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Filing Date: (81) Designated States (Unless Otherwise Indicated, for Every 07 December 2018 (07 ( (51) International Patent Classification: o Flagship Pioneering Innovations V, Inc., 55 Cambridge A61K 47/46 (2006.01) A61K 38/00 (2006.01) Parkway 8th Floor, Cambridge, MA 02142 (US). A61K 47/24 (2006.01) A61K 31/7105 (2006.01) (74) Agent: KOYFMAN, Hannah, R. et al.; Lando & Anastasi, (21) International Application Number: LLP, Riverfront Office Park, One Main Street, Suite 1100, PCT/US20 18/064571 Cambridge, MA 02142 (US). (22) International Filing Date: (81) Designated States (unless otherwise indicated, for every 07 December 2018 (07. 12.2018) kind of national protection av ailable) . AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, (25) Filing Language: English CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, (26) Publication Language: English 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, (30) Priority Data: KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, 62/595,841 07 December 2017 (07. 12.2017) US MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (71) Applicant: FLAGSHIP PIONEERING INNO¬ OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, VATIONS V, INC. [US/US]; 55 Cambridge Parkway, 8th SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, Floor, Cambridge, MA 02142 (US). TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (72) Inventors: VON MALTZAHN, Geoffrey, A.; c/o Flag¬ (84) Designated States (unless otherwise indicated, for every ship Pioneering Innovations V, Inc., 55 Cambridge Park¬ kind of regional protection available) . ARIPO (BW, GH, way 8th Floor, Cambridge, MA 02142 (US). MILWID, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, John, Miles; c/o Flagship Pioneering Innovations V, Inc., UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 55 Cambridge Parkway 8th Floor, Cambridge, MA 02142 TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (US). RUBENS, Jacob, Rosenblum; c/o Flagship Pioneer¬ EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, ing Innovations V, Inc., 55 Cambridge Parkway 8th Floor, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, Cambridge, MA 02142 (US). MEE, Michael, Travis; c/ TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, o Flagship Pioneering Innovations V, Inc., 55 Cambridge KM, ML, MR, NE, SN, TD, TG). Parkway 8th Floor, Cambridge, MA 02142 (US). STEB- BINS, Nathan, Wilson; c/o Flagship Pioneering Innova¬ Published: tions V, Inc., 55 Cambridge Parkway 8th Floor, Cam¬ — with international search report (Art. 21(3)) bridge, MA 02142 (US). GIBSON, Molly, Krisann; c/ — before the expiration of the time limit for amending the o Flagship Pioneering Innovations V, Inc., 55 Cambridge claims and to be republished in the event of receipt of Parkway 8th Floor, Cambridge, MA 02142 (US). GOR¬ amendments (Rule 48.2(h)) DON, Neal, Francis; c/o Flagship Pioneering Innovations V, Inc., 55 Cambridge Parkway 8th Floor, Cambridge, MA 02142 (US). ZHANG, Bo; c/o Flagship Pioneering Inno¬ vations V, Inc., 55 Cambridge Parkway 8th Floor, Cam¬ bridge, MA 02142 (US). TRUDEAU, Kyle, Marvin; c/ o Flagship Pioneering Innovations V, Inc., 55 Cambridge Parkway 8th Floor, Cambridge, MA 02142 (US). HART¬ LEY, Brigham, Jay; c/o Flagship Pioneering Innovations V, Inc., 55 Cambridge Parkway 8th Floor, Cambridge, MA 02142 (US). PUTIRI, Tamar, Rose; c/o Flagship Pioneer¬ ing Innovations V, Inc., 55 Cambridge Parkway 8th Floor, Cambridge, MA 02142 (US). MAHDAVIANI, Kiana; c/ o Flagship Pioneering Innovations V, Inc., 55 Cambridge Parkway 8th Floor, Cambridge, MA 02142 (US). SHAH, Jagesh, Vijaykumar; c/o Flagship Pioneering Innovations V, Inc., 55 Cambridge Parkway 8th Floor, Cambridge, MA 02142 (US). CONNOR, Michael; c/o Flagship Pioneer¬ ing Innovations V, Inc., 55 Cambridge Parkway 8th Floor, Cambridge, MA 02142 (US). JONES, Peter, Anthony; c/ (54) Title: CYTOBIOLOGICS AND THERAPEUTIC USES THEREOF (57) Abstract: This disclosure provides, e.g., cytobiologic compositions and methods of use thereof. The cytobiologics can be used, e.g. , to deliver a protein or nucleic acid to a target cell. CYTOBIOLOGICS AND THERAPEUTIC USES THEREOF RELATED APPLICATIONS This application c priority to U.S. Serial No. 62/595,841 filed December 7, 2017, which is incorporated herein by reference in its entirety. BACKGROUND An enucleated cell retains numerous biological properties