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WO 2U11/119773 Al (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 Χ t it t n n 29 September 2011 (29.09.2011) WO 2U1 1/1 19773 Al (51) International Patent Classification: FOGLER, William E. [US/US]; 3 Halifax Court, C12N 15/00 (2006.01) Rockville, Maryland 20850 (US). (21) International Application Number: (74) Agents: McCABE, Kevin W. et al; Sterne, Kessler, PCT/US201 1/029682 Goldstein & Fox, P.L.L.C., 1100 New York Avenue, N.W., Washington, District of Columbia 20005-3934 (22) International Filing Date: (US). 23 March 201 1 (23.03.201 1) (81) Designated States (unless otherwise indicated, for every (25) Filing Language: English kind of national protection available): AE, AG, AL, AM, (26) Publication Langi English AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (30) Priority Data: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 61/3 16,792 23 March 2010 (23.03.2010) US HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, 61/366,731 22 July 2010 (22.07.2010) US KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, 61/43 1,364 10 January 201 1 (10.01 .201 1) u s ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (72) Inventors; and NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (71) Applicants : ROETH, Jeremiah F. [US/US]; 3915 En- SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, glewood C , Blacksburg, Virginia 24060 (US). REED, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. Charles C. [US/US]; 134 Skippack Creek Road, Souder- (84) Designated States (unless otherwise indicated, for every ton, Pennsylvania 18964 (US). CUTHBERTSON, Bran¬ kind of regional protection available): ARIPO (BW, GH, don [US/US]; 374 Parkway Trails Circle, Newland, Con GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, necticut 28657 (US). CHADA, Sunil [US/US]; 4007 Wa- ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, terview Court, Missouri City, Texas 77459 (US). TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, [Continued on nextpage] (54) Title: VECTORS CONDITIONALLY EXPRESSING THERAPEUTIC PROTEINS, HOST CELLS COMPRISING THE VECTORS, AND USES THEREOF (57) Abstract: This invention relates to the field of therapeutics. Most specifically, the invention pro Left A 5 1TR vides methods of generating conditionally expressing Ad5 mu 0-1 vectors for one or more immunomodulators under the E caps dati signal control of a gene expression modulation system in the / / SC3i-P9-stuf2 Txn Blocker presence of activating ligand and uses for therapeutic A p(R / 6xGal4RE purposes in animals. These vector may be provided to treat a variety of disorders, e.g., neoplastic disorders, c insert through direct injection or through in vitro engi insert neered cells, such as dendritic cells. Synthetic Minimal promoter TATA box ~SPL-1 UT -1 A 5 u 9.2-16 Kozak 4 - lL-12 '*MCV IRES P35 L 2 SV40pA Late SV40 early pA stuf A ' V. UbC (short) promoter \ \ 5'UTR (p !yG) \ Kozak \ UV-VP16-2 UV- X o -c c 5utr ires (m t) Kozak UV-GAL4DBD-V2 FIG, 1 o w o 2011/119773 Ai II II II I III I1 1 I II III II llll III II I II EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, before the expiration of the time limit for amending the LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, claims and to be republished in the event of receipt of SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, amendments (Rule 48.2(h)) GW, ML, MR, NE, SN, TD, TG). with sequence listing part of description (Rule 5.2(a)) Published: VECTORS CONDITIONALLY EXPRESSING THERAPEUTIC PROTEINS, HOST CELLS COMPRISING THE VECTORS, AND USES THEREOF BACKGROUND OF THE INVENTION Field of the Invention This invention relates to the field of gene therapy for the treatment of diseases and disorders, for example, cancer, lysosomal storage disorders, ocular diseases, liver diseases, or infectious diseases. In one embodiment, the invention provides the engineering of immune cells or therapy support cells (TSC) to express one or more therapeutic proteins (e.g., immunomodulators) and use of the cells as therapeutics. In another embodiment, the invention includes a vector, e.g., adenovirus, for conditional expression of therapeutic proteins (e.g., immunodulators) disclosed herein, e.g., IL-12, TNF-alpha and methods of using such vectors. Background Interleukin-12 (IL-12) is a member of the type I cytokine family involved in contributing to a number of biological processes including, but not limited to, protective immune response and suppression of tumorigenesis (Abdi et al, 2006; Adorini, 1999; Adorini, 2001; Adorini et al, 2002; Adorini et al, 1996; Akhtar et al, 2004; Akiyama et al, 2000; Al-Mohanna et al, 2002; Aliberti et al, 1996; Allavena et