THERAPEUTIC APPLICATION OF ISOLATED NATURALLY-OCCURRING SOLUBLE TRUNCATED FORMS OF IL-23 RECEPTOR

• US 20130183755A1
• Filed: 01/23/2013
• Published: 07/18/2013
• Est. Priority Date: 03/31/2010
• Status: Abandoned Application

• Current Assignee: Grant Gallagher, Jonathan Brazaitis, Raymond Yu
• Original Assignee: Grant Gallagher, Jonathan Brazaitis, Raymond Yu
• Inventors: Gallagher, Grant, Yu, Raymond, Brazaitis, Jonathan
• Application Number:
  US13/748,066
• Publication Number:
  US 20130183755A1
• Time in Patent Office: Days
• US Class Current: 435/369
• CPC Class Codes: A61K 38/00 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 Class Codes: C07K 14/7155 for interleukins [IL]
• CPC Class Codes: C12N 5/0602 Vertebrate cells
• CPC Class Codes: G01N 2333/705 Assays involving receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: G01N 2800/065 Bowel diseases, e.g. Crohn, ulcerative colitis, IBS
• CPC Class Codes: G01N 2800/368 Pregnancy complicated by disease or abnormalities of pregnancy, e.g. preeclampsia, preterm labour
• CPC Class Codes: G01N 33/6863 Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
• CPC Class Codes: G01N 33/6893 related to diseases not provided for elsewhere

Abstract

The present invention relates to an isolated naturally-occurring soluble truncated IL-23Rα protein, which is a translated protein resulting from a mRNA splice variant of IL-23Rα. The soluble IL-23Rα proteins (e.g., Δ9 and Δ8,9) represents a novel soluble IL-23Rα protein, which is lacking a transmembrane domain and has a unique eight (8) amino acids (GLKEGSYC) at its C-terminus end (due to frame-shift). ELISA reveals that Δ9 is present in blood and can serve as a diagnostic tool for auto-immune diseases including Crohn'"'"'s disease. There is also provided a method of recombinant production for this soluble truncated form of IL-23Rα protein. More importantly, the present invention provides an utility application of the Δ9 and Δ8,9 protein in inhibit IL-23R-mediated cell signaling. More particularly, Δ9 and Δ8,9 blocks STAT3 formation as well as Th17 maturation. There is provided a therapeutic application of Δ9 and Δ8,9 in treating a human patient inflicted with Crohn'"'"'s disease.

Claims

1. A method of inhibiting IL-23R-mediated cell signaling in a mammalian cell, comprising the steps of:

a) providing a mammalian cell in need thereof;

b) providing a recombinant IL-23Rα

protein, said recombinant IL-23Rα

protein has an amino acid sequence selected from the group consisting of SEQ ID NO;

2 and SEQ ID NO;

4; and

c) exposing said mammalian cell to an effective amount of said recombinant IL-23Rα

protein, thereby inhibits IL-23R mediated cell signaling in said mammalian cell.

2. The method of claim 1, wherein said recombinant IL-23Rα

protein has an amino acid sequence consisting of SEQ ID NO;

2.

3. The method of claim 1, wherein said recombinant IL-23Rα

protein has an amino acid sequence consisting of SEQ ID NO;

4.

4. The method of claim 1, wherein said IL-23 mediated cell signaling is phosphorylation of STAT1, STAT2, STAT3, or STAT5.

5. The method of claim 1, wherein said IL-23 mediated cell signaling is phosphorylation of STAT3.

6. The method of claim 1, wherein said IL-23 mediated cell signaling is secretion of IL-17A or IL-17F.

7. The method of claim 1, wherein said IL-23 mediated cell signaling is secretion of IL-17A.

8. The method of claim 1, wherein said IL-23 mediated cell signaling is Th-17 cell maturation.

9. The method of claim 1, wherein said mammalian cell is a human cell.

10. The method of claim 1, wherein said mammalian cell is 293T cell.