US 201701 65230A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0165230 A1 RUDD et al. (43) Pub. Date: Jun. 15, 2017 (54) USE OF GSK-3 INHIBITORS OR A63L/433 (2006.01) ACTIVATORS WHICH MODULATE PD-1 OR A6IR 9/00 (2006.01) T-BET EXPRESSION TO MODULATE T (52) U.S. Cl. CELL IMMUNITY CPC .......... A61K 31/404 (2013.01); A61K 31/433 (2013.01); A61K 9/0053 (2013.01); A61 K (71) Applicant: Christopher RUDD, Montreal (CA) 38/10 (2013.01); A61K 31/426 (2013.01); A6 IK3I/506 (2013.01) (72) Inventors: Christopher RUDD, Montreal (CA): Dae Choon LEE, Springfield, MO (57) ABSTRACT (US); David Mark ROTHSTEIN, Pittsburgh, PA (US); Young Mee LEE, The present application generally relates to the discovery Springfield, MO (US) that glycogen synthase kinase 3 (GSK-3) is an upstream signalling molecule that controls PD-1 transcription and (21) Appl. No.: 15/302,589 Tbet expression by immune cells and in particular T-cells. Based on this discovery, and in view of the known immu (22) PCT Fed: Apr. 9, 2015 nosuppressive effect of PD-1 on immunity and the promot ing effect of Tbet on T cell immunity, the present invention (86) PCT No.: PCT/B2O15/OS2606 relates to the use of GSK-3 inhibitors to promote immunity, S 371 (c)(1), including cytotoxic T cell immunity in Subjects in need (2) Date: Oct. 7, 2016 thereof, especially subjects with chronic conditions wherein inhibiting PD-1 expression and/or blockade or Tbet up Related U.S. Application Data regulation is therapeutically desirable Such as cancer and infectious conditions. Further, based on this discovery the (60) Provisional application No. 61/977.340, filed on Apr. present invention relates to the use of compounds which 9, 2014. promote GSK-3 expression or activity to Suppress immunity, especially aberrant T cell immunity in Subjects in need Publication Classification thereof, e.g., subjects with chronic conditions wherein PD-1 (51) Int. C. upregulation or Tbet down regulation is therapeutically A6 IK 3/404 (2006.01) desirable Such as allergic, autoimmune or inflammatory A6 IK3I/506 (2006.01) conditions. Also, screening methods for identifying immune A6 IK 38/10 (2006.01) agonists and antagonists, especially antibodies, are pro A6 IK 3/426 (2006.01) vided. Patent Application Publication Jun. 15, 2017 Sheet 3 of 20 US 2017/O165230 A1 "e CO CO G e V w G e CO shcy) w O H O CC D N O N e C 2 s. So S 3 2 s so g g g g g XBNJO 96 XBNJO % XeWJO % b cy) S. SC ', a a a Y O O N d r w e ad co ced to ced ed go ko r on d cd co do a d o o o o tes w d oo co r N d do so r n r Y XeWJO 96 XENO % Patent Application Publication US 2017/O165230 A1 ceWO % 00; 08 09 0;} 02 Xew Z?un6|- Patent Application Publication Jun. 15, 2017 Sheet 5 of 20 US 2017/O165230 A1 O C S. w w ? O O S S. west ws O yon - Of v- o cr) a t a ?h w"c ch S. d s wer O CC ce O d O wa wa x - S 3 3 S. 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Grimes, et al., Prog. Neurobiol. 65, 391-426 (2001), H. RELATED APPLICATIONS Eldar-Finkelman, Trends in Molecular Medicine, 8, 126-132 0001. The present application claims benefit of priority to (2002), and P. Cohen, et al., Nature, 2, 1-8, (2001). Accord U.S. provisional application No. 61/977.340 filed on Apr. 9. ingly, targeting the activity of GSK-3 has significant thera 2014, the contents of which are incorporated by reference peutic potential in the treatment of many disparate patholo herein. gies and conditions, for example, Alzheimer's disease (A. Castro, et al., Exp. Opin. Ther. Pat., 10, 1519-1527 (2000)); FIELD asthma (P. J. Barnes, Ann. Rev. Pharmacol. Toxicol., 42, 81-98 (2002)); cancer (Beals, et al., Science, 275, 1930 0002 The present application generally relates to the 1933 (1997), L. Kim, et al., Curr. Opin. Genet. Dev., 10, discovery that glycogen synthase kinase 3 (GSK-3) is an 508-514 (2000), and Q. Eastman, et al., Curr. Opin. Cell upstream signalling molecule that controls PD-1 transcrip Biol., 11, 233 (1999); diabetes and its related sequelae, for tion and Tbet expression by immune cells and in particular example, Syndrome X and obesity (S. E. Nikoulina, et al., expression thereof by T-cells. Based on this discovery, and Diabetes, 51, 2190-2198 (2002), Orena, et al., JBC, 15765 in view of the known immunosuppressive effect of PD-1 on 15772 (2000), and Summers, et al., J. Biol. Chem., 274 immunity and the promoting effect of Tbet on T cell immu 17934-17940 (1999)); hair loss (S. E. Millar, et al., Dev. nity, the present invention relates to the use of GSK-3 Biol. 207, 133-149 (1999) and E. Fuchs, et al., Dev. Cell, 1, inhibitors to promote immunity, including cytotoxic T cell 13-25 (2001)); inflammation (P.