al, 1994; Alii and Khar, 2004; Alzona et al, 1996; Amemiya et al, 2006; Araujo et al, 2001; Arulanandam et al, 1999; Athie et al, 2000; Athie-Morales et al, 2004; Bertagnolli et al, 1992; Bhardwaj et al, 1996; Biedermann et al, 2006; Brunda and Gately, 1994; Buchanan et al, 1995; Romani et al, 1997; Rothe et al, 1996; Satoskar et al, 2000; Schopf et al, 1999; Thomas et al, 2000; Tsung et al, 1997; Wolf et al, 1994; Yuminamochi et al, 2007). A growing body of evidence suggests that IL-12 may be a promising target to control human diseases (e.g., cancer). Despite the fact that IL-12 remains promising as a cancer therapeutic agent based on its potent supportive activity on Type-1 anti-tumor NK cells, CD4+ T cells and CD8+ T cells (Trinchieri, 2003), the reported toxicity of recombinant human IL-12 (rhIL-12) in patients (Atkins et al, 1997), together with limited sources of GMP-giade rhIL-12 for clinical application, have prevented successful IL-12-based therapeutic approaches. Thus it seems reasonable that gene therapy approaches may represent safer, more tenable treatment options. Indeed, phase I clinical trials implementing intra- or peri-tumoral delivery of recombinant viral- (Sangro et al, 2004; Triozzi et al, 2005) or plasmid-based IL-12 cDNA (Heinzerling et al, 2005), or L- 2 gene modified autologous fibroblasts (Kang et al, 2001) have been found safe and well-tolerated. [0004] However, objective clinical responses in patients with melanoma or a diverse range of carcinomas receiving these gene therapies have been rare, variable, transient and largely focused at the site of treatment (Heinzerling et al, 2005; Kang et al, 2001; Sangro et al, 2004; Triozzi et al, 2005). In cases where disease resolution was partial or complete, increased frequencies of tumor-infiltrating lymphocytes (Heinzerling et al, 2005; Sangro et al, 2004) and elevated levels of circulating tumor-specific CD8+ T cells (Heinzerling et al, 2005) have been noted, consistent with the improved cross-priming of antigen-specific T cells in these patients. [0005] Since the cross-priming of specific T cells is best accomplished by dendritic cells (DC) that serve as a natural but regulated source of IL-12 (Berard et al, 2000), recent reports of the superior pre-clinical efficacy of DC-based IL-12 gene therapy have been of great interest (Satoh et al, 2002; Tatsumi et al, 2003; Yamanaka et al, 2002). For example, it was shown that intratumoral (i.t.) injection of DC engineered to produce IL- 12p70 (via recombinant adenovirus infection) results in the dramatically improved cross- priming of a broadly-reactive, tumor-specific CD8+ T cell repertoire in concert with tumor rejection in murine models (Tatsumi et al, 2003). Given the previous use of a recombinant adenovirus encoding mIL-12 under a CMV-based promoter (rAd.cIL12, (Tatsumi et al, 2003)), engineered DC production of IL-12 was constitutive, hence the immunologic impact of this cytokine early within the tumor lesion and later within tumor- draining lymph nodes could not be resolved with regards to therapeutic outcome. Thus, a need exists for DC engineered for conditional expression of IL-12 for the purpose of regulating both the level of transgene expression and the timing of the transgene activation. The invention provides a promising therapeutic outcome for the use of such cells. [0006] Many of the therapeutic proteins currently under investigation in pre-clinical or clinical trials do not exhibit harmful side effects when present in a patient prior to expression of the nucleic acid sequence in the host cell of the patient or the proper physiologic context. Some proteins, however, such as tumor necrosis factor (TNF), cause adverse effects when expressed outside the normal physiologic tissues or context (e.g., exposed to non-target tissues). Systemic or even local administration of this protein is extremely toxic to many non-tumor cell types, potentiating anaphylaxis and cachexia. In addition, prolonged exposure to TNF-alpha may yield profoundly different cellular responses than acute stimulations. For these reasons, safe and effective TNF-alpha therapies against cancer have remained elusive. [0007] In view of the problems associated with gene expression of genes through vector compositions containing the protein encoded by the nucleic acid sequence of interest in, there remains a need for an improved transfer vector compositions to be used for direct injection or for use in cell based therapies. [0008] Lysosomal storage diseases (LSDs) represent a class of inherited genetic disorders that can currently be treated only by protein therapeutics, in the form of enzyme replacement therapy.
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