but loses its ability to divide. SUMMARY OF THE INVENTION The present disclosure provides, in some aspects, cytobiologics, e.g., enucleated cells or cells having an inactivated nucleus. The cytobiologic can be used, e.g., for delivery of a cargo in the lumen or lipid bilayer of the cytobiologic to a target cell. Cargo includes, e.g., therapeutic proteins, nucleic acids, and small molecules. The present disclosure provides, in some aspects, a purified cytobiologic composition comprising a cytobiologic from a source cell, e.g., a mammalian source cell, e.g., a human source cell, wherein the cytobiologic has partial or complete nuclear inactivation (e.g., nuclear removal), and wherein one or more of: i) the cytobiologic comprises an exogenous agent, e.g., a therapeutic agent, e.g., at a copy number of at least 1,000 copies, e.g., as measured by an assay of Example 31; ii) the cytobiologic comprises a lipid 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 75% of the corresponding lipid level in the source cell; iii) the cytobiologic comprises a proteomic composition similar to that of the source cell, e.g., using an assay of Example 30; iv) the cytobiologic is capable of signal transduction, e.g., transmitting an extracellular signal, e.g., AKT phosphorylation in response to insulin, or glucose (e.g., labeled glucose, e.g., 2-NBDG) uptake in response to insulin, e.g., by at least 10% more than a negative control, e.g., an otherwise similar cytobiologic in the absence of insulin, e.g., using an assay of Example 48; v) the cytobiologic targets a tissue, e.g., liver, lungs, heart, spleen, pancreas, gastrointestinal tract, kidney, testes, ovaries, brain, reproductive organs, central nervous system, peripheral nervous system, skeletal muscle, endothelium, inner ear, or eye, when administered to a subject, e.g., a mouse, e.g., wherein at least 0.1%, or 10%, of the cytobiologics in a population of administered cytobiologics are present in the target tissue after 24 hours, e.g., by an assay of Example 71; or vi) the source cell is selected from a neutrophil, a granulocyte, a mesenchymal stem cell, a bone marrow stem cell, an induced pluripotent stem cell, an embryonic stem cell, a myeloblast, a myoblast, a hepatocyte, or a neuron e.g., retinal neuronal cell. The present disclosure also provides, in some aspects, a purified cytobiologic composition comprising a cytobiologic, wherein: i) the cytobiologic is from a source cell, e.g., a mammalian source cell, and ii) the cytobiologic is an enucleated cell or a cell having partial or complete nuclear inactivation (e.g., nuclear removal). The present disclosure also provides, in some aspects, a purified cytobiologic composition comprising a cytobiologic and an exogenous agent, e.g., a therapeutic agent, wherein: iii) the cytobiologic is from a source cell, e.g., a mammalian source cell, and iv) the cytobiologic is an enucleated cell or a cell having partial or complete nuclear inactivation (e.g., nuclear removal). The present disclosure also provides, in some aspects, a purified cytobiologic composition, e.g., a frozen cytobiologic composition, comprising a cytobiologic, wherein: i) the cytobiologic is from a source cell, e.g., a mammalian source cell, and ii) the cytobiologic is an enucleated cell or a cell having partial or complete nuclear inactivation (e.g., nuclear removal), which is at a temperature of less than 4, 0, -4, -10, -12, -16, -20, -80, or -160 C. In some embodiments, the cytobiologic is not from an erythroid cell or a platelet. In some embodiments, one or more of the following is present: i) the cytobiologic is not from an erythroid cell or a platelet; ii) the cytobiologic comprises an enucleated cell; iii) the cytobiologic comprises an inactivated nucleus; iv) the cytobiologic comprises an exogenous agent or a therapeutic agent (e.g., an exogenous 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 31; v) the cytobiologic 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; vi) the cytobiologic comprises a proteomic composition similar to that of the source cell, e.g., using an assay of Example 30; vii) the cytobiologic 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 37; viii) the cytobiologic 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 38; ix) the cytobiologic comprises a ratio of lipids to nucleic acids (e.g., DNA) that is within 10%, 20%, 30%, 40%, or 50%
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