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WO 2015/073587 A2 21 May 2015 (21.05.2015) P O P CT (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 2015/073587 A2 21 May 2015 (21.05.2015) P O P CT (51) International Patent Classification: Noubar, B.; c/o Rubius Therapeutics, Inc., 1 Memorial B82Y5/00 (201 1.01) Drive, 7th Floor, Cambridge, MA 02142 (US). (21) International Application Number: (74) Agents: YEE, Gene et al; Fenwick & West LLP, 801 PCT/US2014/065304 California Street, Mountain View, CA 94041 (US). (22) International Filing Date: (81) Designated States (unless otherwise indicated, for every 12 November 2014 (12.1 1.2014) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, English (25) Filing Language: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (26) Publication Language: English DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (30) Priority Data KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 61/962,867 18 November 2013 (18. 11.2013) US MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, 61/919,432 20 December 201 3 (20. 12.2013) US PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 61/973,764 1 April 2014 (01.04.2014) us SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 61/991,3 19 9 May 2014 (09.05.2014) us TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 62/006,829 2 June 2014 (02.06.2014) us 62/006,832 2 June 2014 (02.06.2014) us (84) Designated States (unless otherwise indicated, for every 62/006,825 2 June 2014 (02.06.2014) us kind of regional protection available): ARIPO (BW, GH, 62/025,367 16 July 2014 (16.07.2014) us GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 62/059,100 2 October 2014 (02. 10.2014) us TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (71) Applicant: RUBIUS THERAPEUTICS, INC. [US/US]; DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, 1 Memorial Drive, 7th Floor, Cambridge, MA 02142 (US). LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (72) Inventors: KAHVEJIAN, Avak; c/o Rubius Therapeutics, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Inc., 1 Memorial Drive, 7th Floor, Cambridge, MA 02142 GW, KM, ML, MR, NE, SN, TD, TG). (US). MATA-FINK, Jordi; c/o Rubius Therapeutics, Inc., Published: 1 Memorial Drive, 7th Floor, Cambridge, MA 02 142 (US). ROUND, John; c/o Rubius Therapeutics, Inc., 1 Memorial — without international search report and to be republished Drive, 7th Floor, Cambridge, MA 02142 (US). BERRY, upon receipt of that report (Rule 48.2(g)) David, A.; c/o Rubius Therapeutics, Inc., 1 Memorial Drive, 7th Floor, Cambridge, MA 02142 (US). AFEYAN, (54) Title: SYNTHETIC MEMBRANE-RECEIVER COMPLEXES Fig 6 25 0 Cs ll only 2 0 !BSA+igG c ate ||BSA + IgG 1 15000 < 10000 liliiiiiil 1 5000 00 © !C binding (57) Abstract: Compositions comprising synthetic membrane -receiver complexes, methods of generating synthetic membrane-re o ceiver complexes, and methods of treating or preventing diseases, disorders or conditions therewith. SYNTHETIC MEMBRANE-RECEIVER COMPLEXES FIELD OF THE INVENTION [0001] The field of the invention is pharmaceutical compositions for the treatment of diseases and disorders. BACKGROUND [0002] The circulatory system permits blood and lymph circulation to transport, e.g., nutrients, oxygen, carbon dioxide, cellular waste products, hormones, cytokines, blood cells, and pathogens to and from cells in the body. Blood is a fluid comprising, e.g., plasma, red blood cells, white blood cells, and platelets that is circulated by the heart through the vertebrate vascular system. The circulatory system becomes a reservoir for many toxins and pathogenic molecules upon their introduction to or production by the body. The circulatory system also serves as a reservoir for cellular secretions or detritus from within the body. The perpetual or aberrant circulation and proliferation of such molecules and entities can drive disease and/or exacerbate existing conditions. [0003] The efficacy of therapeutic compositions that alleviate or prevent diseases and conditions associated with the circulatory system is often limited by their half-life, which is typically up to a few days. The short half-life often necessitates repeated injections and hospitalizations. It is thought that the short half-life may be due to both renal clearance, e.g., of proteins smaller than 60 kDa, and non-renal clearance, e.g., via liver excretion or immune- mediated removal. The activity of therapies is also often limited by an immune reaction elicited against them (see, e.g., Wang et al, Leukemia 2003, 17:1583). Several approaches are practiced in the art. [0004] One approach includes the use of "erythrocyte ghosts" that are derived from a hemolyzed red blood cell. To prepare erythrocyte ghosts, red blood cells undergo hypotonic lysis. The red blood cells are exposed to low ionic strength buffer causing them to burst. The