US2006003377A1PendingUtilityA1
Therapeutic and diagnostic proteins comprising a SOCS box
Est. expiryNov 1, 2016(expired)· nominal 20-yr term from priority
Inventors:Douglas HiltonWarren AlexanderElizabeth M. VineyTracy WillsonRachael T. RichardsonRobyn StarrSandra E. NicholsonDonald MetcalfNicos A. Nicola
C07K 2319/60A01K 67/0276C07K 14/47A01K 2217/075C07K 14/4703A01K 2267/03A01K 2227/105C07K 2319/43A61K 38/00C07K 2319/00C12N 15/8509G01N 33/6863
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Claims
Abstract
The present invention relates generally to therapeutic and diagnostic agents. More particularly, the present invention provides therapeutic molecules capable of modulating signal transduction such as but not limited to cytokine-mediated signal transduction. The molecules of the present invention are useful, therefore, in modulating cellular responsiveness to cytokines as well as other mediators of signal transduction such as endogenous or exogenous molecules, antigens, microbes and microbial products, viruses or components thereof, ions, hormones and parasites.
Claims
exact text as granted — not AI-modified1 . A nucleic acid molecule comprising a sequence of nucleotides encoding or complementary to a sequence encoding a protein or a derivative, homologue, analogue or mimetic thereof or a nucleotide sequence capable of hybridizing thereto under low stringency conditions at 42° C. wherein said protein comprises a SOCS box in its C-terminal region.
2 . A nucleic acid molecule according to claim 1 wherein the protein further comprises a protein:molecule interacting region.
3 . A nucleic acid molecule according to claim 1 wherein the protein:molecule interacting region is located in a region N-terminal of the SOCS box.
4 . A nucleic acid molecule according to claim 2 or 3 wherein the protein:molecule interacting region is a protein:DNA binding region or a protein:protein binding region.
5 . A nucleic acid molecule according to claim 4 wherein the protein:molecule interacting region is one or more of an SH2 domain, WD-40 repeats or ankyrin repeats.
6 . A nucleic acid molecule according to claim 1 wherein the SOCS box comprises the amino acid sequence:
(SEQ ID NO: 59)
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 i ] n X 17 X 18 X 19 X 20 X 21 X 22 X 23 [Xj] n X 24
X 25 X 26 X 27 X 28
wherein:
X 1 is L, I, V, M, A or P;
X 2 is any amino acid residue;
X 3 is P, T or S;
X 4 is L, I, V, M, A or P;
X 5 is any amino acid;
X 6 is any amino acid;
X 7 is L, I, V, M, A, F, Y or W;
X 8 is C, T or S;
X 9 is R, K or H;
X 10 is any amino acid;
X 11 is any amino acid;
X 12 is L, I, V, M, A or P;
X 13 is any amino acid;
X 14 is any amino acid;
X 15 is any amino acid;
X 16 is L, I, V, M, A, P, G, C, T or S;
[X i ] n is a sequence of n amino acids wherein n is from 1 to 50 amino acids and wherein the sequence X i may comprise the same or different amino acids selected from any amino acid residue;
X 17 is L, I, V, M, A or P;
X 18 is any amino acid;
X 19 is any amino acid;
X 20 L, I, V, M, A or P;
X 21 is P;
X 22 is L, I, V, M, A, P or G;
X 23 is P or N;
[X j ] n is a sequence of n amino acids wherein n is from 0 to 50 amino acids and wherein the sequence X j may comprise the same or different amino acids selected from any amino acid residue;
X 24 is L, I, V, M, A or P;
X 25 is any amino acid;
X 26 is any amino acid;
X 27 is Y or F; and
X 28 is L, I, V, M, A or P, with the proviso that said protein is not CIS.
7 . A nucleic acid molecule according to claim 6 wherein the protein modulates signal transduction.
8 . A nucleic acid molecule according to claim 7 wherein the signal transduction is modulated by a cytokine or a hormone, a microbe or a microbial product, a parasite, an antigen or other effector molecule.
