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WO 2017/077382 Al 11 May 2017 (11.05.2017) P O P C T (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 2017/077382 Al 11 May 2017 (11.05.2017) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12N 15/62 (2006.01) C07K 14/505 (2006.01) kind of national protection available): AE, AG, AL, AM, C07K 14/525 (2006.01) C07K 14/52 (2006.01) 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, (21) Number: International Application DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/IB20 16/00 1668 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, 7 November 2016 (07.1 1.2016) 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, (25) Filing Language: English SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (26) Publication Language: English TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 62/252,282 6 November 2015 (06. 11.2015) US (84) Designated States (unless otherwise indicated, for every 62/252,286 6 November 2015 (06. 11.2015) US kind of regional protection available): ARIPO (BW, GH, 62/335,868 13 May 2016 (13.05.2016) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (71) Applicants: ORIONIS BIOSCIENCES NV [BE/BE]; TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, Rijvisschestraat 120, B-9052 Zwijnaarde (BE). VIB VZW DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, [BE/BE]; Rijvisschestraat 120, 9052 Gent (BE). UNI- LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, VERSITEIT GENT [BE/BE]; Sint-Pietersnieuwstraat 25, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, 9000 Gent (BE). GW, KM, ML, MR, NE, SN, TD, TG). (72) Inventors: KLEY, Nikolai; C/o Orionis Biosciences, Inc., Published: 275 Grove Street, Suite 2-400, Newton, MA 02466 (US). — with international search report (Art. 21(3)) TAVERNIER, Jan; Bottelweg 2, B-9860 Balegem (BE). HUYGHE, Leander; Stijn Streuvelsstraat 29, 8730 — with sequence listing part of description (Rule 5.2(a)) Beernem (BE). WUEEST, Thomas; Rijvisschestraat 120, B-9052 Zwijnaarde (BE). (54) Title: BI-FUNCTIONAL CHIMERIC PROTEINS AND USES THEREOF (l) aj i (57) Abstract: The present invention relates, in part, to targeted chimeric proteins with beneficial therapeutic effects, including, for example, effects mediated by mutant forms of soluble agents that are part of the chimeric proteins. Pharmaceutical compositions comprising the chimeric proteins are also provided. The present invention finds use in the treatment of various disease and disorders. BI-FUNCTIONAL CHIMERIC PROTEINS AND USES THEREOF RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62/252,282, filed November 6, 201 5, U.S. Provisional Patent Application No. 62/252,286, filed November 6, 201 5, and U.S. Provisional Patent Application No. 62/335,868, filed May 13, 201 6, the entire disclosures of all of which are hereby incorporated by reference in their entireties. FIELD The present invention relates, in part, to targeted chimeric proteins with beneficial therapeutic properties. The present invention also provides use of the chimeric proteins in pharmaceutical compositions and methods of treating various diseases and disorders. DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety: a computer readable format copy of the Sequence Listing (filename: ORN-007PC_Sequence_listing.txt; date recorded: November 03, 201 6; file size: 300 KB). BACKGROUND Soluble agents such as cytokines, hormones, and growth factors are naturally occurring substances capable of modulating cellular growth and differentiation. These soluble agents play important roles in a variety of physiological processes including, for example, metabolism, respiration, sleep, excretion, healing, movement, reproduction, mood, stress, tissue function, immune function, sensory perception, and growth and development. Typically, cytokines, hormones, and growth factors exert their biological effects through binding to specific receptors on the surface of target cells. Clinically, cytokines, hormones, and growth factors are used in the treatment of a variety of diseases and disorders including, for example, cancers, microbial infections, hematological disorders, and metabolic diseases. Despite this common use, the administration of these soluble agents is not without risks. The therapeutic use of cytokines, hormones, and growth factors is often associated with systemic toxicity and deleterious side effects thus limiting the dose levels that these agents can be used. As a result, only relatively small numbers of cytokines are currently approved by regulatory agencies. Of these, fourteen of the FDA-approved cytokine preparations carry warnings, ten of which are black box warnings. Furthermore, and relatedly, many of these soluble agents have promiscuous binding activity and therefore provide for the possibility of