resulting lysed cell membranes are isolated by centrifugation. The pellet of lysed red blood cell membranes is resuspended and incubated in the presence of the therapeutic agent, for example, such as an antibiotic or chemotherapeutic agent in a low ionic strength buffer. The therapeutic agent distributes within the cells. Erythrocyte ghosts and derivatives used to encapsulate payloads, such as therapeutic agents, can shield those payloads from the immune system, but the erythrocyte ghosts themselves are subject to rapid clearance by the reticulo endothelial system (see, e.g., Loegering et al. 1987 Infect Immun 55(9):2074). Erythrocyte ghosts also elicit an immune response in mammalian subjects. These vesicles are typically constituted of both lipids and proteins, including potentially high amounts of phosphatidylserine, which is normally found on the inner leaflet of the plasma membrane. This leads to potential immunological reactions in the recipient mammalian subjects. The undesirable effects seriously limit the potential for therapeutic applications of technologies based on erythrocyte ghosts. [0005] Another approach for drug encapsulation includes the use of exosomes. "Exosomes" include cell-derived vesicles that are present in many and perhaps all biological fluids, including blood, urine, and cultured medium of cell cultures. The reported diameter of exosomes is between 30 and 100 nm, which is larger than low-density lipoprotein (LDL), but smaller than, for example, red blood cells. Exosomes are either released from the cell when multivesicular bodies fuse with the plasma membrane or they are released directly from the plasma membrane. Exosome delivery methods require a better understanding of their biology, as well as the development of production, characterization, targeting and cargo- loading nanotechnologies. Attempts have been made to manufacture exosomes using human embryonic stem cell derived mesenchymal stem cells (hESC-MSCs). However, as hESC- MSCs are not infinitely expansible, large scale production of exosomes would require replenishment of hESC-MSC through derivation from hESCs and incur recurring costs for testing and validation of each new batch (Chen et al. 201 1 Journal of Translational Medicine 9:47). Clinical translation is also hindered by the lack of suitable and scalable nanotechnologies for the purification and loading of exosomes (Lakhal and Wood 201 1 BioEssays 33(10):737). Current ultracentrifugation protocols are commercially unreproducible, as they produce a heterogeneous mix of exosomes, other cellular vesicles and macromolecular complexes. Therefore, purification methods based on the use of specific, desired markers, such as the expression of a targeting moiety on the surface of the exosome, are required. In addition, siR A loading into exosomes is relatively inefficient and cost- ineffective, highlighting the need for the development of transfection reagents tailored for nanoparticle applications. Further, exosomes are rapidly cleared from circulation and substantially accumulate in the liver within 24 hours of administration (Ohno et al, 2013 Mol Therapy 21(1): 185), limiting their application for long-term drug delivery to the circulatory of a subject. [0006] Polyethylene glycol-coated liposomes are presently used as carriers for in vivo drug delivery. A "liposome" includes an artificially-prepared spherical vesicle composed of a lamellar phase lipid bilayer. The liposome can be used as a vehicle for administration of nutrients and pharmaceutical agents. Liposomes can be prepared by disrupting biological membranes, e.g., by sonication. Liposomes are often composed of phosphatidylcholine- enriched phospholipids and may also contain mixed lipid chains with surfactant properties such as egg phosphatidylethanolamine. A liposome design may employ surface ligands for attaching to a target, e.g., unhealthy tissue. Types of liposomes include the multilamellar vesicle (MLV), the small unilamellar liposome vesicle (SUV), the large unilamellar vesicle (LUV), and the cochleate vesicle. Liposomes as cariers of anthracycline antibiotics have been a subject of a great number of studies. As a result, liposome formulations of daunorubicin (DaunoXome™) and doxorubicin (Doxil™) are now commercially available. The pharmacokinetics of the liposomal forms of anthracycline antibiotics differ from that of their free forms in higher peak concentrations and longer circulations times of the drugs. The kinetics of DaunoXome and Doxil clearance from plasma is close to mono-exponential. The half-life of DaumoXome in patient plasma is on the order of a few hours. In Doxil, polyethylene glycol-coated liposomes are used. The immune system poorly recognizes such liposomes; therefore the plasma half-life of Doxil is in the order of tens of hours.
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