, S, E, T, or H;
X 9 is Y, T, P, I, or N;
X 10 is Y, N, T, H, K, S, or G;
X 11 is N, or Y;
X 12 is P, N, A, D, or S;
X 13 is S, E, D, or P;
X 14 is L, K, D, T, or Y;
X 15 is K, F, V, M, R, or A;
X 16 is S, K, Q, P, or is not present;
X 17 is D, G, R, or is not present;
X 18 is F, or is not present;
X 19 is Q, or is not present; and
X 20 is D, or is not present;
CDR-H3: selected from the group consisting of:
(SEQ ID NO: 57)
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 ,
wherein;
X 1 is R, N, or W;
X 2 is G, T, R, P, or H;
X 3 is I, R, F, Y, or Q;
X 4 is R, V, Y, F, or A;
X 5 is S, N, G, A, or R;
X 6 is A, Y, L, F, or M;
X 7 is M, A, D, L, or F;
X 8 is D, M, Y, or W;
X 9 is Y, D, or N;
X 10 is Y, A, or is not present;
X 11 is M, or is not present;
X 12 is D, or is not present; and
X 13 is Y, or is not present;
amino acid residues 99-106 of SEQ ID NO:39;
amino acid residues 99-106 of SEQ ID NO:41;
amino acid residues 99-106 of SEQ ID NO:43;
amino acid residues 99-101 of SEQ ID NO:45;
amino acid residues 99-106 of SEQ ID NO:47; and
amino acid residues 99-107 of SEQ ID NO:53;
CDR-L1:
(SEQ ID NO: 58)
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 ,
wherein;
X 1 is K, or R;
X 2 is A;
X 3 is 5;
X 4 is Q, or E;
X 5 is S, or N;
X 6 is V, or I;
X 7 is S, G, or D;
X 8 is N, T, or K;
X 9 is D, N, or Y;
X 10 is V, G, or L;
X 11 is A, I, or H;
X 12 is S, or is not present;
X 13 is F, or is not present;
X 14 is M, or is not present; and
X 15 is N, or is not present;
CDR-L2:
(SEQ ID NO: 59)
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 ,
wherein;
X 1 is Y, or S;
X 2 is A, or T;
X 3 is S, or A;
X 4 is N, H, S, or Q;
X 5 is R, N, or S;
X 6 is Y, Q, or I;
X 7 is T, S, or G; and
X 8 is S, or is not present;
and
CDR-L3:
(SEQ ID NO: 60)
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 ,
wherein;
X 1 is Q;
X 2 is Q;
X 3 is D, Y, or S;
X 4 is Y, N, K, or I;
X 5 is N, T, S, or E;
X 6 is S, Y, V, or W;
X 7 is P;
X 8 is W, F, Y, L, or P; and
X 9 is T, or S.
2 . A method for reducing human IL-12 activity comprising contacting human IL-12 with a binding protein comprising an antigen binding domain, said binding protein capable of binding a p40 subunit of IL-12, said antigen binding domain comprising six CDRs CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, as defined below:
CDR-H1:
(SEQ ID NO: 55)
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 ,
X 1 is D, K, T, or S;
X 2 is Y, S, or T;
X 3 is Y, V, G, W, S, or F;
X 4 is I, or M;
X 5 is H, G, E, or V;
X 6 is V, or is not present; and
X 7 is S, or is not present;
CDR-H2:
(SEQ ID NO: 56)
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -
X 15 -X 16 -X 17 X 18 -X 19 -X 20 ,
wherein;
X 1 is H, D, G, W, S, Y or R;
X 2 is I, or F;
X 3 is Y, W, L, S, N, D or G;
X 4 is W, P, H, T, or S;
X 5 is D, G, E, A, or I;
X 6 is D, G, S, T, or N;
X 7 is D, G, S, or P;
X 8 is K, N, S, E, T, or H;
X 9 is Y, T, P, I, or N;
X 10 is Y, N, T, H, K, S, or G;
X 11 is N, or Y;
X 12 is P, N, A, D, or S;
X 13 is S, E, D, or P;
X 14 is L, K, D, T, or Y;
X 15 is K, F, V, M, R, or A;
X 16 is S, K, Q, P, or is not present;
X 17 is D, G, R, or is not present;
X 18 is F, or is not present;
X 19 is Q, or is not present; and
X 20 is D, or is not present;
CDR-H3: is selected from the group consisting of:
(SEQ ID NO: 57)
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 ,
wherein;
X 1 is R, N, or W;
X 2 is G, T, R, P, or H;
X 3 is I, R, F, Y, or Q;
X 4 is R, V, Y, F, or A;
X 5 is S, N, G, A, or R;
X 6 is A, Y, L, F, or M;
X 7 is M, A, D, L, or F;
X 8 is D, M, Y, or W;
X 9 is Y, D, or N;
X 10 is Y, A, or is not present;
X 11 is M, or is not present;
X 12 is D, or is not present; and
X 13 is Y, or is not present;
