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WO 2018/231759 Al 20 December 2018 (20.12.2018) W !P O PCT

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WO 2018/231759 Al 20 December 2018 (20.12.2018) W !P O PCT (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 2018/231759 Al 20 December 2018 (20.12.2018) W !P O PCT (51) International Patent Classification: 199 Wolcott Road, Brookline, Massachusetts 02467 (US). A61K38/1 7 (2006.01) C07K 16/28 (2006.01) DOLINSKI, Brian; 1030 Massachusetts Avenue, Fourth A61K 39/39 (2006.01) C07K 19/00 (2006.01) Floor, Cambridge, Massachusetts 02138 (US). KULKA- RNI, Abhishek; 360 Tappan Street #3, Brookline, Massa (21) International Application Number: chusetts 02445 (US). INNISS, Mara, Christine; 11 High PCT/US20 18/037005 land Ave. Unit 2, Beverly, Massachusetts 01915 (US). SUN, (22) International Filing Date: Dexue; 1030 Massachusetts Avenue, Fourth Floor, Cam 12 June 2018 (12.06.2018) bridge, Massachusetts 02138 (US). LI, Dan, Jun; 1030 Massachusetts Avenue, Fourth Floor, Cambridge, Mass (25) Filing Language: English achusetts 02138 (US). OLINGER, Grace, Y.; 22 W a (26) Publication Language: English ter Street #43 1, Cambridge, Massachusetts 02141 (US). HELLER, Scott, Francis; 559 Plain St., Stoughton, Mass Data: (30) Priority achusetts 02072 (US). 62/5 18,078 12 June 2017 (12.06.2017) US 62/523,850 23 June 2017 (23.06.2017) US (74) Agent: WARD, Donna, T. et al; DT Ward, P.C., 142A 62/523,862 23 June 2017 (23.06.2017) US Main Street, Groton, Massachusetts 01450 (US). 62/555,3 13 07 September 2017 (07.09.2017) US (81) Designated States (unless otherwise indicated, for every (71) Applicant: OBSIDIAN THERAPEUTICS, INC. kind of national protection available): AE, AG, AL, AM, [US/US]; 1030 Massachusetts Avenue, Fourth Floor, Cam AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, bridge, Massachusetts 02138 (US). CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (72) Inventors: SURI, Vipin; 3 Coolidge Road, Belmont, Mass HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, achusetts 02478 (US). DELABARRE, Byron; 50 Can- KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, dia Street, Arlington, Massachusetts 02474 (US). GLADS¬ MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, TONE, Michael, N.; 400 Technology Square, 10th Floor, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, Cambridge, MA 02139 (US). RICHARDSON, Celeste; (54) Title: PDE5 COMPOSITIONS AND METHODS FOR IMMUNOTHERAPY (57) Abstract: The present invention relates to compositions and meth Figure i 9 ods for the regulated and controlled expression of proteins. Methods for inducing anti-cancer immune responses in a subject are also provided. C A Γ 2 8 2 4 2 0 o 1 6 < o 1 2 8 4 Tadalafil (nM) o o [Continued on nextpage] WO 2018/231759 Al llll II II 11III II I I III 11III 111III II I II SC, 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. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published: — with international search report (Art. 21(3)) — with amended claims (Art. 19(1)) — with sequence listing part of description (Rule 5.2(a)) PDE5 COMPOSITIONS AND METHODS FOR IMMUNOTHERAPY CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to 62/518,078 filed on June 12, 2017 entitled PDE5 Tunable Protein Regulation, 62/523,850 filed on June 23, 2017 entitled PDE5 Tunable Protein Regulation, 62/523,862 filed on June 23, 2017 entitled PDE5 Compositions and Methods for Immunotherapy, 62/555,313 filed on September 7, 2017 entitled PDE5 Tunable Protein Regulation, the contents of each of which are herein incorporated by reference in their entirety. REFERENCE TO SEQUENCE LISTING [0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 2095_1003PCT_SL.txt, created on June 12, 2018, which is 18,074,972 bytes in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety. FIELD OF THE INVENTION [0003] The present invention relates to tunable biocircuit systems for the development of controlled and/or regulated therapeutic systems. In particular, regulatable biocircuits containing destabilizing domains (DD) derived from mutant human cGMP-specific phosphodiesterase type 5 (PDE5) are disclosed. The present invention also relates to compositions and methods for immunotherapy. [0004] Provided in the present invention include polypeptides of biocircuit systems, effector modules, stimulus response elements (SREs) and immunotherapeutic agents, polynucleotides encoding the same, vectors and cells containing the polypeptides and/or polynucleotides for use in cancer immunotherapy. In one embodiment, the compositions comprise destabilizing domains (DDs) which tune protein stability. BACKGROUND OF THE INVENTION [0005] Safe