9 . A nucleic acid molecule according to claim 8 wherein the protein modulates cytokine-mediated signal transduction.
10 . A nucleic acid molecule according to claim 9 wherein the signal transduction is mediated by one or more of the cytokines EPO, TPO, G-CSF, GM-CSF, IL-3, IL-2, IL-4, IL-7, IL-1 3, IL-6, LIF, IL-12, IFNγ, TNFα, IL-1 and/or M-CSF.
11 . A nucleic acid molecule according to claim 10 wherein the signal transduction is mediated by one or more of IL-6, LIF, OSM, IFN-γ and/or thrombopoietin.
12 . A nucleic acid molecule according to claim 11 wherein the signal transduction is mediated by IL-6.
13 . A nucleic acid molecule according to claim 1 wherein the nucleotide sequence encodes an amino acid sequence substantially as set forth in SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 18, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 36, SEQ ID NO: 41, SEQ ID NO: 44, SEQ ID NO: 46 or SEQ ID NO: 48 or an amino acid sequence having at least about 15% similarity to all or part of the listed sequences or a nucleotide sequence which hybridizes to the nucleic acid molecule under low stringency conditions at 42° C.
14 . A nucleic acid molecule according to claim 1 wherein the nucleotide sequence is substantially as set forth in SEQ ID NO: 3,SEQ ID NO: 5, SEQ ID NO: 7,SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 45 or SEQ ID NO: 47 or a nucleotide sequence having at least 15% similarity to all or a part of the listed sequences or a nucleotide sequence capable of hybridizing to the listed sequences under low stringency conditions at 42° C.
15 . A nucleic acid molecule comprising a sequence of nucleotides encoding or complementary to a sequence encoding a protein or a derivative, homologue, analogue or mimetic thereof or a nucleotide sequence capable of hybridizing thereto under low stringency conditions at 42° C. wherein said protein exhibits the following characteristics:
(i) comprises a SOCS box in its C-terminal region wherein said SOCS box comprises the amino acid sequence: (SEQ ID NO: 59) 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 i ] n X 17 X 18 X 19 X 20 X 21 X 22 X 23 [Xj] n X 24 X 25 X 26 X 27 X 28 wherein: X 1 is L, I, V, M, A or P; X 2 is any amino acid residue; X 3 is P, T or S; X 4 is L, I, V, M, A or P; X 5 is any amino acid; X 6 is any amino acid; X 7 is L, I, V, M, A, F, Y or W; X 8 is C, T or S; X 9 is R, K or H; X 10 is any amino acid; X 11 is any amino acid; X 12 is L, I, V, M, A or P; X 13 is any amino acid; X 14 is any amino acid; X 15 is any amino acid; X 16 is L, I, V, M, A, P, G, C, T or S; [X i ] n is a sequence of n amino acids wherein n is from 1 to 50 amino acids and wherein the sequence X i may comprise the same or different amino acids selected from any amino acid residue; X 17 is L, I, V, M, A or P; X 18 is any amino acid; X 19 is any amino acid; X 20 L, I, V, M, A or P; X 21 is P; X 22 is L, I, V, M, A, P or G; X 23 is P or N; [X j ] n is a sequence of n amino acids wherein n is from 0 to 50 amino acids and wherein the sequence X j may comprise the same or different amino acids selected from any amino acid residue; X 24 is L, I, V, M, A or P; X 25 is any amino acid; X 26 is any amino acid; X 27 is Y or F; X 28 is L, I, V, M, A or P; and (ii) comprises at least one of an SH2 domain, WD-40 repeats and/or ankyrin repeats or other protein:molecule interacting domain in a region N-terminal of the SOCS box; and (iii) modulates signal transduction.
16 . A method of modulating levels of a SOCS protein in a cell said method comprising contacting a cell containing a SOCS gene with an effective amount of a modulator of SOCS gene expression or SOCS protein activity for a time and under conditions sufficient to modulate levels of said SOCS protein.