amino acid residues 99-106 of SEQ ID NO:39;
amino acid residues 99-106 of SEQ ID NO:41;
amino acid residues 99-106 of SEQ ID NO:43;
amino acid residues 99-101 of SEQ ID NO:45;
amino acid residues 99-106 of SEQ ID NO:47; and
amino acid residues 99-107 of SEQ ID NO:53;
CDR-L1:
(SEQ ID NO: 58)
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 ,
wherein;
X 1 is K, or R;
X 2 is A;
X 3 is 5;
X 4 is Q, or E;
X 5 is S, or N;
X 6 is V, or I;
X 7 is S, G, or D;
X 8 is N, T, or K;
X 9 is D, N, or Y;
X 10 is V, G, or L;
X 11 is A, I, or H;
X 12 is S, or is not present;
X 13 is F, or is not present;
X 14 is M, or is not present; and
X 15 is N, or is not present;
CDR-L2:
(SEQ ID NO: 59)
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 ,
wherein;
X 1 is Y, or S;
X 2 is A, or T;
X 3 is S, or A;
X 4 is N, H, S, or Q;
X 5 is R, N, or S;
X 6 is Y, Q, or I;
X 7 is T, S, or G; and
X 8 is S, or is not present;
and
CDR-L3:
(SEQ ID NO: 60)
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 ,
wherein;
X 1 is Q;
X 2 is Q;
X 3 is D, Y, or S;
X 4 is Y, N, K, or I;
X 5 is N, T, S, or E;
X 6 is S, Y, V, or W;
X 7 is P;
X 8 is W, F, Y, L, or P; and
X 9 is T, or S,
such that human IL-12 activity is reduced.
3 . A method for reducing human IL-12 activity in a human subject suffering from a disorder in which IL-12 activity is detrimental, comprising administering to the human subject a binding protein comprising an antigen binding domain, said binding protein capable of binding a p40 subunit of IL-12, said antigen binding domain comprising six CDRs CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, as defined below:
CDR-H1:
(SEQ ID NO: 55)
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 ,
wherein;
X 1 is D, K, T, or S;
X 2 is Y, S, or T;
X 3 is Y, V, G, W, S, or F;
X 4 is I, or M;
X 5 is H, G, E, or V;
X 6 is V, or is not present; and
X 7 is S, or is not present;
CDR-H2:
(SEQ ID NO: 56)
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -
X 17 X 18 -X 19 -X 20 ,
wherein;
X 1 is H, D, G, W, S, Y or R;
X 2 is I, or F;
X 3 is Y, W, L, S, N, D or G;
X 4 is W, P, H, T, or S;
X 5 is D, G, E, A, or I;
X 6 is D, G, S, T, or N;
X 7 is D, G, S, or P;
X 8 is K, N, S, E, T, or H;
X 9 is Y, T, P, I, or N;
X 10 is Y, N, T, H, K, S, or G;
X 11 is N, or Y;
X 12 is P, N, A, D, or S;
X 13 is S, E, D, or P;
X 14 is L, K, D, T, or Y;
X 15 is K, F, V, M, R, or A;
X 16 is S, K, Q, P, or is not present;
X 17 is D, G, R, or is not present;
X 18 is F, or is not present;
X 19 is Q, or is not present; and
X 20 is D, or is not present;
CDR-H3: selected from the group consisting of:
(SEQ ID NO: 57)
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 ,
wherein;
X 1 is R, N, or W;
X 2 is G, T, R, P, or H;
X 3 is I, R, F, Y, or Q;
X 4 is R, V, Y, F, or A;
X 5 is S, N, G, A, or R;
X 6 is A, Y, L, F, or M;
X 7 is M, A, D, L, or F;
X 8 is D, M, Y, or W;
X 9 is Y, D, or N;
X 10 is Y, A, or is not present;
X 11 is M, or is not present;
X 12 is D, or is not present; and
X 13 is Y, or is not present;
amino acid residues 99-106 of SEQ ID NO:39;
amino acid residues 99-106 of SEQ ID NO:41;
amino acid residues 99-106 of SEQ ID NO:43;
amino acid residues 99-101 of SEQ ID NO:45;
amino acid residues 99-106 of SEQ ID NO:47; and
amino acid residues 99-107 of SEQ ID NO:53;
(SEQ ID NO: 58)
CDR-L1:
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -
X 15 ,
wherein;
X 1 is K, or R;
X 2 is A;
X 3 is 5;
X 4 is Q, or E;
X 5 is S, or N;
X 6 is V, or I;
X 7 is S, G, or D;
X 8 is N, T, or K;
X 9 is D, N, or Y;
X 10 is V, G, or L;
X 11 is A, I, or H;
X 12 is S, or is not present;
X 13 is F, or is not present;
X 14 is M, or is not present; and
X 15 is N, or is not present;
