Type i interferon mimetics as therapeutics for cancer, viral infections, and other diseases

Patent metadata

Field	Value
Publication number	US-2016289288-A1
Application number	US-201415103600-A
Country	US
Kind code	A1
Filing date	Dec 11, 2014
Priority date	Jun 21, 2011
Publication date	Oct 6, 2016
Grant date	—

Abstract

The subject invention pertains to agonist peptides of type I interferons and methods of using the peptides. These peptides are based on the amino acid sequence of the C-terminus region of the type I IFN molecules and are capable of binding to the cytoplasmic domain of type I IFN receptors. Surprisingly, these peptides were found to possess the same or similar biological activity as that associated with the full-length, mature type I IFN proteins, even though these peptides do not bind to the extracellular domain of the type I IFN receptors. In one embodiment, the peptide is a peptide of IFNα. In another embodiment, the peptide is a peptide of IFNβ. Exemplified peptides of the invention include those having SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:38, SEQ ID NO:39, and SEQ ID NO:40. The subject peptides have been shown to effect increased resistance to viral infection. Peptides of the invention can be used to treat or prevent viral infections, to treat oncological disorders, and to treat autoimmune disorders, such as multiple sclerosis.

First claim

1 . An agonist peptide of a type I interferon (IFN), or a polynucleotide encoding the agonist peptide; or a polynucleotide expression construct comprising the polynucleotide encoding the agonist peptide; or a composition comprising the agonist peptide, the polynucleotide, and/or the polynucleotide expression construct; wherein the peptide does not bind to the extracellular domain of a type I IFN receptor but does bind to the cytoplasmic domain of a type I IFN receptor and wherein the peptide comprises the amino acid sequence of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40, or a fragment or variant thereof that exhibits substantially the same activity as the full-length non-variant peptide, or the peptide comprises an amino acid sequence having 60% or greater sequence identity with the amino acid sequence of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40, or a fragment or variant thereof that exhibits substantially the same activity as the full-length non-variant peptide; or
a kit comprising in one or more containers: i) the agonist peptide; and/or ii) the polynucleotide encoding the peptide agonist; and/or iii) the polynucleotide expression construct comprising the polynucleotide; and/or iv) a composition comprising the peptide agonist, the polynucleotide, the polynucleotide expression construct or the composition.

2 . The peptide according to claim 1 , wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or more than 40 amino acids are, independently, removed from and/or added to one or both termini of the peptide.

3 . The peptide according to claim 1 , wherein the peptide comprises a protein or nucleic acid that is attached to the peptide and that targets delivery to the cell and/or that provides for translocation of the peptide across a biological membrane of the cell; or wherein a lipophilic group is attached to the peptide.

4 . (canceled)

5 . The peptide according to claim 3 , wherein the lipophilic group is a palmitoyl-lysine group or a palmitic acid.

6 . The peptide according to claim 3 , wherein the peptide comprises one or more arginine amino acids at the N-terminus of the peptide, or at the C-terminus of the peptide, or both termini of the peptide.

7 . The peptide according to claim 1 , wherein the peptide comprises a nuclear localization sequence (NLS) or a cell-penetrating peptide (CPP).

8 . (canceled)

9 . The peptide according to claim 7 , wherein the CPP comprises the amino acid sequence of SEQ ID NO:19; SEQ ID NO:20; SEQ ID NO:21; SEQ ID NO:22; SEQ ID NO:23; SEQ ID NO:24; SEQ ID NO:25; SEQ ID NO:26; SEQ ID NO:27; SEQ ID NO:28; SEQ ID NO:29; 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:36; or SEQ ID NO:37.

10 . The peptide according to claim 7 , wherein the CPP comprises only arginine (R) or only lysine (K) amino acids.

11 . The peptide according to claim 1 , wherein the peptide has the same or similar biological activity as that associated with a full-length type I IFN protein.

12 . The composition according to claim 1 , wherein the composition comprises a suitable carrier, diluent, or buffer; or wherein the composition further comprises i) one or more antiviral compounds, and/or ii) one or more anticancer or antitumor compounds, and/or one or more compounds for treating autoimmune disorders.

