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Wo 2010/011347 A9 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) CORRECTED VERSION (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 28 January 2010 (28.01.2010) WO 2010/011347 A9 (51) International Patent Classification: (72) Inventors; and A61K 38/08 (2006.01) A61P 1/16 (2006.01) (75) Inventors/Applicants (for US only): NEWELL, Martha, A61K 33/06 (2006.01) A61P 37/08 (2006.01) Karen [US/US]; 3930 Mariposa Street, Colorado A61P 31/18 (2006.01) A61P 33/06 (2006.01) Springs, CO 80907 (US). NEWELL, Evan [US/US]; 400 Ravenswood Avenue, #4, Menlo Park, CA 84025 (US). (21) International Application Number: KELEDJIAN, Haig [US/US]; 2290 Huntington Drive, PCT/US2009/004328 Suite 200, San Marino, CA 9 1108 (US). AGAD- (22) International Filing Date: JANYAN, Michael [US/US]; 7371-100 Seabluff Drive, 23 July 2009 (23.07.2009) Huntington Beach, CA 92648 (US). (25) Filing Language: English (74) Agent: LOCKHART, Helen, C ; Wolf, Greenfield & Sacks, P.C , Federal Reserve Plaza, 600 Atlantic Avenue, (26) Publication Language: English Boston, MA 02210-2206 (US). (30) Priority Data: (81) Designated States (unless otherwise indicated, for every 61/135,942 25 July 2008 (25.07.2008) US kind of national protection available): AE, AG, AL, AM, (71) Applicants (for all designated States except US): THE AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, REGENTS OF THE UNIVERSITY OF COLORADO CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, [US/US]; 1800 Grant Street, 8th Floor, Denver, CO DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 80203 (US). VIRAL GENETICS, INC. [US/US]; 2290 HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, Huntington Drive, Suite 200, San Marino, CA 9 1108 KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (US). ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, [Continued on next page] (54) Title: CLIP INHIBITORS AND METHODS OF MODULATING IMMUNE FUNCTION (57) Abstract: The invention relates to methods for modulating the immune function through targeting of CLIP molecules. The result is wide range of new therapeutic regimens for treating, inhibiting the development of, or otherwise dealing with, a multitude of illnesses and conditions, including autoimmune disease, allergic disease trans plant and cell graft rejection, cancer, bacterial infection, HIV infec tion, and AIDS. NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, Published: SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, -,; - i i u uv i — without international search report andA to be repubhshedA T T T T Λ T IΓ n o T Γ T Λ 7 1 r r TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. ., . e -,( w) upon receip t oj that report (/Rr >ul 4Λ8O.2 gj (84) Designated States (unless otherwise indicated, for every _ wUh sequence listingpart of description (Rule 5.2(a)) kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (48) Date of publication of this corrected version: ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, 8 April 2010 TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, τ , .. ES, FI, FR, GB GR, HR, HU, IE, IS IT LT LU, LV (15) fo tion about Correcti on: MC, MK, kr, NL, NO, PL, PT, RO, SE, SI, SK, SM, See N θtlCe ° f 8 Apnl 201 ° TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). CLIP INHIBITORS AND METHODS OF MODULATING IMMUNE FUNCTION RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 1 19 from U.S. provisional application serial number 61/135,942, filed July 25, 2008, the contents of which are incorporated herein in their entirety. BACKGROUND OF INVENTION Major Histocompatibility Complex (MHC)-encoded molecules are key components of T cell immunity. The significance of these molecules as tissue compatibility molecules was first observed in the late 1930s. Peter Gorer and George Snell observed that when tumors were transplanted from a genetically non-identical member of the same species, the tumors were always rejected, but when tumors were transplanted between genetically identical members of the same species, the tumor would "take" and would grow in the syngeneic animal. The genetic complex responsible for the rejection was subsequently found to be a series of genes that encode protein products known as Major Histocompatibility molecules. These genes, also known as immune response or IR genes, and their protein products are responsible for all graft rejection. There are two types of MHC molecules: MHC class I and MHC class II. All nucleated cells express cell surface MHC class I. A subset of specialized cells express class II MHC. Included in the specialized, professional antigen-presenting