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WO 2018/151820 Al 23 August 2018 (23.08.2018) W !P O PCT

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WO 2018/151820 Al 23 August 2018 (23.08.2018) 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 2018/151820 Al 23 August 2018 (23.08.2018) W !P O PCT (51) International Patent Classification: Declarations under Rule 4.17: A61K 39/395 (2006.01) C07K 14/705 (2006.01) — as to applicant's entitlement to apply for and be granted a (21) International Application Number: patent (Rule 4.1 7(H)) PCT/US20 18/00003 1 — as to the applicant's entitlement to claim the priority of the earlier application (Rule 4.17(Hi)) (22) International Filing Date: 16 February 2018 (16.02.2018) Published: — with international search report (Art. 21(3)) (25) Filing Language: English — before the expiration of the time limit for amending the (26) Publication Langi English claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) (30) Priority Data: 62/459,846 16 February 2017 (16.02.2017) 62/491,626 28 April 2017 (28.04.2017) 62/501,620 04 May 2017 (04.05.2017) (71) Applicant: ELSTAR THERAPEUTICS, INC. [US/US]; 840 Memorial Drive, 4th Floor, Cambridge, MA 02139 (US). (72) Inventors: LOEW, Andreas; 476 Shawmut Avenue, Apt. 6, Boston, MA 021 18 (US). VASH, Brian, Edward; 303 3rd St Unit 717, Cambridge, MA 02 142 (US). MAIOCCO, Stephanie, J.; 215 Massachusetts Ave, Apt 15, Arlington, MA 02474 (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, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). o 00 00 (54) Title: MULTIFUNCTIONAL MOLECULES COMPRISING A TRIMERIC LIGAND AND USES THEREOF o (57) Abstract: Disclosed herein are novel multifunctional, e.g., bifunctional, or trifunctional, molecules (e.g., fusion polypeptides or nucleic acids) that include a trimeric ligand, and optionally, an immunoglobulin constant domain, as well as methods of making and using the multifunctional molecules, e.g., for treating cancer. MULTIFUNCTIONAL MOLECULES COMPRISING A TRIMERIC LIGAND AND USES THEREOF RELATED APPLICATION This application claims priority to U.S. Serial No. 62/459846 filed February 16, 2017 and U.S. Serial No. 62/501620 filed May 4, 2017, the content of each of which is incorporated herein by reference in its entirety. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on February 16, 2018, is named E2070-7004WO_SL.txt and is 522,047 bytes in size. BACKGROUND Multifunctional molecules comprising a trimeric ligand, e.g., one, two or three tumor necrosis factor superfamily (TNFSF) or TNFSF-like members, and, optionally, a dimerization module, e.g., an immunoglobulin constant region, are disclosed. SUMMARY OF THE INVENTION The present application discloses, at least in part, a novel multifunctional molecule (also interchangeably referred to herein as "multispecific molecule") comprising a trimeric ligand, e.g., one, two or three trimeric ligands. In embodiments, the trimeric ligand includes three monomer molecules, e.g., wherein two of the monomer molecules are coupled, e.g., covalently linked, to one another, and the third monomer molecule is non-covalently associated to the other two monomer molecules. In some embodiments, the multifunctional molecule comprises two, three or more trimeric ligands that are the same or different. In some embodiments, the trimeric ligand in the multifunctional molecule is a homotrimer, e.g., is composed of the same monomer molecules, or a heterotrimer, e.g., is composed of two or three different monomer molecules. In some embodiments, the trimeric ligand is a member of the tumor necrosis factor superfamily (TNFSF) or TNFSF-like members, or a combination of TNFSF- and TNFSF-like monomers. In some embodiments, the multifunctional molecule comprises a trimeric ligand (e.g., one or more (e.g., one, two or three) trimeric ligands), wherein said trimeric ligand comprises three monomer molecules, (e.g., three monomer molecules of the tumor necrosis factor superfamily (TNFSF) or TNSF-like member, or a combination thereof), wherein two of the monomer molecules are coupled, e.g., covalently linked, to one another, and the third monomer molecule is non-covalently