(SEQ ID NO: 59)
CDR-L2:
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 ,
wherein;
X 1 is Y, or S;
X 2 is A, or T;
X 3 is S, or A;
X 4 is N, H, S, or Q;
X 5 is R, N, or S;
X 6 is Y, Q, or I;
X 7 is T, S, or G; and
X 8 is S, or is not present;
and
(SEQ ID NO: 60)
CDR-L3:
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 ,
wherein;
X 1 is Q;
X 2 is Q;
X 3 is D, Y, or S;
X 4 is Y, N, K, or I;
X 5 is N, T, S, or E;
X 6 is S, Y, V, or W;
X 7 is P;
X 8 is W, F, Y, L, or P; and
X 9 is T, or S,
such that human IL-12 activity in the human subject is reduced.
4 . A method for treating a subject for a disease or a disorder in which IL-12 activity is detrimental by administering to the subject a binding protein comprising an antigen binding domain, said binding protein capable of binding a p40 subunit of IL-12, said antigen binding domain comprising six CDRs CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, as defined below:
(SEQ ID NO: 55)
CDR-H1:
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 ,
wherein;
X 1 is D, K, T, or S;
X 2 is Y, S, or T;
X 3 is Y, V, G, W, S, or F;
X 4 is I, or M;
X 5 is H, G, E, or V;
X 6 is V, or is not present; and
X 7 is S, or is not present;
(SEQ ID NO: 56)
CDR-H2:
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -
X 15 -X 16 -X 17 X 18 -X 19 -X 20 ,
wherein;
X 1 is H, D, G, W, S, Y or R;
X 2 is I, or F;
X 3 is Y, W, L, S, N, D or G;
X 4 is W, P, H, T, or S;
X 5 is D, G, E, A, or I;
X 6 is D, G, S, T, or N;
X 7 is D, G, S, or P;
X 8 is K, N, S, E, T, or H;
X 9 is Y, T, P, I, or N;
X 10 is Y, N, T, H, K, S, or G;
X 11 is N, or Y;
X 12 is P, N, A, D, or S;
X 13 is S, E, D, or P;
X 14 is L, K, D, T, or Y;
X 15 is K, F, V, M, R, or A;
X 16 is S, K, Q, P, or is not present;
X 17 is D, G, R, or is not present;
X 18 is F, or is not present;
X 19 is Q, or is not present; and
X 20 is D, or is not present;
CDR-H3: is selected from the group consisting of:
(SEQ ID NO: 57)
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 ,
wherein;
X 1 is R, N, or W;
X 2 is G, T, R, P, or H;
X 3 is I, R, F, Y, or Q;
X 4 is R, V, Y, F, or A;
X 5 is S, N, G, A, or R;
X 6 is A, Y, L, F, or M;
X 7 is M, A, D, L, or F;
X 8 is D, M, Y, or W;
X 9 is Y, D, or N;
X 10 is Y, A, or is not present;
X 11 is M, or is not present;
X 12 is D, or is not present; and
X 13 is Y, or is not present;
amino acid residues 99-106 of SEQ ID NO:39;
amino acid residues 99-106 of SEQ ID NO:41;
amino acid residues 99-106 of SEQ ID NO:43;
amino acid residues 99-101 of SEQ ID NO:45;
amino acid residues 99-106 of SEQ ID NO:47; and
amino acid residues 99-107 of SEQ ID NO:53;
(SEQ ID NO: 58)
CDR-L1:
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -
X 15 ,
wherein;
X 1 is K, or R;
X 2 is A;
X 3 is S;
X 4 is Q, or E;
X 5 is S, or N;
X 6 is V, or I;
X 7 is S, G, or D;
X 8 is N, T, or K;
X 9 is D, N, or Y;
X 10 is V, G, or L;
X 11 is A, I, or H;
X 12 is S, or is not present;
X 13 is F, or is not present;
X 14 is M, or is not present; and
X 15 is N, or is not present;
(SEQ ID NO: 59)
CDR-L2:
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 ,
wherein;
X 1 is Y, or S;
X 2 is A, or T;
X 3 is S, or A;
X 4 is N, H, S, or Q;
X 5 is R, N, or S;
X 6 is Y, Q, or I;
X 7 is T, S, or G; and
X 8 is S, or is not present;
and
(SEQ ID NO: 60)
CDR-L3:
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 ,
wherein;
X 1 is Q;
X 2 is Q;
X 3 is D, Y, or S;
X 4 is Y, N, K, or I;
X 5 is N, T, S, or E;
X 6 is S, Y, V, or W;
X 7 is P;
X 8 is W, F, Y, L, or P; and
X 9 is T, or S,
such that treatment is achieved.
