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(51) International Patent Classification: C07K 16/28 (2006.01

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(51) International Patent Classification: C07K 16/28 (2006.01 ( 1 (51) International Patent Classification: Declarations under Rule 4.17: C07K 16/28 (2006.01) — as to applicant's entitlement to apply for and be granted a (21) International Application Number: patent (Rule 4.17(H)) PCT/US20 19/022284 — as to the applicant's entitlement to claim the priority of the earlier application (Rule 4.17(iii)) (22) International Filing Date: 14 March 2019 (14.03.2019) Published: — without international search report and to be republished (25) Filing Language: English upon receipt of that report (Rule 48. 2(g)) (26) Publication Language: English (30) Priority Data: 62/642,689 14 March 2018 (14.03.2018) US (71) Applicant: ELSTAR THERAPEUTICS, INC. [US/US]; 840 Memorial Drive, 4th floor, Cambridge, MA 02139 (US). (72) Inventors: LOEW, Andreas; 840 Memorial Drive, 4th floor, Cambridge, MA 02139 (US). LAMBERTO, Ilar- ia; 840 Memorial Drive, 4th floor, Cambridge, MA 02139 (US). HERRMANN, John, Leonard; 840 Memorial Dri¬ ve, 4th floor, Cambridge, MA 02139 (US). VASH, Brian, Edward; 840 Memorial Drive, 4th floor, Cambridge, MA 02139 (US). (74) Agent: COLLAZO, Diana, M. et al.; Lando & Anastasi, LLP, Riverfront Office Park, One Main Street, Suite 1100, Cambridge, MA 02142 (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, 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, Cl, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (54) Title: MULTIFUNCTIONAL MOLECULES AND USES THEREOF (57) Abstract: Multispecific molecules that include a first tumor-targeting moiety; a second tumor- targeting moiety; and one, two or all of: an immune cell engager (e.g., chosen from an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager); a cytokine molecule or a modulator of a cytokine molecule; and/or a stromal modifying moiety are disclosed. Additionally disclosed are nucleic acids encoding the same, methods of producing the aforesaid molecules, and methods of treating a cancer using the aforesaid molecules. MULTIFUNCTIONAL MOLECULES AND USES THEREOF RELATED APPLICATION This application claims priority to U.S. Serial No. 62/642,689 filed March 14, 2018, the content of which is incorporated herein by reference in its entirety. BACKGROUND Myeloproliferative neoplasms (MPNs) are a group of conditions that cause blood cells to grow abnormally in the bone marrow. Common myeloproliferative neoplasms include primary or idiopathic myelofibrosis (MF), essential thrombocytosis (ET), polycythemia vera (PV), and chronic myelogenous leukemia (CML). Primary myelofibrosis is a chronic blood cancer in which excessive scar tissue forms in the bone marrow and impairs its ability to produce normal blood cells. Given the ongoing need for improved treatment of myeloproliferative neoplasms such as myelofibrosis, new compositions and treatments targeting myeloproliferative neoplasms are highly desirable. SUMMARY OF THE INVENTION The disclosure relates, inter alia, to novel multispecific or multifunctional molecules that include (i) a first tumor-targeting moiety that binds to a first tumor antigen; and (ii) a second tumor-targeting moiety that binds to a second tumor antigen, wherein the first and second tumor antigens are each independently chosen from: CD34, CD41, G6B, P-selectin, Clec2, cKIT, FLT3, MPL, ITGB3, ITGB2, GP5, GP6, GP9, GP1BA, DSC2, FCGR2A, TNFRSF10A, TNFRSF10B, or TM4SF1. In some embodiments, the multifunctional molecule further comprises a third tumor-targeting moiety that binds to a third tumor antigen, wherein the third tumor antigen is chosen from: CD34, CD41, G6B, P-selectin, Clec2, cKIT, FLT3, MPL, ITGB3, ITGB2, GP5, GP6, GP9, GP1BA, DSC2, FCGR2A, TNFRSF10A, TNFRSF10B, or TM4SF1. In some embodiments, the multifunctional molecule further comprises one, two, or all of: (iii) an immune cell engager chosen from a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager; (iv) a cytokine molecule or a modulator of a cytokine molecule; and (v) a stromal modifying moiety. The terms “multispecific” or “multifunctional” are used interchangeably herein. Without wishing to be bound by theory, the multispecific or multifunctional molecules disclosed herein are expected to target (e.g., localize, bridge and/or activate) an immune cell (e.g., an immune effector cell chosen form an NK cell, a T cell, a B cell, a dendritic cell or a macrophage), at