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Fig. 1A (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/155738 A2 15 October 2015 (15.10.2015) P O P C T (51) International Patent Classification: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A61K 38/45 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (21) International Application Number: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, PCT/IB20 15/052606 MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (22) International Filing Date: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, April 2015 (09.04.2015) SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 61/977,340 April 2014 (09.04.2014) US TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (72) Inventor; and DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (71) Applicant : RUDD, Christopher [GB/US]; 39E Bellis LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Circle, Cambridge, Massachusetts 02140 (US). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (72) Inventors: LEE, Dae Choon; 485 1 South Ashton Court, Springfield, MO 65810 (US). ROTHSTEIN, David Published: Mark; 213 Timber Ridge Road, Pittsburgh, PA 15238 — without international search report and to be republished (US). LEE, Young Mee; 485 1 South Ashton Court, upon receipt of that report (Rule 48.2(g)) Springfield, MO 65810 (US). — with information concerning incorporation by reference of (81) Designated States (unless otherwise indicated, for every missing parts and/or elements (Rule 20.6) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (54) Title: USE OF GSK-3 INHIBITORS OR ACTIVATORS WHICH MODULATE PD-1 OR T-BET EXPRESSION TO MODU LATE T CELL IMMUNITY FIG. 1A OVA alone < OVA + SB4 15286 (57) Abstract: The present application generally relates to the discovery that glycogen synthase kinase 3 (GSK-3) is an upstream signalling molecule that controls PD-1 transcription and Tbet expression by immune cells and in particular T-cells. Based on this discovery, and in view of the known immunosuppressive effect of PD-1 on immunity and the promoting effect of Tbet on T cell im munity, the present invention relates to the use of GSK-3 inhibitors to promote immunity, including cytotoxic T cell immunity in subjects in need thereof, especially subjects with chronic conditions wherein inhibiting PD-1 expression and/or blockade or Tbet up - o regulation is therapeutically desirable such as cancer and infectious conditions. Further, based on this discovery the present inven tion relates to the use of compounds which promote GSK-3 expression or activity to suppress immunity, especially aberrant T cell immunity in subjects in need thereof, e.g., subjects with chronic conditions wherein PD-1 upregulation or Tbet down regulation is therapeutically desirable such as allergic, autoimmune or inflammatory conditions. Also, screening methods for identifying immune agonists and antagonists, especially antibodies, are provided. USE OF GSK-3 INHIBITORS OR ACTIVATORS WHICH MODULATE PD-1 OR T- BET EXPRESSION TO MODULATE T CELL IMMUNITY RELATED APPLICATIONS [1] The present application claims benefit of priority to US provisional application No. 61/977,340 filed on April 9 , 2014, the contents of which are incorporated by reference herein. FIELD [2] The present application generally relates to the discovery that glycogen synthase kinase 3 (GSK-3) is an upstream signalling molecule that controls PD-1 transcription and Tbet expression by immune cells and in particular expression thereof by T-cells. Based on this discovery, and in view of the known immunosuppressive effect of PD-1 on immunity and the promoting effect of Tbet on T cell immunity, the present invention relates to the use of GSK-3 inhibitors to promote immunity, including cytotoxic T cell immunity in subjects in need thereof, especially subjects with chronic conditions wherein inhibition of PD-1 transcription or expression or Tbet upregulation is therapeutically desirable such as cancer and infectious conditions. Further, based on this discovery the present invention relates to the use of GSK-3 activators to suppress immunity, especially aberrant T cell immunity in subjects in need thereof, e.g., subjects with chronic conditions wherein T cell activity is elevated such as allergic, autoimmune or inflammatory conditions. BACKGROUND [3] Immune negative checkpoint regulator (NCR) pathways have proven to be extraordinary clinical targets in the treatment of human immune-related diseases. Blockade of two NCRs, CTLA-4 