13 . (canceled)

14 . The composition according to claim 12 , wherein the one or more antiviral compound is IFNα, IFNβ, IFNγ, acyclovir (Zovirax), zidovudine (AZT), lamivudine (3TC), zanamivir (Relenza), oseltamivir (Tamiflu), valacyclovir (Valtrex), amantadine (Symmetrel), rimantadine (Flumadine), cidofovir (Vistide), foscarnet (Foscavir), ganciclovir (Cytovene), ribavirin (Virazole), nelfinavir (Viracept), ritonavir (Norvir), rifampin (Rifadin), or famciclovir (Famvir).

15 . The composition according to claim 12 , wherein the one or more antiviral compounds is an interferon-gamma (IFN-γ) peptide mimetic.

16 . The composition according to claim 15 , wherein the IFN-γ peptide mimetic comprises the amino acid sequence shown in SEQ ID NO:7 or SEQ ID NO:8, or a fragment or variant thereof that exhibits substantially the same activity as the full-length non-variant peptide.

17 . The composition according to claim 12 , wherein the one or more anticancer or antitumor compound is taxol, vinblastine, cyclophosamide, ifosfamide, 5-fluorouracil, hydroxyurea, adriamycin, bleomycin, etoposide, camptothecin, angiostatin, tamoxifen, GLEEVEC, HERCEPTIN, Bortezomib, Carfilzomib, or Salinosporamide A.

18 . The composition according to claim 1 , wherein the composition further comprises a peptide comprising the amino acid sequence shown in SEQ ID NO:9 and/or SEQ ID NO:10, or a fragment or variant thereof that exhibits substantially the same activity as the full-length non-variant peptide.

19 . The composition according to claim 1 , wherein the peptide or polynucleotide is encapsulated in a liposome.

20 . The polynucleotide expression construct according to claim 1 , wherein said expression construct comprises one or more regulatory elements.

21 . (canceled)

22 . An antibody, or an antigen binding fragment or variant thereof, that binds to an agonist peptide of a type I interferon, wherein the peptide does not bind to the extracellular domain of a type I IFN receptor but does bind to the cytoplasmic domain of a type I IFN receptor, wherein the peptide comprises the amino acid sequence of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40, or a fragment or variant thereof that exhibits substantially the same activity as the full-length non-variant peptide, or the peptide comprises an amino acid sequence having 60% or greater sequence identity with the amino acid sequence of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40, or a fragment or variant thereof that exhibits substantially the same activity as the full-length non-variant peptide.

23 . A method for treating or preventing infection by a virus in a human or animal or treating or preventing a viral associated disorder in a human or animal, said method comprising administering to the human or animal an effective amount of
i) a peptide that is an agonist of a type I interferon of claim 1 , wherein the peptide does not bind to the extracellular domain of a type I IFN receptor but does bind to the cytoplasmic domain of a type I IFN receptor, and/or ii) a polynucleotide that encodes a peptide that is an agonist of a type I interferon of claim 1 , wherein the peptide does not bind to the extracellular domain of a type I IFN receptor but does bind to the cytoplasmic domain of a type I IFN receptor, and/or iii) a polynucleotide expression construct comprising the polynucleotide encoding the agonist peptide, and/or iv) a composition comprising the peptide agonist, the polynucleotide, the polynucleotide expression construct or composition of claim 1 ; or a method for inducing an antiviral state in a cell against a virus or inhibiting the growth of a cancer cell, comprising contacting the cell in vitro or in vivo with an effective amount of not bind to the extracellular domain of a type I IFN receptor but does bind to the cytoplasmic domain of a type I IFN receptor, and/or ii) a polynucleotide that encodes a peptide that is an agonist of a type I interferon (IFN) of claim 1 wherein the peptide does not bind to the extracellular domain of a type I IFN receptor but does b

Assignees

• Univ Florida

Inventors

• Johnson Howard M
• Ahmed Chulbul M

Classifications

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61K39/39

  characterised by the immunostimulating additives, e.g. chemical adjuvants · CPC title

• C07K14/555

  Interferons [IFN] · CPC title

• C07K14/7156

  for interferons [IFN] · CPC title

• A61K2039/55522

  Cytokines; Lymphokines; Interferons · CPC title