5 . A method of treating a patient suffering from a disorder in which IL-12 is detrimental comprising the step of administering a binding protein comprising an antigen binding domain, said binding protein capable of binding a p40 subunit of IL-12, said antigen binding domain comprising six CDRs CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, as defined below:
(SEQ ID NO: 55)
CDR-H1:
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 ,
wherein;
X 1 is D, K, T, or S;
X 2 is Y, S, or T;
X 3 is Y, V, G, W, S, or F;
X 4 is I, or M;
X 5 is H, G, E, or V;
X 6 is V, or is not present; and
X 7 is S, or is not present;
(SEQ ID NO: 56)
CDR-H2:
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -
X 15 -X 16 -X 17 X 18 -X 19 -X 20 ,
wherein;
X 1 is H, D, G, W, S, Y or R;
X 2 is I, or F;
X 3 is Y, W, L, S, N, D or G;
X 4 is W, P, H, T, or S;
X 5 is D, G, E, A, or I;
X 6 is D, G, S, T, or N;
X 7 is D, G, S, or P;
X 8 is K, N, S, E, T, or H;
X 9 is Y, T, P, I, or N;
X 10 is Y, N, T, H, K, S, or G;
X 11 is N, or Y;
X 12 is P, N, A, D, or S;
X 13 is S, E, D, or P;
X 14 is L, K, D, T, or Y;
X 15 is K, F, V, M, R, or A;
X 16 is S, K, Q, P, or is not present;
X 17 is D, G, R, or is not present;
X 18 is F, or is not present;
X 19 is Q, or is not present; and
X 20 is D, or is not present;
CDR-H3: is selected from the group consisting of:
(SEQ ID NO: 57)
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 ,
wherein;
X 1 is R, N, or W;
X 2 is G, T, R, P, or H;
X 3 is I, R, F, Y, or Q;
X 4 is R, V, Y, F, or A;
X 5 is S, N, G, A, or R;
X 6 is A, Y, L, F, or M;
X 7 is M, A, D, L, or F;
X 8 is D, M, Y, or W;
X 9 is Y, D, or N;
X 10 is Y, A, or is not present;
X 11 is M, or is not present;
X 12 is D, or is not present; and
X 13 is Y, or is not present;
amino acid residues 99-106 of SEQ ID NO:39;
amino acid residues 99-106 of SEQ ID NO:41;
amino acid residues 99-106 of SEQ ID NO:43;
amino acid residues 99-101 of SEQ ID NO:45;
amino acid residues 99-106 of SEQ ID NO:47; and
amino acid residues 99-107 of SEQ ID NO:53;
(SEQ ID NO: 58)
CDR-L1:
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -
X 15 ,
wherein;
X 1 is K, or R;
X 2 is A;
X 3 is 5;
X 4 is Q, or E;
X 5 is S, or N;
X 6 is V, or I;
X 7 is S, G, or D;
X 8 is N, T, or K;
X 9 is D, N, or Y;
X 10 is V, G, or L;
X 11 is A, I, or H;
X 12 is S, or is not present;
X 13 is F, or is not present;
X 14 is M, or is not present; and
X 15 is N, or is not present;
(SEQ ID NO: 59)
CDR-L2:
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 ,
wherein;
X 1 is Y, or S;
X 2 is A, or T;
X 3 is S, or A;
X 4 is N, H, S, or Q;
X 5 is R, N, or S;
X 6 is Y, Q, or I;
X 7 is T, S, or G; and
X 8 is S, or is not present;
and
(SEQ ID NO: 60)
CDR-L3:
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 ,
wherein;
X 1 is Q;
X 2 is Q;
X 3 is D, Y, or S;
X 4 is Y, N, K, or I;
X 5 is N, T, S, or E;
X 6 is S, Y, V, or W;
X 7 is P;
X 8 is W, F, Y, L, or P; and
X 9 is T, or S
before, concurrently with, or after the administration of a second agent, wherein the second agent is selected from the group consisting of budenoside, epidermal growth factor, corticosteroids, cyclosporin, sulfasalazine, aminosalicylates, 6-mercaptopurine, azathioprine, metronidazole, lipoxygenase inhibitors, mesalamine, olsalazine, balsalazide, antioxidants, thromboxane inhibitors, IL-1 receptor antagonists, anti-IL-1β monoclonal antibodies, anti-IL-6 monoclonal antibodies, growth factors, elastase inhibitors, pyridinyl-imidazole compounds, antibodies or agonists of TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-15, IL-16, IL-18, EMAP-II, GM-CSF, FGF, and PDGF, antibodies of CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or their ligands, methotrexate, cyclosporin, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, ibuprofen, corticosteroids, prednisolone, phosphodiesterase inhibitors, adensosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, IRAK, NIK, IKK, p38, MAP kinase inhibitors, IL-1β converting enzyme inhibitors, TNFαconverting enzyme inhibitors, T-cell signalling inhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6-mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptors, soluble p55 TNF receptor, soluble p75 TNF receptor, sIL-1RI, sIL-1RII, sIL-6R, antiinflammatory cytokines, IL-4, IL-10, IL-11, IL-13 and TGFβ.