17 . A method of modulating signal transduction in a cell containing a SOCS gene comprising contacting said cell with an effective amount of a modulator of SOCS gene expression or SOCS protein activity for a time sufficient to modulate signal transduction.
18 . A method of influencing interaction between cells wherein at least one cell carries a SOCS gene, said method comprising contacting the cell carrying the SOCS gene with an effective amount of a modulator of SOCS gene expression or SOCS protein activity for a time sufficient to modulate signal transduction.
19 . A method according to any one of claims 16 - 18 wherein signal transduction is mediated by a cytokine, a hormone, a microbe or a microbial product, a parasite, an antigen or other effector molecule.
20 . A method according to claim 19 wherein the cytokine is one or more of EPO, TPO, G-CSF, GM-CSF, IL-3, IL-2, IL-4, IL-7, IL-13, IL-6, LIF, IL-12, IFNγ, TNFα, IL-1 and/or M-CSF.
21 . A method according to claim 20 wherein the cytokine is one or more of IL-6, LIF, OSM, IFN-γ and/or thrombopoietin.
22 . A method according to claim 21 wherein the cytokine is IL-6.
23 . A method according to any one of claims 16 - 18 wherein the SOCS gene encodes a protein having a SOCS box comprising the amino acid sequence:
(SEQ ID NO: 59)
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 i ] n X 17 X 18 X 19 X 20 X 21 X 22 X 23 [Xj] n X 24
X 25 X 26 X 27 X 28
wherein:
X 1 is L, I, V, M, A or P;
X 2 is any amino acid residue;
X 3 is P, T or S;
X 4 is L, I, V, M, A or P;
X 5 is any amino acid;
X 6 is any amino acid;
X 7 is L, I, V, M, A, F, Y or W;
X 8 is C, T or S;
X 9 is R, K or H;
X 10 is any amino acid;
X 11 is any amino acid;
X 12 is L, I, V, M, A or P;
X 13 is any amino acid;
X 14 is any amino acid;
X 15 is any amino acid;
X 16 is L, I, V, M, A, P, G, C, T or S;
[X i ] n is a sequence of n amino acids wherein n is from 1 to 50 amino acids and wherein the sequence X i may comprise the same or different amino acids selected from any amino acid residue;
X 17 is L, I, V, M, A or P;
X 18 is any amino acid;
X 19 is any amino acid;
X 20 L, I, V, M, A or P;
X 21 is P;
X 22 is L, I, V, M, A, P or G;
X 23 is P or N;
[X j ] n is a sequence of n amino acids wherein n is from 0 to 50 amino acids and wherein the sequence X j may comprise the same or different amino acids selected from any amino acid residue;
X 24 is L, I, V, M, A or P;
X 25 is any amino acid;
X 26 is any amino acid;
X 27 is Y or F; and
X 28 is L, I, V, M, A or P, with the proviso that said protein is not CIS.
24 . A method according to claim 23 wherein the SOCS gene comprises a nucleotide sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 45 and SEQ ID NO: 47.
25 . A method according to claim 23 wherein the SOCS gene encodes a protein comprising an amino acid sequence substantially as set forth in SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 18, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 36, SEQ ID NO: 41, SEQ ID NO: 44, SEQ ID NO: 46 or SEQ ID NO: 48.
