Type I Interferon Antagonists
Disclosed in certain embodiments is a method of preparing a Type 1 interferon antagonist comprising modifying a Type 1 interferon at the site of interaction with the interferon receptor subunit IFNAR-1 such that the binding affinity of the interferon to the IFNAR-1 subunit is reduced as compared to the native interferon, and corresponding compositions and methods of treatment thereof.
1 . A method of preparing a Type I interferon antagonist comprising modifying a Type 1 interferon at the site of interaction with the interferon receptor subunit IFNAR-1 such that the binding affinity of the interferon to the IFNAR-1 subunit is reduced as compared to the native interferon.
2 . The method of claim 1 , wherein the binding affinity of the interferon to the IFNAR-2 subunit is maintained as compared to the native interferon.
3 . The method of claim 1 , further comprising modifying the interferon at the site of interaction with the interferon receptor subunit IFNAR-2 such that the binding affinity of the interferon to the IFNAR-2 subunit is increased as compared to the native interferon.
4 . A method of preparing a Type I interferon antagonist comprising modifying an interferon such that (i) the binding affinity of the interferon to the IFNAR-1 subunit is reduced as compared to the native interferon and (ii) the binding affinity of the interferon to the IFNAR-2 subunit is increased as compared to the native interferon.
5 . The method of any claims 1 - 4 , wherein the interferon is selected from the group consisting of IFN-α, IFN-β, IFN-ω, IFN-κ, INF-ε, IFN-τ, IFN-ζ/limitin, IFN-δ and IFN-ν.
6 . The method of claim 1 , wherein the modifying comprises mutating, one or more amino acids in the IFNAR-1 binding region of the interferon.
7 . The method of any of claims 1 - 4 , wherein the interferon originates from a mammal.
8 . The method of claim 8 , wherein the mammal is a human or a mouse.
9 . The method of any of claims 1 - 4 , wherein the interferon is IFN-α2, preferably IFN-α2a or IFN-α2b.
10 . The method of claim 9 , wherein the IFN-α2b is modified at one or more amino acid positions in region 120-125.
11 . The method of claim 10 , wherein the IFN-α2b is modified at one or more sites selected from the group consisting of Arg120, Lys121 and Gln124.
12 . The method of claim 11 , wherein the Arg 120 of the IFN-α2b is substituted with Glu.
13 . The method of claim 11 , wherein the Arg 120 of the IFN-α2b is substituted with Glu and the Lys 121 is substituted with Glu.
14 . A Type I interferon produced according to any of the methods of claims 1 - 13 .
15 . A Type I interferon that has sufficiently low binding affinity to the interferon receptor subunit IFNAR-1 such that the interferon exhibits antagonist activity.
16 . The Type I interferon of claim 15 that has a sufficient binding affinity to the interferon receptor subunit. IFNA R-2 to interfere with the binding of a native or endogenous interferon.
17 . A Type I interferon that has (i) sufficiently low binding affinity to the interferon receptor subunit IFNAR-1 such that the interferon exhibits antagonist activity and (ii) sufficient binding affinity to the interferon receptor subunit IFNAR-2 to interfere with the binding of a native or endogenous interferon
18 . The Type I interferon of any of claims 15 - 17 , wherein the interferon is selected from the group consisting of IFN-α. IFN-β, IFN-ω, IFN-κ, IFN-ε, IFN-τ, and IFN-ζ/limitin, IFN-δ and IFN-ν.
19 . The Type I interferon of any of claims 15 - 17 , wherein the interferon originates from a mammal.
20 . The Type I interferon of claim 20 , wherein the mammal is a human or a mouse.
21 . The Type I interferon of any of claims 15 - 17 wherein the interferon is IFN-α2b.
22 . The Type I interferon of any of claims 15 - 17 , having a Glu at the 120 amino acid position.
23 . The Type I interferon of any of claims 15 - 17 , having a Glu at the 121 amino acid position.
24 . The Type I interferon of any of claim 15 - 17 , having a Glu at the 120 and 121 amino acid position.
25 . A method of antagonizing the effects of interferon comprising contacting an interferon receptor with a Type I interferon antagonist of any of claims 14 - 17 .
26 . The method of claim 26 , wherein the contacting is in-vitro or in-vivo.
27 . A method of treating a disease or condition in a mammal comprising administering a Type I interferon antagonist of any of claims 14 - 17 , in an effective amount to antagonize the effects of a native or endogenous interferon.
28 . The method of claim 27 , wherein the disease or condition is auto-immune mediated.
29 . The method of claim 27 , wherein the disease or condition is selected from the group consisting of systemic lupus erythematosus, Sjogren's syndrome, Type 1 diabetes, polymyositis, and periodontitis.
30 . The method of claim 27 , wherein the administration is associated with allogeneic grafts or transplants.
31 . A method of treating a disease or condition in a mammal comprising administering a nucleic acid encoding a Type I interferon antagonist of any of claims 14 - 17 , in an effective amount to antagonize the effects of a native or endogenous interferon.
32 . The method of claim 31 , wherein the nucleic acid comprises DNA.
33 . The method of claim 31 , wherein the nucleic acid comprises RNA.
34 . The method of claim 31 , wherein the nucleic acid is contained within a vector.
35 . The method of claim 34 , wherein the vector is a plasmid.
36 . The method of claim 34 , wherein the vector is a virus.
37 . A nucleic acid encoding a Type I interferon antagonist of any of claims 14 - 17 .
38 . The nucleic acid of claim 37 , wherein the nucleic acid comprises DNA.
39 . The nucleic acid of claim 37 , wherein the nucleic acid comprises RNA.
40 . The method of claim 31 , wherein the disease or condition is auto-immune mediated.
41 . The method of claim 31 , wherein the disease or condition is selected from the group consisting of systemic lupus erythematosus, Sjogren's syndrome; Type 1 diabetes, polymyositis, and periodontitis.
42 . The method of claim 31 , wherein the administration is associated with allogeneic grafts or transplants.
43 . The method of any of claims 27 - 36 , wherein the administration is selected from the group consisting of parenteral, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, topical, pulmonary and oral routes.
44 . A pharmaceutical composition comprising the interferon of any of claims 14 - 24 and a pharmaceutically acceptable excipient.
45 . The pharmaceutical composition of claim 44 , in a form selected from the group consisting of a solution, suspension, emulsion, tablet, capsule, powder and sustained-release formulation.