and effective gene therapy requires tightly regulated expression of a therapeutic transgenic product (e.g., the protein product). Similarly, the analysis of gene function in development, cell differentiation and other physiological activities requires the controllable expression of a protein under investigation. However, current technologies do not allow titration of levels of target protein induced or kinetics of induction. Inadequate exogenous and/or endogenous gene control is a critical issue in numerous settings including ex vivo and in vivo gene therapy. This lack of tunability also makes it difficult to safely express proteins with narrow or uncertain therapeutic windows or those requiring more titrated, controlled or transient expression. [0006] One approach to regulated protein expression or function is the use of Destabilizing Domains (DDs). Destabilizing domains are small protein domains that can be appended to a payload such as a protein of interest (POI). DDs render the attached protein of interest (POI) unstable in the absence of a DD-binding ligand such that the protein is rapidly degraded by the ubiquitin-proteasome system of the cell (Stankunas, K., et al., (2003). Mol. Cell 12, 1615-1624; Banaszynski, L.A., et al., (2006) Cell; 126(5): 995-1004; reviewed in Banaszynski, L.A., and Wandless, T.J. (2006) Chem. Biol. 13, 11-21; Iwamoto, M., et al. (2010). Chem Biol. 17(9):981-8; Egeler, E.L.et al. (201 1). J Biol Chem. 286(36):3 1328-36; and Rakhit R, Navarro R, Wandless TJ (2014) Chem Biol. Sep 18;21(9): 1238-52; Navarro, R . et al. (2016) ACS Chem Biol. 11(8): 2101-2104). In some cases, the protein of interest is not completely processed and may not be secreted or presented on the membrane in the absence of DD-binding ligand (Sellmeyer et al., (2012), doi.org/10.1371/journal.pone.0043297; the contents of which are incorporated by reference in their entirety). However, when a specific small molecule ligand binds its intended DD as a ligand binding partner, the instability is reversed and protein function is restored or, in some cases, processing is restored and the protein of interest is presented on the membrane or secreted. Such a system is herein referred to as a biocircuit, with the canonical DD-containing biocircuit described above being the prototypical model biocircuit [0007] It is believed that improvements of biocircuits, including those containing DDs can form the basis of a new class of cell and gene therapies that employ tunable and temporal control of gene expression and function. Such novel moieties are described by the present inventors as stimulus response elements (SREs) which act in the context of an effector module to complete a biocircuit arising from a stimulus and ultimately producing a signal or outcome. When properly formatted with a polypeptide payload, and when activated by a particular stimulus, e.g., a small molecule, biocircuit systems can be used to regulate transgene and/or protein levels either up or down by perpetuating a stabilizing signal or destabilizing signal. This approach has many advantages over existing methods of regulating protein function and/or expression, which are currently focused on top level transcriptional regulation via inducible promoters. [0008] The present invention provides novel protein domains, in particular, destabilizing domains (DDs) derived from mutant human cGMP-specific phosphodiesterase type 5 (PDE5), particularly the catalytic domain of human PDE5, that display small molecule dependent stability, and the biocircuit systems and effector modules comprising such DDs. Methods for tuning transgene functions using the same are also provided. [0009] Cancer immunotherapy aims to eradicate cancer cells by rejuvenating the tumoricidal functions of tumor-reactive immune cells, predominantly T cells. Strategies of cancer immunotherapy including the recent development of checkpoint blockade, adoptive cell transfer (ACT) and cancer vaccines which can increase the anti-tumor immune effector cells have produced remarkable results in several tumors. [0010] The impact of host anti-tumor immunity and cancer immunotherapy is impeded by three major hurdles: 1) low number of tumor antigen-specific T cells due to clonal deletion; 2) poor activation of innate immune cells and accumulation of tolerogenic antigen-presenting cells in the tumor microenvironment; and 3) formation of an immunosuppressive tumor microenvironment. Particularly, in solid tumors the therapeutic efficacy of immunotherapeutic regimens remains unsatisfactory due to lack of an effective an anti-tumor response in the immunosuppressive tumor microenvironment.
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