26 . A nucleic acid molecule according to claim 1 wherein the SOCS box comprises the amino acid sequence:
(SEQ ID NO: 59)
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 i ] n X 17 X 18 X 19 X 20 X 21 X 22 X 23 [Xj] n X 24
X 25 X 26 X 27 X 28
wherein: X 1 is L, I, V, M or P;
X 2 is any amino acid residue;
X 3 is P, T or S;
X 4 is L, I, V, M, A or P;
X 5 is any amino acid;
X 6 is any amino acid;
X 7 is L, I, V, M, A, F, Y or W;
X 8 is C, T or S;
X 9 is R, K or H;
X 10 is any amino acid;
X 11 is any amino acid;
X 12 is L, I, V, M, A or P;
X 13 is any amino acid;
X 14 is any amino acid;
X 15 is any amino acid;
X 16 is L, I, V, M, A, P, G, C, T or S;
[X i ] n is a sequence of n amino acids wherein n is from 1 to 50 amino acids and wherein the sequence X i can comprise the same or different amino acids selected from any amino acid residue;
X 17 is L, I, V, M, A or P;
X 18 is any amino acid;
X 19 is any amino acid;
X 20 L, I, V, M, A or P;
X 21 is P;
X 22 is L, I, V, M, A, P or G;
X 23 is P or N;
[X j ] n is a sequence of n amino acids wherein n is from 0 to 50 amino acids and wherein the sequence X j can comprise the same or different amino acids selected from any amino acid residue;
X 24 is L, I, V, M, A or P;
X 25 is any amino acid;
X 26 is any amino acid;
X 27 is Y or F; and
X 28 is L, I, V, M, A or P.
27 . The isolated nucleic acid molecule of claim 6 , wherein said SOCS box comprises a sequence selected from any one of SEQ ID NOs: 64-81.
28 . The isolated nucleic acid molecule of claim 6 , wherein said SOCS box comprises a sequence having at least about 70% similarity to any one of SEQ ID NOs: 64-81.
29 . The isolated nucleic acid molecule of claim 26 , wherein said SOCS box comprises a sequence selected from any one of SEQ ID NOs: 64-81.
30 . The isolated nucleic acid molecule of claim 26 , wherein said SOCS box comprises a sequence having at least about 70% similarity to any one of SEQ ID NOs: 64-81.
31 . The method according to anyone of claims 16 - 18 , wherein the SOCS gene encodes a protein having a SOCS box comprising the amino acid sequence
(SEQ ID NO: 59)
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 i ] n X 17 X 18 X 19 X 20 X 21 X 22 X 23 [Xj] n X 24
X 25 X 26 X 27 X 28
wherein: X 1 is L, I, V, M or P;
X 2 is any amino acid residue;
X 3 is P, T or S;
X 4 is L, I, V, M, A or P;
X 5 is any amino acid;
X 6 is any amino acid;
X 7 is L, I, V, M, A, F, Y or W;
X 8 is C, T or S;
X 9 is R, K or H;
X 10 is any amino acid;
X 11 is any amino acid;
X 12 is L, I, V, M, A or P;
X 13 is any amino acid;
X 14 is any amino acid;
X 15 is any amino acid;
X 16 is L, I, V, M, A, P, G, C, T or S;
[X i ] n is a sequence of n amino acids wherein n is from 1 to 50 amino acids and herein the sequence X i can comprise the same or different amino acids selected from any amino acid residue;
X 17 is L, I, V, M, A or P;
X 18 is any amino acid;
X 19 is any amino acid;
X 20 L, I, V, M, A or P;
X 21 is P;
X 22 is L, I, V, M, A, P or G;
X 23 is P or N;
[X j ] n is a sequence of n amino acids wherein n is from 0 to 50 amino acids and wherein the sequence X j can comprise the same or different amino acids selected from any amino acid residue;
X 24 is L, I, V, M, A or P;
X 25 is any amino acid;
X 26 is any amino acid;
X 27 is Y or F; and
X 28 is L, I, V, M, A or P.
32 . The method of claim 23 , wherein said SOCS box comprises a sequence selected from any one of SEQ ID NOs: 64-81.
33 . The method of claim 23 , wherein said SOCS box comprises a sequence having at least about 70% similarity to any one of SEQ ID NOs: 64-81.
34 . The method of claim 31 , wherein said SOCS box comprises a sequence selected from any one of SEQ ID NOs: 64-81.
35 . The method of claim 31 , wherein said SOCS box comprises a sequence having at least about 70% similarity to any one of SEQ ID NOs: 64-81.Cited by (0)
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