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WO 2018/144999 Al 09 August 2018 (09.08.2018) 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 2018/144999 Al 09 August 2018 (09.08.2018) W ! P O PCT (51) International Patent Classification: Lennart; c/o Orionis Biosciences NV, Rijvisschestraat 120, A61K 38/00 (2006.01) C07K 14/555 (2006.01) Zwijnaarde, B-9052 (BE). TAVERNIER, Jan; c/o Orionis A61K 38/21 (2006.01) C12N 15/09 (2006.01) Biosciences NV, Rijvisschestraat 120, Zwijnaarde, B-9052 C07K 14/52 (2006.01) (BE). (21) International Application Number: (74) Agent: ALTIERI, Stephen, L. et al; Morgan, Lewis & PCT/US2018/016857 Bockius LLP, 1111 Pennsylvania Avenue, NW, Washing ton, D.C. 20004 (US). (22) International Filing Date: 05 February 2018 (05.02.2018) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (25) Filing Language: English AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, (26) Publication Language: English 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, (30) Priority Data: HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, 62/454,992 06 February 2017 (06.02.2017) US KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (71) Applicants: ORIONIS BIOSCIENCES, INC. [US/US]; MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 275 Grove Street, Newton, MA 02466 (US). ORIONIS OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, BIOSCIENCES NV [BE/BE]; Rijvisschestraat 120, Zwij- SC, SD, SE, SG, SK, SL, SM, ST, SV, SY,TH, TJ, TM, TN, naarde, BE B-9052 (BE). TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (72) Inventors: KLEY, Nikolai; c/o Orionis Biosciences, Inc., (84) Designated States (unless otherwise indicated, for every 275 Grove Street, Newton, MA 02466 (US). ZABEAU, kind of regional protection available): ARIPO (BW, GH, (54) Title: TARGETED ENGINEERED INTERFERON AND USES THEREOF Figure 1A FNa2 15Ί -■ - CD20 positive t - CD20 negative . 5 1Q- 2 10° 102 104 concentration (ng m! (57) Abstract: The present invention relates to chimeric proteins comprising a consensus interferon as a signaling agent. In some embodiments, the consensus interferon is modified and comprises one or more mutations. In an embodiment, the modified consensus interferon comprise one or more mutations that reduce its affinity for IFNARl and comprises one or more mutations that reduce its affinity for IFNAR2. The present invention provides pharmaceutical compositions comprising the chimeric proteins and their use in 00 the treatment of various diseases. The present invention relates to a method for treating cancer, comprising administering an effective o amount of the chimeric protein. [Continued on nextpage] WO 2018/144999 Al llll II II 11III II I 11II III 11111III II I II 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). Published: — with international search report (Art. 21(3)) — with sequence listing part of description (Rule 5.2(a)) TARGETED ENGINEERED INTERFERON AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62/454,992 filed February 6, 2017, the content of which is hereby incorporated by reference in its entirety. FIELD The present invention relates, in part, to chimeric proteins comprising consensus interferon and their use as therapeutic agents. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on January 29, 2018, is named ORN- 024PC_ST25.txt and is 327,680 bytes in size. BACKGROUND Type I interferons (IFNs) form a family of multifunctional cytokines that play major roles in the immune response. The human type I IFNs comprises 13 distinct non-allelic alpha subtypes, one beta subtype, and one omega subtype. Type I interferons all appear to bind a common receptor, type I interferon-α/β receptor (IFNAR), composed of the IFNAR1 and IFNAR2 subunits. Upon binding of type I IFNs, IFNAR activates the JAK-STAT signaling pathway to elicit various biological effects. Differential activities of IFN subtypes have been reported and used in the clinic for the treatment of various disease and disorders, including, for example, viral hepatitis (IFN-a2). The consensus interferon (CI FN, also known as interferon alfacon-1 or Infergen®) is a synthetic, recombinant type I interferon engineered to contain the most commonly observed amino acids among several non-allelic IFN-a subtypes. In vitro studies demonstrate that the consensus interferon has ten-fold higher antiviral activity compared with wildtype IFN-a2a. The consensus interferon was approved by the U.S. Food and Drug Administration (FDA) for the treatment of chronic hepatitis C infections. Due to its pharmacokinetic properties, clinical use of the consensus interferon is plagued by serious side effects and low patient compliance. In the U.S., the consensus interferon is being used at concentrations of 15 g three times weekly. Following subcutaneous