6 . A method for detecting human IL-12 and/or human IL-23 in vitro comprising contacting a biological sample with a binding protein comprising an antigen binding domain, said binding protein capable of binding a p40 subunit of human IL-12, said antigen binding domain comprising six CDRs, CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, wherein:
CDR-H1 is an amino acid sequence: X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 (SEQ ID NO: 55), wherein;
X 1 is D, K, T, or S;
X 2 is Y, S, or T;
X 3 is Y, V, G, W, S, or F;
X 4 is I, or M;
X 5 is H, G, E, or V;
X 6 is V, or is not present; and
X 7 is S, or is not present;
CDR-H2 is an amino acid sequence X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 X 18 -X 19 -X 20 (SEQ ID NO: 56), wherein;
X 1 is H, D, G, W, S, Y or R;
X 2 is I, or F;
X 3 is Y, W, L, S, N, D or G;
X 4 is W, P, H, T, or S;
X 5 is D, G, E, A, or I;
X 6 is D, G, S, T, or N;
X 7 is D, G, S, or P;
X 8 is K, N, S, E, T, or H;
X 9 is Y, T, P, I, or N;
X 10 is Y, N, T, H, K, S, or G;
X 11 is N, or Y;
X 12 is P, N, A, D, or S;
X 13 is S, E, D, or P;
X 14 is L, K, D, T, or Y;
X 15 is K, F, V, M, R, or A;
X 16 is S, K, Q, P, or is not present;
X 17 is D, G, R, or is not present;
X 18 is F, or is not present;
X 19 is Q, or is not present; and
X 20 is D, or is not present;
CDR-H3 is an amino acid sequence selected from the group consisting of: X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 (SEQ ID NO: 57), wherein;
X 1 is R, N, or W;
X 2 is G, T, R, P, or H;
X 3 is I, R, F, Y, or Q;
X 4 is R, V, Y, F, or A;
X 5 is S, N, G, A, or R;
X 6 is A, Y, L, F, or M;
X 7 is M, A, D, L, or F;
X 8 is D, M, Y, or W;
X 9 is Y, D, or N;
X 10 is Y, A, or is not present;
X 11 is M, or is not present;
X 12 is D, or is not present; and
X 13 is Y, or is not present;
amino acids 99-106 of SEQ ID NO:39;
amino acids 99-106 of SEQ ID NO:41;
amino acids 99-106 of SEQ ID NO:43;
amino acids 99-101 of SEQ ID NO:45;
amino acids 99-106 of SEQ ID NO:47; and
amino acids 99-107 of SEQ ID NO:53;
CDR-L1 is an amino acid sequence: X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 (SEQ ID NO: 58), wherein;
X 1 is K, or R;
X 2 is A;
X 3 is 5;
X 4 is Q, or E;
X 5 is S, or N;
X 6 is V, or I;
X 7 is S, G, or D;
X 8 is N, T, or K;
X 9 is D, N, or Y;
X 10 is V, G, or L;
X 11 is A, I, or H;
X 12 is S, or is not present;
X 13 is F, or is not present;
X 14 is M, or is not present; and
X 15 is N, or is not present;
CDR-L2 is an amino acid sequence: X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 (SEQ ID NO: 59), wherein;
X 1 is Y, or S;
X 2 is A, or T;
X 3 is S, or A;
X 4 is N, H, S, or Q;
X 5 is R, N, or S;
X 6 is Y, Q, or I;
X 7 is T, S, or G; and
X 8 is S, or is not present;
and
CDR-L3 is an amino acid sequence: X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 (SEQ ID NO: 60),
wherein;
X 1 is Q;
X 2 is Q;
X 3 is D, Y, or S;
X 4 is Y, N, K, or I;
X 5 is N, T, S, or E;
X 6 is S, Y, V, or W;
X 7 is P;
X 8 is W, F, Y, L, or P; and
X 9 is T, or S.