and PD-1 , using monoclonal antibodies (mabs) to enhance tumor immunity is revolutionizing the treatment of cancer and has established these pathways as clinically validated targets in human disease. Recently, soluble versions of NCR Iigands that trigger or block NCR pathways have entered the clinic as immunosuppressive drugs to treat autoimmunity (e.g. AMP- 110/B7-H4-lg for Rheumatoid arthritis). [4] The present invention relates to a specific protein kinase Glycogen Synthase Kinase-3 (GSK-3) and the discovery of its role in regulation of T cell immunity. Specifically, this invention provides a greater understanding of the signaling pathways affected by this molecule and how this discovery may be exploited to regulate T cell immunity as a means of treating chronic disease conditions. [5] GSK-3 is a proline-directed, serine/threonine kinase for which two isoforms, GSK-3a and GSK-3p, have been identified, phosphorylates the rate- limiting enzyme of glycogen synthesis, glycogen synthase (GS). See, for example, Embi, et al., Eur. J. Biochem., 107, 519-527 (1980). GSK-3 a and GSK-3p are both highly expressed in the body. See, for example, Woodgett, et al., EMBO, 9 , 2431- 2438 (1990) and Loy, et al., J. Peptide Res., 54, 85-91 (1999). Besides GS, a number of other GSK-3 substrates have been identified, including many metabolic, signaling, and structural proteins. Notable among the plurality of signaling proteins regulated by GSK-3 are many transcription factors, including activator protein-1 ; cyclic AMP response element binding protein (CREB); the nuclear factor (NF) of activated T-cells; heat shock factor-1; β-catenin; c-Jun; c-Myc; c-Myb; and NF-KB See, for example, C. A . Grimes, et al., Prog. Neurobiol., 65, 391-426 (2001), H. Eldar-Finkelman, Trends in Molecular Medicine, 8 , 126-132 (2002), and P. Cohen, et al., Nature, 2 , 1-8, (2001). Accordingly, targeting the activity of GSK-3 has significant therapeutic potential in the treatment of many disparate pathologies and conditions, for example, Alzheimer's disease (A. Castro, et al., Exp. Opin. Ther. Pat., 10, 1519-1527 (2000)); asthma (P. J. Barnes, Ann. Rev. Pharmacol. Toxicol., 42, 81- 98 (2002)); cancer (Beals, et al., Science, 275, 1930-1933 (1997), L . Kim, et al., Curr. Opin. Genet. Dev., 10, 508-514 (2000), and Q . Eastman, et al., Curr. Opin. Cell Biol., 11, 233 (1999)); diabetes and its related sequelae, for example, Syndrome X and obesity (S. E . Nikoulina, et al., Diabetes, 5 1, 2190-2198 (2002), Orena, et al., JBC, 15765-15772 (2000), and Summers, et al., J. Biol. Chem., 274 17934-17940 (1999)); hair loss (S. E. Millar, et al., Dev. Biol., 207, 133-149 (1999) and E. Fuchs, et al., Dev. Cell, 1, 13-25 (2001)); inflammation (P. Cohen, Eur. J. Biochem., 268, 5001-501 0 (2001)); mood disorders, such as depression (A. Adnan, et al., Chem. Rev., 101 , 2527-2540 (2001) and R. S . B. Williams, et al., Trends Phamacol. Sci., 2 1, 61-64 (2000)); neuronal cell death and stroke (D. A . E . Cross, et al., J. Neurochem., 77, 94-102 (2001) and C. Sasaki, et al., Neurol. Res., 23, 588-592 (2001)); bipolar disorder (Klein, et al., PNAS, 93, 8455-8459 (1996)); skeletal muscle atrophy (G. J. Brunn, et al., Science, 277, 99-101 (1997), R. E. Rhoads, J. Biol. Chem., 274, 30337-30340 (1999), V. R. Dharmesh, et al., Am. J. Physiol. Cell Physiol. 283, C545-551 (2002), and K. Baar, et al., A . J . Physiol., 276, C120-C127 (1999)); decreased sperm motility (Vijayaraghavan, et al., Biol. Reproduction, 54, 709-718 (1996)); protozoan infection, (Fugel et al., J Med. Chem., 56(1):264-75 (2013), Ojo et al., Antimicrob. Agents, Chemotherapy, 52(10):3710-7 (2008), Nurul et al., Trop Biomed., 27(3):624-31 (2010); tick infection , Fabres et al, Parasitology, 137(1): 1537-46 (2010) ; viral replication, (Sun et al., PLos One., 7(4):e34761 (2012), Kehn-Hall et al., Virology, 415(1):56-68 (201 1), Fujimuro et al., J Virol., 79:16:10429- 41(2005); W u et al„ J Biol. Chem, 284(8): 5229-39 (2009)) infections ( cardio- protection (C. Badorff, et al., J. Clin. Invest., 109, 373-381 (2002), S . Haq, et al., J. Cell Biol., 151 , 117-129 (2000), H . Tong, et al., Circulation Res., 90, 377-379 (2002), protozoan diseases (septic shock, (Martin, US Patent Publication No.201 20309807). [6] The invention further relates to novel therapies involving the regulation of PD-1 and/or Tbet expression, molecules respectively known to elicit a suppressive or potentiating effect on T-cell immunity.
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