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(12) Patent Application Publication (10) Pub. No.: US 2010/0135901 A1 Moller Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2010/0135901 A1 Moller Et Al US 20100135901A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0135901 A1 Moller et al. (43) Pub. Date: Jun. 3, 2010 (54) COMBINATION THERAPY now abandoned, which is a continuation of application No. PCT/DK2004/000683, filed on Oct. 8, 2004. (76) Inventors: Niels Peter Hundahl Moller, (60) Provisional application No. 60/513,422, filed on Oct. Kobenhavn O (DK); Kresten Skak, 22, 2003, provisional application No. 60/569,566, Soborg (DK); Jorn Roland Miller, filed on May 10, 2004. Virum (DK) (30) Foreign Application Priority Data Correspondence Address: WOODCOCKWASHIBURN LLP Oct. 17, 2003 (DK) ............................. PA2OO3O1529 CIRA CENTRE, 12TH FLOOR, 2929 ARCH May 4, 2004 (DK) ............................. PA2004OO707 STREET PHILADELPHIA, PA 19104-2891 (US) Publication Classification (51) Int. Cl. (21) Appl. No.: 12/637,109 A6II 5L/00 (2006.01) A638/20 (2006.01) (22) Filed: Dec. 14, 2009 A6IP35/00 (2006.01) (52) U.S. Cl. ....................................... 424/1.11; 424/85.2 Related U.S. Application Data (57) ABSTRACT (63) Continuation of application No. 12/112,452, filed on Apr. 30, 2008, now abandoned, which is a continuation The invention provides combination treatments with IL-21, of application No. 1 1/404,733, filed on Apr. 14, 2006, analogues and derivatives thereof. US 2010/0135901 A1 Jun. 3, 2010 COMBINATION THERAPY cells have been shown to kill some types of tumor cells via KIR ligand dependent activation. CROSS-REFERENCE TO RELATED PATENT 0007. The immunology involved in cancer disease APPLICATIONS includes a variety of different cells derived from the immune system. Compounds which stimulate Such responses may be 0001. This patent application is a continuation of U.S. used in combination to provide an improved response to patent application Ser. No. 12/112,452 filed on Apr. 30, 2008, tumor treatment. which is a continuation of U.S. patent application Ser. No. 0008 Interleukin 21 (IL-21) has been shown to affect a 1 1/404.733, filed on Apr. 14, 2006, now abandoned, which is number of different cells of the immune system. Of particular a continuation of International Patent Application PCT/ interest is the observed activation of cytotoxic T lymphocytes DK2004/000683 (published as WO 2005/037306), filed Oct. (CTLs) and NK cells. Both cell types are known to be criti 8, 2004 (and designating the US) and claims the benefit cally involved in combating tumors. Thus, the presence of (under 35 USC S119) of U.S. Provisional Patent Application intratumoral T lymphocytes is correlated with improved Nos. 60/513,422 and 60/569,566, filed Oct. 22, 2003 and May clinical outcome for a number of different cancers (Zhang et 10, 2004, respectively, as well as Danish Patent Application al. 2003). However, tumor infiltrating lymphocytes (TILs) are Nos. PA 2003 01529 and PA 2004 00707, filed October 17, not always sufficiently activated to control tumor growth 2003 and May 4, 2004, respectively, the entirety of each of (Dunn et al. 2002: Kataki et al. 2002: Blohm et al. 2002: which is hereby incorporated by reference. Khong and Restifo 2002). Therefore, there is a need for improved therapeutic regimens for treatment, management FIELD OF THE INVENTION and prevention of cancers. Another important aspect of 0002 The present invention relates to IL-21, analogues or IL-21's effect on the immune system is the effect on B cells, derivatives and their use in combination with other pharma which can lead to an improved antibody response against ceutical compounds in treatment of cancer and viral infec tumor cells and virus-infected cells. The present invention tions. relates to combined use of IL-21 and other modalities for treatment and management of cancer and viral infections. BACKGROUND OF THE INVENTION 0009. Although synthetic therapeutic vaccines consisting 0003 Cytokines generally stimulate proliferation or dif of one or only few defined antigens have shown some utility ferentiation of cells of the hematopoietic lineage or partici in cancer treatment there is a strong need for improvement. pate in the immune and inflammatory response mechanisms The present invention also relates to a timely combination of of the body. The interleukins are a family of cytokines that (i) release of tumor antigens leading to an immune response mediate immunological responses by producing many cytok directed towards these tumor antigens and (ii) the unique ines and effect adaptive immunity to antigens. Mature T cells ability of IL-21 to induce a sustained cytotoxic T cell (CTL) can be activated, i.e., by an antigen or other stimulus, to response. The release of tumor antigens can be obtained with produce, for example, cytokines, biochemical signaling mol a number of different approaches including the following ecules, or receptors that further influence the fate of the T cell non-limiting examples: (i) conventional chemotherapy, (ii) population. induction of apoptosis, (ii) induction of tumor cell death via 0004 Cytokines produced by the T cell have been classi interference with the blood supply to the tumor, (iv) interfer fied as type 1 and type 2 (Kelso, A. Immun. Cell Biol. 76:300 ence with growth factor stimulation and signal transduction. 