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(2006.01) A61k 47/64 ( 1 (51) International Patent Classification: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, A61K 38/16 (2006.01) A61K 47/64 (2017.01) UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, C07K 14/21 (2006.01) C12N 9/10 (2006.01) TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, C07K 14/28 (2006.01) 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, (21) International Application Number: TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, PCT/US20 19/02 1474 KM, ML, MR, NE, SN, TD, TG). (22) International Filing Date: 08 March 2019 (08.03.2019) Published: — with international search report (Art. 21(3)) (25) Filing Language: English — with sequence listing part of description (Rule 5.2(a)) (26) Publication Language: English (30) Priority Data: 62/640,188 08 March 2018 (08.03.2018) US 62/640,194 08 March 2018 (08.03.2018) US 62/640,168 08 March 2018 (08.03.2018) US (71) Applicant: APPLIED MOLECULAR TRANSPORT INC. [US/US]; 1 Tower Place, Suite 850, South San Fran¬ cisco, California 94080 (US). (72) Inventors; and (71) Applicants: LIU, Keyi [US/US]; 1Tower Place, Suite 850, South San Francisco, California 94080 (US). MACKAY, Julia Dawn [—/US]; 1 Tower Place, Suite 850, South San Francisco, California 94080 (US). FENG, Weijun [—/US]; 1 Tower Place, Suite 850, South San Francisco, Califor¬ nia 94080 (US). HUNTER, Thomas Carl [—/US]; 1Tow¬ er Place, Suite 850, South San Francisco, California 94080 (US). (72) Inventor: MRSNY, Randall J.; 1 Tower Place, Suite 850, South San Francisco, California 94080 (US). (74) Agent: MEYER, Jan-Philip; WILSON SONSINI GOODRICH & ROSATI, 650 Page Mill Road, Palo Alto, California 94304 (US). (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, (54) Title: TOXIN-DERIVED DELIVERY CONSTRUCTS FOR ORAL DELIVERY (57) Abstract: The present disclosure relates to isolated non-naturally occurring delivery constructs comprising a bacterial toxin-de¬ rived delivery construct coupled to a biologically active therapeutic cargo; wherein the delivery construct is capable of delivering the biologically active cargo via transcytosis transport across an epithelial cell; and wherein the delivery construct does not comprise a bacterial toxin-derived translocation domain or a bacterial toxin-derived catalytic (cytotoxic) domain. TOXIN-DERIVED DELIVERY CONSTRUCTS FOR ORAL DELIVERY CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Application Nos. 62/640,168 filed March 8, 2018; 62/640,188 filed March 8, 2018; and 62/640,194 filed March 8, which applications are incorporated herein by reference in their entirety for all purposes. SEQUENCE LISTING [0002] The instant application contains a Sequence Listing in the form of a “paper copy” (PDF File) and a file containing the referenced sequences (SEQ ID NO: 1 - SEQ ID NO: 221) in computer readable form (ST25 format text file) which is submitted herein. The Sequence Listing is shown using standard three letter code for amino acids, as defined in 37 C.F.R. 1.822. Said ASCII copy, created on March 8, 2019, is named 40566-71 l_60l_SL.txt and is 350,816 bytes in size. BACKGROUND [0003] The gut epithelium has thwarted efforts to orally administer large molecule biologies because proteins cannot diffuse across the barrier or sneak through the tight junctions. When they are taken up by endocytosis — the only route left to them — they are typically degraded in lysosomes rather than being transported into the body. This inability to be readily absorbed across the intestinal epithelium continues to be a limiting factor in developing commercially viable oral formulations of these agents. The most common solution is to use systemic administration, but that can often create considerable side effects and reduce patient convenience that negatively affects compliance. INCORPORATION BY REFERENCE [0004] All references disclosed herein are hereby incorporated by reference in their entirety for all purposes. SUMMARY [0005] The present disclosure provides methods and composition for transport and/or delivery of a cargo molecule to certain location(s) within a cell (e.g., a supranuclear location) or across a cell (e.g., epithelial cell), either in vitro or in vivo (e.g., in a rodent or a human). Such cargo can be directed to a set of location(s) by coupling it to a carrier molecule. Such carrier molecule can interact with unique receptors both on the cell surface and intracellularly for the targeted delivery of the cargo. Various such carrier, cargos, and uses thereof are described herein. [0006] The disclosure provides an isolated delivery construct that can comprise: a carrier derived from a domain I of an exotoxin and lacking a