a target cell, e.g., a cancer cell, expressing the first, second, and/or third tumor antigens, and/or alter the tumor stroma, e.g., alter the tumor microenvironment near the cancer site. Increasing the proximity and/or activity of the immune cell using the multispecific molecules described herein is expected to enhance an immune response against the target cell (e.g., the cancer cell), thereby providing a more effective therapy (e.g., a more effective cancer therapy). Without being bound by theory, a targeted, localized immune response against the target cell (e.g., the cancer cell) is believed to reduce the effects of systemic toxicity of the multispecific molecules described herein. Accordingly, provided herein are, inter alia, multispecific molecules (e.g., multispecific or multifunctional antibody molecules) that include the aforesaid moieties, nucleic acids encoding the same, methods of producing the aforesaid molecules, and methods of treating a cancer using the aforesaid molecules. Accordingly, in one aspect, the disclosure features a multifunctional molecule (e.g., polypeptide or nucleic acid encoding the same) that includes: (i) a first tumor-targeting moiety that binds to a first tumor antigen, and (ii) a second tumor-targeting moiety that binds to a second tumor antigen, wherein: the first and second tumor antigens are each independently chosen from: CD34, CD41, G6B, P-selectin, Clec2, cKIT, FLT3, MPL, ITGB3, ITGB2, GP5, GP6, GP9, GP1BA, DSC2, FCGR2A, TNFRSF10A, TNFRSF10B, or TM4SF1. In some embodiments, the first tumor antigen is different from the second tumor antigen. In another aspect, the disclosure features a multifunctional molecule (e.g., polypeptide or nucleic acid encoding the same) that includes: (i) a first tumor-targeting moiety that binds to a first tumor antigen; (ii) a second tumor-targeting moiety that binds to a second tumor antigen; and one, two, or all of: (iii) an immune cell engager chosen from a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager; (iv) a cytokine molecule or a modulator of a cytokine molecule; and (v) a stromal modifying moiety, wherein: the first and second tumor antigens are each independently chosen from: CD34, CD41, G6B, P-selectin, Clec2, cKIT, FLT3, MPL, ITGB3, ITGB2, GP5, GP6, GP9, GP1BA, DSC2, FCGR2A, TNFRSF10A, TNFRSF10B, or TM4SF1. In some embodiments, the first tumor antigen is different from the second tumor antigen. In some embodiments, the multifunctional molecule further comprises (vi) a third tumor targeting moiety that binds to a third tumor antigen. In some embodiments, the third tumor antigen is chosen from: CD34, CD41, G6B, P-selectin, Clec2, cKIT, FLT3, MPL, ITGB3, ITGB2, GP5, GP6, GP9, GP1BA, DSC2, FCGR2A, TNFRSF10A, TNFRSF10B, or TM4SF1. In some embodiments, the third tumor antigen is different from the first or second tumor antigen. In some embodiments, the first and second tumor antigens are present on the same tumor cell. In some embodiments, the first and third tumor antigens are present on the same tumor cell. In some embodiments, the second and third tumor antigens are present on the same tumor cell. In some embodiments, the first, second, and third tumor antigens are present on the same tumor cell. In some embodiments, the first and second tumor antigens are present on different tumor cells. In some embodiments, the first and third tumor antigens are present on different tumor cells. In some embodiments, the second and third tumor antigens are present on different tumor cells. In some embodiments, the first, second, and third tumor antigens are present on different tumor cells. In some embodiments, the first, second, and/or third tumor antigens show higher expression in a tumor cell, e.g., a myeloproliferative neoplasm cell, than a non-tumor cell. In some embodiments, the expression of the first, second, and/or third tumor antigens in a tumor cell, e.g., a myeloproliferative neoplasm cell, is at least 1.5, 2, 4, 6, 8, or lO-fold higher than the expression of the first, second, and/or third tumor antigens in a non-tumor cell. In some embodiments, the multifunctional molecule preferentially binds to a tumor cell, e.g., a myeloproliferative neoplasm cell, over a non-tumor cell. In some embodiments, the binding between the multifunctional molecule and the tumor cell, e.g., a myeloproliferative neoplasm cell, is more than 10, 20, 30, 40, 50-fold greater than the binding between the multifunctional molecule and a non-tumor cell.
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