7 . The method of any one of claim 3 , 4 , or 6 , wherein said disorder is selected from the group comprising of rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, septic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis, spondyloarthropathy, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, insulin dependent diabetes mellitus, thyroiditis, asthma, allergic diseases, psoriasis, dermatitis scleroderma, graft versus host disease, organ transplant rejection, acute or chronic immune disease associated with organ transplantation, sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki's disease, Grave's disease, nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, Henoch-Schoenlein purpurea, microscopic vasculitis of the kidneys, chronic active hepatitis, uveitis, septic shock, toxic shock syndrome, sepsis syndrome, cachexia, infectious diseases, parasitic diseases, acquired immunodeficiency syndrome, acute transverse myelitis, Huntington's chorea, Parkinson's disease, Alzheimer's disease, stroke, primary biliary cirrhosis, hemolytic anemia, malignancies, heart failure, myocardial infarction, Addison's disease, sporadic, polyglandular deficiency type I and polyglandular deficiency type II, Schmidt's syndrome, adult (acute) respiratory distress syndrome, alopecia, alopecia greata, seronegative arthopathy, arthropathy, Reiter's disease, psoriatic arthropathy, ulcerative colitic arthropathy, enteropathic synovitis, chlamydia, yersinia and salmonella associated arthropathy, spondyloarthopathy, atheromatous disease/arteriosclerosis, atopic allergy, autoimmune bullous disease, pemphigus vulgaris, pemphigus foliaceus, pemphigoid, linear IgA disease, autoimmune haemolytic anaemia, Coombs positive haemolytic anaemia, acquired pernicious anaemia, juvenile pernicious anaemia, myalgic encephalitis/Royal Free Disease, chronic mucocutaneous candidiasis, giant cell arteritis, primary sclerosing hepatitis, cryptogenic autoimmune hepatitis, Acquired Immunodeficiency Disease Syndrome, Acquired Immunodeficiency Related Diseases, Hepatitis B, Hepatitis C, common varied immunodeficiency (common variable hypogammaglobulinaemia), dilated cardiomyopathy, female infertility, ovarian failure, premature ovarian failure, fibrotic lung disease, cryptogenic fibrosing alveolitis, post-inflammatory interstitial lung disease, interstitial pneumonitis, connective tissue disease associated interstitial lung disease, mixed connective tissue disease associated lung disease, systemic sclerosis associated interstitial lung disease, rheumatoid arthritis associated interstitial lung disease, systemic lupus erythematosus associated lung disease, dermatomyositis/polymyositis associated lung disease, Sjögren's disease associated lung disease, ankylosing spondylitis associated lung disease, vasculitic diffuse lung disease, haemosiderosis associated lung disease, drug-induced interstitial lung disease, fibrosis, radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocytic infiltrative lung disease, postinfectious interstitial lung disease, gouty arthritis, autoimmune hepatitis, type-1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis), type-2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmune mediated hypoglycaemia, type B insulin resistance with acanthosis nigricans, hypoparathyroidism, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, osteoarthrosis, primary sclerosing cholangitis, psoriasis type 1, psoriasis type 2, idiopathic leucopaenia, autoimmune neutropaenia, renal disease NOS, glomerulonephritides, microscopic vasulitis of the kidneys, lyme disease, discoid lupus erythematosus, male infertility idiopathic or NOS, sperm autoimmunity, multiple sclerosis (all subtypes), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture's syndrome, pulmonary manifestation of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic sclerosis, Sjorgren's syndrome, Takayasu's