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WO 2018/208728 Al 15 November 2018 (15.11.2018) W !P O PCT

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WO 2018/208728 Al 15 November 2018 (15.11.2018) 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 2018/208728 Al 15 November 2018 (15.11.2018) W !P O PCT (51) International Patent Classification: MEE, Michael Travis; 55 Cambridge Parkway, 8th Floor, C12N 15/88 (2006.01) A61K 47/00 (2006.01) Suite 800E, Cambridge, MA 02142 (US). RUBENS, Ja¬ C12N 5/00 (2006.01) cob Rosenblum; 55 Cambridge Parkway, 8th Floor, Suite 800E, Cambridge, MA 02142 (US). STEBBINS, Nathan (21) International Application Number: Wilson; 55 Cambridge Parkway, 8th Floor, Suite 800E, PCT/US20 18/0315 15 Cambridge, MA 02142 (US). GIBSON, Molly Krisann; (22) International Filing Date: 55 Cambridge Parkway, 8th Floor, Suite 800E, Cambridge, 08 May 2018 (08.05.2018) MA 02142 (US). GORDON, Neal Francis; 55 Cambridge Parkway, 8th Floor, Suite 800E, Cambridge, MA 02142 (25) Filing Language: English (US). ZHANG, Bo; 55 Cambridge Parkway, 8th Floor, (26) Publication Language: English Suite 800E, Cambridge, MA 02142 (US). TRUDEAU, Kyle Marvin; 55 Cambridge Parkway, 8th Floor, Suite (30) Priority Data: 800E, Cambridge, MA 02142 (US). HARTLEY, Brigham 62/502,998 08 May 2017 (08.05.2017) US Jay; 55 Cambridge Parkway, 8th Floor, Suite 800E, Cam 62/575,147 20 October 2017 (20.10.2017) US bridge, MA 02142 (US). PUTIRI, Tamar Rose; 55 Cam 62/595,862 07 December 20 17 (07. 12.20 17) US bridge Parkway, 8th Floor, Suite 800E, Cambridge, MA (71) Applicant: FLAGSHIP PIONEERING, INC. [US/US]; 02142 (US). MAHDAVIANI, Kiana; 55 Cambridge Park 55 Cambridge Parkway, 8th Floor, Suite 800E, Cambridge, way, 8th Floor, Suite 800E, Cambridge, MA 02142 (US). MA 02 142 (US). DOBBIN, Matthew Milnes; 55 Cambridge Parkway, 8th Floor, Suite 800E, Cambridge, MA 02142 (US). (72) Inventors: VON MALTZAHN, Geoffrey A.; 55 Cam bridge Parkway, 8th Floor, Suite 800E, Cambridge, MA (74) Agent: YANG, Peter et al; Lando & Anastasi, LLP, River 02142 (US). MILWID, John Miles; 55 Cambridge Park front Office Park, One Main Street, Suite 1100, Cambridge, way, 8th Floor, Suite 800E, Cambridge, MA 02142 (US). MA 02142 (US). (54) Title: COMPOSITIONS FOR FACILITATING MEMBRANE FUSION AND USES THEREOF 0.0 ' 00 C mp B -A :: ER Green -A l Fig. 1 o00 00 (57) Abstract: In some aspects, fusosome compositions and methods are described herein that comprise membrane enclosed prepara- tions, comprising a fusogen. In some embodiments, the fusosome can the target cell, thereby delivering complex biologic agents to the target cell cytoplasm. [Continued on nextpage] WO 2018/208728 Al llll II II 11III II I 11III I III II I III II I II (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, 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, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, 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, 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). Declarations under Rule 4.17: — as to applicant's entitlement to applyfor and be granted a patent (Rule 4.1 7(H)) — as to the applicant's entitlement to claim the priority of the earlier application (Rule 4.17(in)) Published: COMPOSITIONS FOR FACILITATINGMEMBRANE FUSION AND USES THEREOF RELATED APPLICATIONS This application claims priority to U.S. Serial No. 62/502,998 filed May 8, 2017, U.S. Serial No. 62/575,147 filed October 20, 2017, and U.S. Serial No. 62/595,862 filed December 7, 2017, each of which is incorporated herein by reference in its entirety. BACKGROUND Complex biologies are promising therapeutic candidiates for a variety of diseases. However, it is difficult to deliver large biologic agents into a cell because the plasma membrane acts as a barrier between the cell and the extracellular space. There is a need in the art for new methods of delivering complex biologies into cells in a subject. SUMMARY OF THE INVENTION Membrane fusion is required in biological processes as diverse as fertilization, development, immune response and tumorigenesis. The present disclosure provides fusion-based methods of delivering complex biologic cargo to cells. Thus, the present disclosure provides, in some aspects, a fusosome comprising a lipid bilayer, a lumen surrounded by the lipid bilayer, and a fusogen. The fusosome can be used, e.g., for delivery of a cargo in the lumen or