cells (APCs) are B cells, macrophages, microglia, dendritic cells, and Langerhans cells among others. As stated above, B cells express MHC class II. Once antigen has been bound by the antigen receptor on the B cell, the antigen and its receptor are engulfed into an endosomal compartment. This compartment fuses with another compartment known as the lysosome. The B cell is very efficient at breaking down antigens into smaller parts and loading the parts into MHC class II in the lysosome. The MHC is then trafficked to the cell surface where the B cell can effectively "show" the antigen to a CD4+ T cell. The activated CD4 cell is also called a helper cell and there are two major categories, ThI and Th2. The MHC molecules are tightly protected in the endosomal/lysosomal compartments to insure that only antigens for which we need a response get presented to T cells. MHC class II molecules, prior to antigen loading, are associated with a molecule called invariant chain, also known as CD74. The invariant chain is associated with MHC class II (and recently shown to be associated with certain MHC class I molecules) prior to antigen loading into the antigen binding grooves of the MHC molecules. As antigen is processed, the invariant chain gets cleaved by proteases within the compartment. First an end piece is removed, and then another known as CLIP (class II invariant chain associated peptide). CLIP fills the groove that will ultimately hold the antigen until the antigen is properly processed. For a detailed review of the invariant chain, including CLIP, see Matza et al. (2003), incorporated herein in its entirety. Despite the fact that this "chaperone" role for invariant chain and CLIP has been identified, the full impact of these molecules on immune signaling and activation has yet to be determined. SUMMARY OF INVENTION The invention is based at least in part on the discovery that CLIP inhibitors are useful in the treatment of disorders such as HIV infection, autoimmune disease and tissue graft rejection. The invention in some aspects is a method for treating a disorder associated with γδT cell expansion, activation and/or effector function by contacting a CLIP molecule expressing cell with a CLIP inhibitor in an effective amount to interfere with γδT cell expansion, activation and/or effector function by the CLIP molecule expressing cell. In some embodiments the γδT cell is a vγ9vδ2 T cell. Disorders associated with γδT cell expansion and/or activation include, for instance autoimmune disease, HIV infection, and cell, tissue and graft rejection. The CLIP molecule expressing cell is a B cell in some embodiments. In other embodiments the CLIP compound expressing cell is a neuron, an oligodendrocyte, a microglial cell, or an astrocyte. In yet other embodiments the CLIP compound expressing cell is a heart cell, a pancreatic beta cell, an intestinal epithelial cell, a lung cell, an epithelial cell lining the uterine wall, and a skin cell. When the cell is a B cell, the method may further involve contacting the B cell with an anti-HLA class I or II antibody in an effective amount to kill the B cell. The invention in some aspects is a composition of an isolated MHC class II CLIP inhibitor comprising a peptide of SEQ ID NO 49, 58, 59, 61, 62, 66, 67, 68, 69, 76, 77, 78, 81, 82, 86, 89, 90, 92, 104, 109, 110, 112, 117, 128, 129, 133, 136, 140, 141, 144, 146, 148, 149, 150, 154, 156, 157, 161, 162, 164, 168, 171, 172, 175, 177, 179, 186, 187, 188, 190, 191, 192, 196, 197, 201, 204, 205, 210, 217, 218, 220, 221, 222, 226, 227, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 3 11, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, or a variant thereof and a carrier. The MHC class II CLIP inhibitor may be synthetic. In some embodiments the composition also includes an adjuvant, such as aluminum hydroxide or aluminum phosphate, calcium phosphate, mono phosphoryl lipid A, ISCOMs with Quil-A, and/or Syntex adjuvant formulations (SAFs) containing the threonyl derivative or muramyl dipeptide. In other embodiments the composition includes an anti-HIV agent and/or an antigen. A method for treating a disease by administering to a subject a composition of a CLIP inhibitor and a pharmaceutically acceptable carrier is also provided. In some aspects the CLIP inhibitor is a MHC class II CLIP inhibitor. In these aspects the disease may be a viral infection, such as HIV, herpes, hepatitis A, B, or C, CMV, EBV, or Borrelia burgdorferi, a parasitic infection such as Leishmania or malaria, allergic disease, Alzheimer's disease, autoimmune disease or a cell or tissue graft.
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