off-target effects, which can underlie deleterious side effects or, at the least, provide a sink for the therapeutic construct away from the site of therapeutic action. There is a need to develop therapeutic soluble agents with improved safety and efficacy. SUMMARY Accordingly, the present invention provides, in various aspects, chimeric proteins that include a soluble agent which has reduced affinity at a therapeutic receptor, which allows for attenuation of binding and/or activity (inclusive of agonism or antagonism), and substantially reduced or ablated affinity at a second receptor, which, for example, prevents or substantially reduces non-therapeutic signaling or undesirable sequestration of the chimeric protein. In the case of the attenuated activity at the therapeutic receptor, the weakened affinity at the therapeutic receptor is restorable by attachment to a targeting moiety (e .g. an antibody or antibody format described herein), such targeting moiety having high affinity for an antigen at the site of therapeutic activity. In this way, the present chimeric proteins provide, in some embodiments, localized, on-target, and controlled therapeutic action at the therapeutic receptor and avoid activity at another receptor that could diminish or interfere with the overall therapeutic effect. Accordingly, in various aspects, the present chimeric constructs make for more therapeutically effective soluble agents by, for example, reducing receptor promiscuity and attenuating activity at the desired therapeutic receptor. In various embodiments, the soluble agent is modified to have a mutation that reduces its binding affinity or activity at a therapeutic receptor. This binding affinity or activity is restorable by connection with a targeting moiety, e .g. an antibody or antibody format described herein, and binding of the targeting moiety to an antigen or epitope at a site of therapeutic activity (e .g. a cell as described herein). In some embodiments, the activity provided by the soluble agent is agonism at the therapeutic receptor (e .g. activation of a cellular effect at a site of therapy). In some embodiments, the activity provided by the soluble agent is antagonism at the therapeutic receptor (e.g. blocking or dampening of a cellular effect at a site of therapy). In various embodiments, the therapeutic chimeric proteins of the present invention reduce off-target effects because their soluble agents have mutations that weaken binding affinity or activity at a therapeutic receptor. In various embodiments, this reduces side effects observed with, for example, wild type soluble agents. However, in various embodiments, the present chimeric proteins also have soluble agents with mutations that substantially reduce or ablate binding or activity at another receptor. This, in some embodiments, further reduces off-target effects of the present chimeric proteins and therefore reduces side effects (e .g. relative to wild type soluble agents). In various embodiments, this affinity or activation at the other receptor is not restorable with a targeting moiety. In various embodiments, substantially reducing or ablating binding or activity at another receptor also prevents deleterious effects that are mediated by another receptor. Alternatively, or in addition, substantially reducing or ablating binding or activity at another receptor causes the therapeutic effect to improve as there is a reduced or eliminated sequestration of the therapeutic chimeric proteins away from the site of therapeutic action and, optionally, the ability to reduce dose of the therapeutic chimeric proteins. In various embodiments, the dual effect at a therapeutic receptor and another receptor can be mediated by the same mutation or different mutations, in various number and varieties as described herein. In various embodiments, the present chimeric proteins find use in the treatment of various diseases or disorders and the present invention encompasses various methods of treatment. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows, in panels A and B, results from cytotoxicity assays using MCF cells. Specifically, the cytotoxicity of various human TNF-R1 selective mutants was tested in MCF cells (panel A) or hCD20-expressing MCF cells (panel B). Figure 1, panel C, shows results from assays using Raji cells, in which the ability of the various human TNF-R1 selective mutants to induce OPRM 1 expression was assessed. Figure 2 shows, in panels A and B, results from cytotoxicity assays using MCF cells. Specifically, the cytotoxicity of various human TNF-R1 selective mutants was tested. Figure 2, panel C, shows results from assays using Raji cells, in which the ability of the various human TNF-R1 selective mutants to induce OPRM 1 expression was assessed.
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