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WO 2018/161000 Al 07 September 2018 (07.09.2018) W !P O PCT

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WO 2018/161000 Al 07 September 2018 (07.09.2018) 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 2018/161000 Al 07 September 2018 (07.09.2018) W !P O PCT (51) International Patent Classification: setts 02138 (US). SUN, Dexue; 1030 Massachusetts Av A 61K 38/1 6 (2006 .01) C12N 7/04 (2006 .01) enue, Fourth Floor, Cambridge, Massachusetts 02138 A 61K 38/1 7 (2006 .01) C12N 15/867 (2006 .0 1) (US). DELABARRE, Byron; 50 Candia Street, Arlington, A 61K 38/44 (2006.01) C12N 15/861 (2006.01) Massachusetts 02474 (US). BALAKRISHNAN, Vijaya; CI2Q 1/26 (2006.01) 142A Main Street, Groton, Massachusetts 01450 (US). DOLINSKI, Brian; 1030 Massachusetts Avenue, Fourth (21) International Application Number: Floor, Cambridge, Massachusetts 02138 (US). INNISS, PCT/US20 18/0207 18 Mara Christine; 11 Highland Ave. Unit 2, Beverly, Mass (22) International Filing Date: achusetts 01915 (US). OLINGER, Grace Y.; 22 Water 02 March 2018 (02.03.2018) Street #43 1, Cambridge, Massachusetts 02141 (US). (25) Filing Language: English (74) Agent: WARD, Donna T. et al; DT WARD, P.C., 142A Main Street, Groton, Massachusetts 01450 (US). (26) Publication Language: English (81) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of national protection available): AE, AG, AL, AM, 62/466,603 03 March 2017 (03.03.2017) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, 62/484,047 11 April 2017 ( 11.04.2017) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, 62/542,400 08 August 2017 (08.08.2017) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (71) Applicant: OBSIDIAN THERAPEUTICS, INC. HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, [US/US]; 1030 Massachusetts Avenue, Fourth Floor, Cam KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, bridge, Massachusetts 02138 (US). MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (72) Inventors: SURI, Vipin; 3 Coolidge Road, Belmont, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, Massachusetts 02478 (US). LI, Dan Jun; 1030 Mass TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. achusetts Avenue, Fourth Floor, Cambridge, Massachu (54) Title: DHFR TUNABLE PROTEIN REGULATION Figure 9 O hDHF -f - H - 5 ( > F Y 22 ) ( DII R {Al 2SF,Y122I) Log OT.lnDHFRS.02i T- D N- 8 FR {G2 , ¥ 122I) llD FK (G21I, Y122I) 8.5 6 0 .5.5 · ·45 - 0 Log Log i 00 (57) Abstract: The present invention is related to compositions and methods for the regulated and controlled expression of proteins. [Continued on nextpage] WO 2018/161000 Al llll II II 11III II I I III 11II II II III II I II (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)) — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) — with sequence listing part of description (Rule 5.2(a)) DHFR TUNABLE PROTEIN REGULATION CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to US Provisional Patent Application No. 62/466,603, filed on March 3, 2017, entitled DHFR Tunable Protein Regulation, US Provisional Patent Application No. 62/484,047, filed on April 11, 2017, entitled DHFR Tunable Protein Regulation, and US Provisional Patent Application No. 62/542,400, filed on August 8, 2017, entitled DHFR Tunable Protein Regulation, the contents of each of which are herein incorporated by reference in their entireties. 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_1002PCT_SL.txt, created on March 2, 2018, which is 647,766 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 regulatable tunable biocircuit systems for the development of controlled and/or regulated therapeutic systems. In particular, regulatable biocircuits containing destabilizing domains (DD) derived from human dihydrofolate reductase protein (hDHFR) are disclosed. BACKGROUND OF THE INVENTION [0004] 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 the timing or levels of target protein induction. Inadequate exogenous and/or endogenous gene control is a critical issue in numerous gene therapy settings. This lack of tunability also makes it difficult to safely express proteins with narrow or uncertain therapeutic windows or those requiring more titrated or transient expression. [0005] 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 target protein of interest. DDs render the attached protein of interest 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). Mo/. 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., etal. (2010). ChemBiol. 17(9):981-8; Egeler, E.L.etal. (201 1). J Biol Chem. 286(36):31328-36; and Rakhit R, Navarro R, Wandless TJ (2014) Chem Biol. Sep 18;21(9): 1238-52; Navarro, etal. (2016) ACS Chem Biol. 11(8): 2101-2104). 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. Such a system is herein referred to as a biocircuit, with the canonical DD-containing biocircuit described above being the prototypical model biocircuit [0006] 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. [0007] The present invention provides novel protein domains, in particular destabilizing domains (DDs) derived from human dihydrofolate reductase (hDHFR) that display small molecule dependent stability, and the biocircuit systems and effector modules comprising such DDs. Methods fortuning transgene functions using the same are also provided. SUMMARY OF THE INVENTION [0008] The present invention provides novel protein domains displaying small molecule dependent stability. Such protein domains are called destabilizing domains (DDs). In the absence of its binding ligand, the DD is destabilizing and causes degradation of a payload fused to the DD (e.g., a protein of interest (POI), while in the presence of its binding ligand, the fused DD and payload can be stabilized, and its stability is dose dependent. These systems are further taught in co-owned U.S. Provisional Patent Application No. 62/320,864 filed April 11, 2016, 62/466,596 filed March 3, 2017 and the International Publication WO2017/180587 (the contents of each of which are herein incorporated by reference in their entirety). [0009] In some embodiments, the present invention provides biocircuit systems, effector modules and compositions comprising the DDs of the present invention. In one aspect, the biocircuit system is a DD biocircuit system. [0010] The present invention provides biocircuit systems which may comprise an effector module. The effector module may comprise a stimulus response element (SRE) and at least one payload. In some embodiments, the payload of the effector module may comprise a protein of interest which is attached, appended or associated with the SRE. In some embodiments, the SRE comprises a destabilizing domain. The destabilizing domain may comprise in whole or in part, a protein such as, but not limited to human dihydrofolate reductase (hDHFR), a hDHFR mutant and a DHFR variant. In one aspect, the DD may comprise, in whole or in part, a hDHFR mutant. [0011 ] In some embodiments, the effector module of the biocircuit may be responsive to one or more stimuli. [0012] In one aspect, the DHFR mutant may comprise one, two or three mutations relative to SEQ ID NO.
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