lipid bilayer to a target cell. Cargo includes, e.g., therapeutic proteins, nucleic acids, and small molecules. The present disclosure provides, in some aspects, a fusosome comprising: (a) a lipid bilayer, (b) a lumen (e.g., comprising cytosol) surrounded by the lipid bilayer; (c) an exogenous or overexpressed fusogen, e.g., wherein the fusogen is disposed in the lipid bilayer, wherein the fusosome is derived from a source cell; and wherein the fusosome has partial or complete nuclear inactivation (e.g., nuclear removal). In some embodiments, one or more of the following is present: i) the fusosome comprises or is comprised by a cytobiologic; ii) the fusosome comprises an enucleated cell; iii) the fusosome comprises an inactivated nucleus; iv) the fusosome fuses at a higher rate with a target cell than with a non-target cell, e.g., by at least at least 1%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 2-fold, 3-fold, 4- fold, 5-fold, 10-fold, 20-fold, 50-fold, or 100-fold, e.g., in an assay of Example 54; v) the fusosome fuses at a higher rate with a target cell than with other fusosomes, e.g., by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20- fold, 50-fold, or 100-fold, e.g., in an assay of Example 54; vi) the fusosome fuses with target cells at a rate such that an agent in the fusosome is delivered to at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, of target cells after 24, 48, or 72 hours, e.g., in an assay of Example 54; vii) the fusogen is present at a copy number of at least, or no more than, 10, 50, 100, 500, 1,000, 2,000, 5,000, 10,000, 20,000, 50,000, 100,000, 200,000, 500,000, 1,000,000, 5,000,000, 10,000,000, 50,000,000, 100,000,000, 500,000,000, or 1,000,000,000 copies, e.g., as measured by an assay of Example 29; viii) the fusosome comprises a therapeutic agent at a copy number of at least, or no more than, 10, 50, 100, 500, 1,000, 2,000, 5,000, 10,000, 20,000, 50,000, 100,000, 200,000, 500,000, 1,000,000, 5,000,000, 10,000,000, 50,000,000, 100,000,000, 500,000,000, or 1,000,000,000 copies, e.g., as measured by an assay of Example 43 or 156; ix) the ratio of the copy number of the fusogen to the copy number of the therapeutic agent is between 1,000,000:1 and 100,000:1, 100,000:1 and 10,000:1, 10,000:1 and 1,000:1, 1,000:1 and 100:1, 100:1 and 50:1, 50:1 and 20:1, 20:1 and 10:1, 10:1 and 5:1, 5:1 and 2:1, 2:1 and 1:1, 1:1 and 1:2, 1:2 and 1:5, 1:5 and 1:10, 1:10 and 1:20, 1:20 and 1:50, 1:50 and 1:100, 1:100 and 1:1,000, 1:1,000 and 1:10,000, 1:10,000 and 1:100,000, or 1:100,000 and 1:1,000,000; x) the fusosome comprises a lipid composition substantially similar to that of the source cell or wherein one or more of CL, Cer, DAG, HexCer, LPA, LPC, LPE, LPG, LPI, LPS, PA, PC, PE, PG, PI, PS, CE, SM and TAG is within 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75% of the corresponding lipid level in the source cell; xi) the fusosome comprises a proteomic composition similar to that of the source cell, e.g., using an assay of Example 42 or 155; xii) the fusosome comprises a ratio of lipids to proteins that is within 10%, 20%, 30%, 40%, or 50% of the corresponding ratio in the source cell, e.g., as measured using an assay of Example 49; xiii) the fusosome comprises a ratio of proteins to nucleic acids (e.g., DNA) that is within 10%, 20%, 30%, 40%, or 50% of the corresponding ratio in the source cell, e.g., as measured using an assay of Example 50; xiv) the fusosome comprises a ratio of lipids to nucleic acids (e.g., DNA) that is within 10%, 20%, 30%, 40%, or 50% of the corresponding ratio in the source cell, e.g., as measured using an assay of Example 5 1 or 159; xv) the fusosome has a half-life in a subject, e.g., in a mouse, that is within 1%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% of the half life of a reference cell, e.g., the source cell, e.g., by an assay of Example 75; xvi) the fusosome transports glucose (e.g., labeled glucose, e.g., 2-NBDG) across a membrane, e.g., by at least 1%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% more (e.g., about 11.6% more) than a negative control, e.g., an otherwise similar fusosome in the absence of glucose, e.g., as measured using an assay of Example 64; xvii) the fusosome comprises esterase activity in the lumen that is within 1%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 60%,
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