disease/arteritis, autoimmune thrombocytopaenia, idiopathic thrombocytopaenia, autoimmune thyroid disease, hyperthyroidism, goitrous autoimmune hypothyroidism (Hashimoto's disease), atrophic autoimmune hypothyroidism, primary myxoedema, phacogenic uveitis, primary vasculitis, vitiligo acute liver disease, chronic liver diseases, alcoholic cirrhosis, alcohol-induced liver injury, choleosatatis, idiosyncratic liver disease, Drug-Induced hepatitis, Non-alcoholic Steatohepatitis, allergy and asthma, group B streptococci (GBS) infection, mental disorders (e.g., depression and schizophrenia), Th2 Type and Th1 Type mediated diseases, acute and chronic pain (different forms of pain), and cancers such as lung, breast, stomach, bladder, colon, pancreas, ovarian, prostate and rectal cancer and hematopoietic malignancies (leukemia and lymphoma), Abetalipoprotemia, Acrocyanosis, acute and chronic parasitic or infectious processes, acute leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute or chronic bacterial infection, acute pancreatitis, acute renal failure, adenocarcinomas, aerial ectopic beats, AIDS dementia complex, alcohol-induced hepatitis, allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis, allograft rejection, alpha-1-antitrypsin deficiency, amyotrophic lateral sclerosis, anemia, angina pectoris, anterior horn cell degeneration, anti cd3 therapy, antiphospholipid syndrome, anti-receptor hypersensitivity reactions, aordic and peripheral aneuryisms, aortic dissection, arterial hypertension, arteriosclerosis, arteriovenous fistula, ataxia, atrial fibrillation (sustained or paroxysmal), atrial flutter, atrioventricular block, B cell lymphoma, bone graft rejection, bone marrow transplant (BMT) rejection, bundle branch block, Burkitt's lymphoma, Burns, cardiac arrhythmias, cardiac stun syndrome, cardiac tumors, cardiomyopathy, cardiopulmonary bypass inflammation response, cartilage transplant rejection, cerebellar cortical degenerations, cerebellar disorders, chaotic or multifocal atrial tachycardia, chemotherapy associated disorders, chromic myelocytic leukemia (CML), chronic alcoholism, chronic inflammatory pathologies, chronic lymphocytic leukemia (CLL), chronic obstructive pulmonary disease (COPD), chronic salicylate intoxication, colorectal carcinoma, congestive heart failure, conjunctivitis, contact dermatitis, cor pulmonale, coronary artery disease, Creutzfeldt-Jakob disease, culture negative sepsis, cystic fibrosis, cytokine therapy associated disorders, Dementia pugilistica, demyelinating diseases, dengue hemorrhagic fever, dermatitis, dermatologic conditions, diabetes, diabetes mellitus, diabetic ateriosclerotic disease, Diffuse Lewy body disease, dilated congestive cardiomyopathy, disorders of the basal ganglia, Down's Syndrome in middle age, drug-induced movement disorders induced by drugs which block CNS dopamine receptors, drug sensitivity, eczema, encephalomyelitis, endocarditis, endocrinopathy, epiglottitis, epstein-barr virus infection, erythromelalgia, extrapyramidal and cerebellar disorders, familial hematophagocytic lymphohistiocytosis, fetal thymus implant rejection, Friedreich's ataxia, functional peripheral arterial disorders, fungal sepsis, gas gangrene, gastric ulcer, glomerular nephritis, graft rejection of any organ or tissue, gram negative sepsis, gram positive sepsis, granulomas due to intracellular organisms, hairy cell leukemia, Hallerrorden-Spatz disease, hashimoto's thyroiditis, hay fever, heart transplant rejection, hemachromatosis, hemodialysis, hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura, hemorrhage, hepatitis (A), His bundle arrythmias, HIV infection/HIV neuropathy, Hodgkin's