associated to the other two monomer molecules. In some embodiments, the multifunctional molecule further comprises a dimerization module (e.g., an immunoglobulin constant domain (e.g., an Fc or a dimerization module comprising a non-immunoglobulin dimerization domain, e.g., a TCRa constant domain and a TCRp constant domain)). In some embodiments, the multifunctional molecule further comprises one or more other binding specificities or functionalities chosen from one, two or more of: a targeting moiety, e.g., a tumor targeting moiety; an immune cell engager (e.g., chosen from one, two, three, or all of an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager); and/or a cytokine molecule. In some embodiments, the multifunctional molecule comprises one trimeric ligand, two trimeric ligands, or three trimeric ligands. In an embodiment, the multifunctional molecule comprises any of the configurations depicted in FIG3. 1lA-1 1C, e.g., mullispecific molecules attached to a dimerization module, e.g., an immunoglobulin constant domain. In embodiments, A, B, C and D, are coupled to, e.g., covalently linked, to a heterodimeric Fc domain, see Fig. 11A. In other embodiments, A, B, C and D, are coupled to, e.g., covalently linked, to a homodimeric Fc domain, see Fig. 1IB. In other embodiments, A, B, C and D, covalently linked to a heterodimeric heavy and light variable region constant domains (e.g., a Fab CHI and a Fab CL), see e.g., FIG. 11C. In one embodiment, the multifunctional molecule comprises a dimerization module comprising an immunoglobulin heavy chain constant region (e.g., an Fc region), e.g., a heterodimeric heavy chain constant region (e.g., a knob-in-hole heterodimer) as illustrated below: In some embodiments, the multifunctional molecule comprises any of the configurations depicted in FIGs. 1lA-1 1C or any of the configurations depicted in FIGs. 1lA-1 1C wherein the dimerization domain does not contain a disulfide bond. In some embodiments, A, B, C and D, are coupled to, e.g., covalently linked, to a heterodimeric or a homodimeric dimerization domain (e.g., an immunoglobulin constant domain (e.g., an Fc or a dimerization module comprising a non-immunoglobulhi dimerization domain, e.g., a 'C a constant domain and a TCR-β constant domain)). In some embodiments, A, B, C and D, are coupled to, e.g., covalently linked, to a heterodimeric Fab heavy and light constant domains (e.g., a CHI domain and a CL domain). In some embodiments, the multifunctional molecule includes the following configuration: A, B-[dimerization module]-C, -D wherein: 1) the dimerization module comprises an immunoglobulin constant domain, e.g., a heavy chain constant domain (e.g., a homodimeric or heterodimeric heavy chain constant region, e.g., an Fc region), or a constant domain of an immunoglobulin Fab region; or a dimerization module comprising a non-immunoglobulin dimerization domain, e.g., a TCRa constant domain and a TCRP constant domain); 2) A, B, C, and D are independently absent; a trimeric ligand; a targeting moiety, e.g., a tumor targeting moiety; an immune cell engager; or a cytokine molecule, Provided that: i) at least one, two or three of A, B, C, and D comprises a trimeric ligand; ii) at least one of A, B, C, and D comprises a trimeric ligand, and any of the remaining A, B, C, and D comprises one, two or more of a targeting moiety, an immune cell engager, or a cytokine molecule; iii) at least two of A, B, C, and D comprise a trimeric ligand, and any of the remaining A, B, C, and D comprises one, or two of a targeting moiety, an immune cell engager, or a cytokine molecule; or iv) at least three of A, B, C, and D comprise a trimeric ligand, and any of the remaining A, B, C, and D is absent. In some embodiments, 1) A, B, C, and D are independently chosen from being absent; a trimeric ligand; a targeting moiety, e.g., a tumor targeting moiety; an immune cell engager; or a cytokine molecule, or a combination thereof, wherein: i) A is or comprises a trimeric ligand, and at least one, two or three of B, C, and D is or comprises a second trimeric ligand, a targeting moiety, an immune cell engager,
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