317, 1998). Type 1 cytokines include interleukin 2 (IL-2), IFN-Y, LTO, and are involved in inflammatory responses, SUMMARY OF THE INVENTION viral immunity, intracellular parasite immunity and allograft 0010. In one aspect, the present invention provides com rejection. Type 2 cytokines include IL-4, IL-5, IL-6, IL-10 positions comprising a combination of a first component and IL-13, and are involved in humoral responses, helminth selected from the group consisting of (a) human IL-21, (b) an immunity and allergic response. Shared cytokines between analogue of IL-21, and (c) a derivative of IL-21; and a second Type 1 and 2 include IL-3, GM-CSF and TNF-C. There is component comprising a radio-pharmaceutical selected from Some evidence to suggest that Type 1 and Type 2 producing T the group consisting of Cesium-137, Iridium-192, Ameri cell populations preferentially migrate into different types of cium-241, Gold-198, Cobalt-57, Copper-67, Technetium-99, inflamed tissue. Iodide-123, Iodid-131 and Indium-111. Another aspect of Mature T cells can be activated, i.e., by an antigen or other invention provides compositions comprising a combination stimulus, to produce, for example, cytokines, biochemical of a first component selected from the group consisting of (a) signaling molecules, or receptors that further influence the human IL-21, (b) an analogue of IL-21, and (c) a derivative of fate of the T cell population. IL-21; and a second component comprising a cell-cycle regu 0005 B cells can be activated via receptors on their cell lator or apoptosis-inducing agent, wherein the second com Surface including B cell receptor and other accessory mol ponent is selected from the group consisting of cdc-25, NSC ecules to perform accessory cell functions, such as production 66384, flavopiridol, 7-hyroxystaurosporine, roscovitine, and of cytokines and antibodies. BIBR1532 XOTO95. 0006 Natural killer (NK) cells have a common progenitor 0011 Further aspects include compositions comprising a cell with T cells and B cells, and play a role in immune combination of a first component selected from the group surveillance. NK cells, which comprise up to 15% of blood consisting of (a) human IL-21, (b) an analogue of IL-21, and lymphocytes, do not express antigen receptors, and therefore (c) a derivative of IL-21; and a second component comprising do not use MHC recognition as requirement for binding to a an anti-angiogenesis drug selected from the group consisting target cell. NK cells are involved in the recognition and killing of avastin, neovastat, thalidomide, PTK787, ZK222584, of certain tumor cells and virally infected cells. In vivo, NK ZD-6474, SU6668, PD547,632 VEGF-Trap, CEP-7055, cells are believed to require activation, however, in vitro, NK NM-3, and SU 11248. US 2010/0135901 A1 Jun. 3, 2010 0012. In another aspect, the present invention provides kaemia (other), liver, liver (secondary), lung, lung (second compositions comprising a combination of a first component ary), lymph nodes (secondary), lymphoma (hodgkin's), lym selected from the group consisting of (a) human IL-21, (b) an phoma (non-hodgkin’s), melanoma, mesothelioma, analogue of IL-21, and (c) a derivative of IL-21; a second myeloma, ovary, pancreas, penis, prostate, skin, soft tissue component comprising IFN-O, and a third component com sarcomas, Stomach, testes, thyroid, unknown primary tumor, prising thymopentin. vagina, Vulva, womb (uterus). 0013 Another aspect provides compositions comprising a 0020 Soft tissue tumors include Benign schwannoma combination of a first component selected from the group Monosomy, Desmoid tumor, Lipo-blastoma, Lipoma, Uter consisting of (a) human IL-21, (b) an analogue of IL-21, and ine leiomyoma, Clear cell sarcoma, Dermatofibrosarcoma, (c) a derivative of IL-21; a second component comprising Ewing sarcoma, Extraskeletal myxoid chondrosarcoma, cis-platin ; and a third component comprising IFN-C. Also, Liposarcoma myxoid, Liposarcoma, well differentiated, embodied are compositions that further comprise atamoxifen Alveolar rhabdomyosarcoma, and Synovial sarcoma. component or a Carmustine component. Variations of the 0021 Specific bone tumor include Nonossifying Fibroma, compositions can include further additions to the composi Unicameral bone cyst, Enchon-droma, Aneurysmal bone tion of decarbazine
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