injection, high level of the consensus interferon is achieved, but the serum concentration drops almost below the detection limit by the next dose. This kinetic profile provides the virus a chance to recover and expand. Protocols involving higher and/or more frequent doses have been tested but are associated with severe side-effects including influenza-like symptoms, myalgia, leucopenia, thrombocytopenia, neutropenia, depression, and weight loss. High patient drop-out rate has also been reported. Accordingly, there remains a need for safe and effective consensus interferon-based therapeutics with improved pharmacokinetic and therapeutic properties and minimal toxicity profiles. SUMMARY In some aspects, the present invention relates to chimeric proteins comprising a consensus interferon as a signaling agent. In an embodiment, the consensus interferon comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or variants thereof. In some embodiments, the consensus interferon is modified and comprises one or more mutations. In some embodiments, the one or more mutations reduce the biological activity of the consensus interferon. For example, the one or more mutations may reduce the affinity of the consensus interferon for a therapeutic receptor. In an embodiment, the therapeutic receptor is the interferon-α/β receptor (IFNAR), which is composed of the IFNAR1 and IFNAR2 subunits. In an embodiment, the modified consensus interferon comprises one or more mutations that reduce its affinity for IFNAR1 . In another embodiment, the modified consensus interferon comprises one or more mutations that reduce its affinity for IFNAR2. In an embodiment, the modified consensus interferon comprises one or more mutations that reduce its affinity for IFNAR1 and comprises one or more mutations that reduce its affinity for IFNAR2. In some embodiments, the chimeric protein comprises one or more additional signaling agents, e.g., without limitation, an interferon, an interleukin, and a tumor necrosis factor, that may be modified. In various embodiments, the chimeric protein of the invention provides improved safety and/or therapeutic activity and/or pharmacokinetic profiles (e.g., increased serum half-life) compared to an untargeted consensus interferon or an unmodified, wildtype IFN-a such as IFN-a2a or IFN-a2b. In various embodiments, the chimeric protein comprises one or more targeting moieties which have recognition domains (e.g. antigen recognition domains, including without limitation various antibody formats, inclusive of single- domain antibodies) which specifically bind to a target e.g. antigen, receptor) of interest. In various embodiments, the targeting moieties have recognition domains that specifically bind to a target (e.g. antigen, receptor) of interest, including those found on one or more immune cells, which can include, without limitation, T cells, cytotoxic T lymphocytes, T helper cells, natural killer (NK) cells, natural killer T (NKT) cells, anti-tumor macrophages (e.g. M 1 macrophages), B cells, and dendritic cells. In some embodiments, the recognition domains specifically bind to a target (e.g. antigen, receptor) of interest and effectively recruit one of more immune cells. In some embodiments, the targets (e.g. antigens, receptors) of interest can be found on one or more tumor cells. In some embodiments, the present chimeric proteins may recruit an immune cell, e.g. an immune cell that can kill and/or suppress a tumor cell, to a site of action (such as, by way of non-limiting example, the tumor microenvironment). In some embodiments, the recognition domains specifically bind to a target e.g. antigen, receptor) of interest which is part of a non-cellular structure. In various embodiments, the present chimeric proteins find use in the treatment of various diseases or disorders such as cancer, infections, immune disorders, autoimmune diseases, cardiovascular diseases, wound healing, ischemia-related diseases, neurodegenerative diseases, metabolic diseases and many other diseases and disorders, and the present invention encompasses various methods of treatment. BRIEF DESCRIPTION OF THE DRAWINGS Figures 1A-E are graphs showing the STAT1 phosphorylation in CD20 positive cells compared to CD20 negative cells after the cells were stimulated with a serial dilution of: wild type human IFNa2 - "IFNa2 "(Figure 1A), an anti- human CD20 VHH linked to wild type human-IFNa2 - "CD20 IFNaZ (Figure 1B), anti-human CD20 VHH linked to R149A mutant human-IFNa2 - "CD20-IFNa2_R149A" (Figure 1C), anti-human CD20 VHH linked to consensus IFNa2 (SEQ ID NO: 2) - "CD20-IFNa_con" (Figure 1D), and anti-human CD20 VHH linked to R150A mutant consensus IFNa2 (SEQ ID NO:2) - "CD20-IFNa_con_R150A" (Figure 1E) for 15 minutes.
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