disease, hyperkinetic movement disorders, hypersensitity reactions, hypersensitivity pneumonitis, hypertension, hypokinetic movement disorders, hypothalamic-pituitary-adrenal axis evaluation, idiopathic Addison's disease, idiopathic pulmonary fibrosis, antibody mediated cytotoxicity, Asthenia, infantile spinal muscular atrophy, inflammation of the aorta, influenza a, ionizing radiation exposure, iridocyclitis/uveitis/optic neuritis, ischemia-reperfusion injury, ischemic stroke, juvenile rheumatoid arthritis, juvenile spinal muscular atrophy, Kaposi's sarcoma, kidney transplant rejection, legionella , leishmaniasis, leprosy, lesions of the corticospinal system, lipedema, liver transplant rejection, lymphederma, malaria, malignamt Lymphoma, malignant histiocytosis, malignant melanoma, meningitis, meningococcemia, metabolic/idiopathic, migraine headache, mitochondrial multi.system disorder, mixed connective tissue disease, monoclonal gammopathy, multiple myeloma, multiple systems degenerations (Mencel Dejerine-Thomas Shi-Drager and Machado-Joseph), myasthenia gravis, mycobacterium avium intracellulare, mycobacterium tuberculosis , myelodyplastic syndrome, myocardial infarction, myocardial ischemic disorders, nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis, nephrosis, neurodegenerative diseases, neurogenic I muscular atrophies, neutropenic fever, non-hodgkins lymphoma, occlusion of the abdominal aorta and its branches, occulsive arterial disorders, okt3 therapy, orchitis/epidydimitis, orchitis/vasectomy reversal procedures, organomegaly, osteoporosis, pancreas transplant rejection, pancreatic carcinoma, paraneoplastic syndrome/hypercalcemia of malignancy, parathyroid transplant rejection, pelvic inflammatory disease, perennial rhinitis, pericardial disease, peripheral atherlosclerotic disease, peripheral vascular disorders, peritonitis, pernicious anemia, pneumocystis carinii pneumonia, pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), post perfusion syndrome, post pump syndrome, post-MI cardiotomy syndrome, preeclampsia, Progressive supranucleo Palsy, primary pulmonary hypertension, radiation therapy, Raynaud's phenomenon and disease, Raynoud's disease, Refsum's disease, regular narrow QRS tachycardia, renovascular hypertension, reperfusion injury, restrictive cardiomyopathy, sarcomas, scleroderma, senile chorea, Senile Dementia of Lewy body type, seronegative arthropathies, shock, sickle cell anemia, skin allograft rejection, skin changes syndrome, small bowel transplant rejection, solid tumors, specific arrythmias, spinal ataxia, spinocerebellar degenerations, streptococcal myositis, structural lesions of the cerebellum, Subacute sclerosing panencephalitis, Syncope, syphilis of the cardiovascular system, systemic anaphalaxis, systemic inflammatory response syndrome, systemic onset juvenile rheumatoid arthritis, T-cell or FAB ALL, Telangiectasia, thromboangitis obliterans, thrombocytopenia, toxicity, transplants, trauma/hemorrhage, type III hypersensitivity reactions, type IV hypersensitivity, unstable angina, uremia, urosepsis, urticaria, valvular heart diseases, varicose veins, vasculitis, venous diseases, venous thrombosis, ventricular fibrillation, viral and fungal infections, vital encephalitis/aseptic meningitis, vital-associated hemaphagocytic syndrome, Wernicke-Korsakoff syndrome, Wilson's disease, xenograft rejection of any organ or tissue.
8 . The method according to any one of claim 1 , 3 , 4 , or 6 , wherein said administering is by at least one mode selected from parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, and transdermal.Cited by (0)
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