domain II, a domain lb and a domain III of the exotoxin; coupled to a heterologous cargo. The carrier can consist essentially of the domain I of the exotoxin. The delivery construct can deliver the heterologous cargo according to one or more of the following: across an epithelial cell via transcytosis; to the basal side of the epithelial cell; to a supranuclear region within the epithelial cell; or to the interior of the epithelial cell via endocytosis. In some aspects, the carrier is configured to deliver a heterologous cargo to the basal side of an epithelial cell. [0007] The disclosure provides an isolated delivery construct that can comprise: a chimeric carrier comprising an intracellular epithelial targeting domain; coupled to a heterologous cargo. [0008] The disclosure provides an isolated delivery construct that can comprise: a chimeric carrier comprising a supranuclear epithelial targeting domain; coupled to the heterologous cargo. [0009] The disclosure provides an isolated delivery construct that can comprise: a carrier coupled to a heterologous cargo, wherein the carrier interacts with one or more of ribophilin 1, SEC24, CK-8, TMEM132, GRP75, ERGIC-53, or perlecan, and does not display interaction with one or more of a clathrin or GPR78, or a combination thereof. The interaction can be a selective interaction. The interaction can be a pH-dependent interaction. The interaction of the carrier with the one or more of ribophilin 1, SEC24, CK-8, TMEM132, GRP75, ERGIC-53, or perlecan can occur on a surface of the epithelial cell, in the interior of an epithelial cell, or a combination thereof. The delivery of the heterologous cargo across the epithelial cell can occur in vitro from the apical surface of the epithelial cell to a basolateral compartment. The delivery of the heterologous cargo can occur in vitro from the apical surface of the epithelial cell to the interior of the epithelial cell. The delivery of the heterologous cargo can occur in vitro from the apical surface of the epithelial cell to the supranuclear region within the epithelial cell. The interaction of the carrier with the one or more of ribophilin 1, SEC24, CK-8,TMEMT32, GRP75, ERGIC-53, or perlecan, or the combination thereof can occur in vitro on the apical surface of the epithelial cell, in the interior of the epithelial cell, or a combination thereof. The epithelial cell can be a polarized epithelial cell. The polarized epithelial cell can be part of a monolayer of polarized epithelial cells. The polarized epithelial cell can be from a rodent or a human. The polarized epithelial cell can be from a human. The human polarized epithelial cell can be a human polarized gut epithelial cell. The human polarized gut epithelial cell can be a Caco-2 cell. The delivery of the heterologous cargo across the epithelial cell can occur in vivo from a gut of a subject to a basolateral compartment of a subject. The delivery of the heterologous cargo can occur in vivo from a gut of a subject to the interior of the epithelial cell of a subject. The delivery of the heterologous cargo can occur in vivo from a gut of a subject to the supranuclear region within the epithelial cell of a subject. The interaction of the carrier with the one or more of ribophilin 1, SEC24, CK-8,TMEMl32, GRP75, ERGIC-53, and perlecan, or the combination thereof, can occur in vivo on the apical surface of the epithelial cell of a subject, in the interior of the epithelial cell of the subject, or a combination thereof. The subject can be a rodent or a human. The subject can be a human and affected by one or more of the following: inflammatory bowel disease, psoriasis, bacterial sepsis, systemic lupus erythematosus (SLE), pemphigus vulgaris, myasthenia gravis, hemolytic anemia, thrombocytopenia purpura, Grave’s disease, Sjogren’s disease, dermatomyositis, Hashimoto’s disease, polymyositis, inflammatory bowel disease, multiple sclerosis (MS), diabetes mellitus, rheumatoid arthritis, scleroderma, non- Hodgkin’s lymphomas, Hodgkin’s lymphoma, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, multiple myeloma, carcinomas of the bladder, kidney ovary, cervix, breast, lung, nasopharynx, malignant melanoma, rituximab resistant NHL or leukemia, diabetes, obesity, diabetes as a consequence of obesity, hyperglycemia, dyslipidemia, hypertriglyceridemia, syndrome X, insulin resistance, impaired glucose tolerance (IGT), diabetic dyslipidemia, hyperlipidemia, growth hormone deficiency (GHD), Turner syndrome (TS), Noonan syndrome, Prader-Willi syndrome, short stature homeobox-containing gene (SHOX) deficiency, chronic renal insufficiency, or idiopathic short stature short bowel syndrome.
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