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WO 2016/073894 Al 12 May 2016 (12.05.2016) W P O P CT

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WO 2016/073894 Al 12 May 2016 (12.05.2016) W P O P CT (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 2016/073894 Al 12 May 2016 (12.05.2016) W P O P CT (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07K 16/24 (2006.01) A61K 39/00 (2006.01) kind of national protection available): AE, AG, AL, AM, A61P 27/02 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) Number: International Application DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US2015/059539 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 6 November 2015 (06.1 1.2015) 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, (25) Filing Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (26) Publication Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 62/077,072 7 November 2014 (07. 11.2014) US kind of regional protection available): ARIPO (BW, GH, 62/087,942 5 December 2014 (05. 12.2014) 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) Applicant: ELEVEN BIOTHERAPEUTICS, INC. TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, [US/US]; 215 First Street, Suite 400, Cambridge, MA DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, 02142 (US). 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, (72) Inventors: SCHMIDT, Michael, March; 42 Eighth GW, KM, ML, MR, NE, SN, TD, TG). Street, Apt. 5 114, Boston, MA 02129 (US). KOVAL- CHIN, Joseph, T.; 159 Salem End Road, Framingham, Published: MA 01702 (US). FURFINE, Eric, Steven; 221 Lincoln — with international search report (Art. 21(3)) Rd, Lincoln, MA 01773 (US). — before the expiration of the time limit for amending the (74) Agent: MYERS, P., Louis; Lando & Anastasi LLP, River claims and to be republished in the event of receipt of front Office Park, One Main Street, Suite 1100, Cam amendments (Rule 48.2(h)) bridge, MA 02142 (US). 00 © v © (54) Title: THERAPEUTIC AGENTS WITH INCREASED OCULAR RETENTION (57) Abstract: Modified agents (e.g., modified therapeutic agents) with improved ocular retention are provided. Also provided are methods of making and using the modified agents, e.g., in the treatment of ocular diseases such as macular edema, macular degener - S ation, and uveitis. THERAPEUTIC AGENTS WITH INCREASED OCULAR RETENTION RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62/077,072, filed November 7, 2014, and U.S. Provisional Application No. 62/087,942, filed December 5, 2014. The entire contents of each of these applications are incorporated herein by reference. FIELD OF THE INVENTION The invention relates to agents that have improved ocular retention. BACKGROUND Ocular diseases can be treated by intraocular administration of therapeutic agents. To achieve greater therapeutic efficacy and/or to improve convenience, patient comfort and compliance, it is desirable to provide engineered therapeutic agents for ocular (e.g., intravitreal) administration that have improved retention in the eye. The present invention relates to engineered agents with improved retention in the eye and compositions comprising the engineered agents, as well as methods for producing and using the engineered agents. For example, the engineered agents can be used in the treatment of eye diseases. SUMMARY The present invention relates to Applicants' discovery that certain antibodies described herein have surprisingly good retention in the eye. The invention relates to compositions comprising engineered agents that have improved ocular retention, methods of producing compositions comprising engineered agents with improved ocular retention, and uses of such compositions for the treatment of ocular disease. In one aspect, the invention provides, an ocular half life extending (OHLE) polypeptide. In an embodiment, the OHLE polypeptide is coupled to, e.g., covalently coupled to, an agent, e.g., a therapeutic or diagnostic agent. In an embodiment, the OHLE polypeptide comprises: a) a heavy chain module comprising, e.g., in the N terminal to C terminal direction, a heavy chain variable region module and an IgG2 module; and b) a light chain module comprising a light chain variable region module. In one embodiment, the heavy chain variable region module comprises at least 60, 70, 75, 80, 85, 90, 95, or 99% identity with a heavy chain variable region of an antibody in Table 4. In one embodiment, the heavy chain variable region module comprises at least 60, 70, 75, 80, 85, 90, 95, or 99% identity with SEQ ID NO: 37 or 17. In one embodiment, the IgG2 constant region module comprises at least 60, 70, 75, 80, 85, 90, 95, or 99% identity with an IgG2 constant region of an antibody in Table 4. In one embodiment, the IgG2 constant region module comprises at least 60, 70, 75, 80, 85, 90, 95, or 99% identity with SEQ ID NO: 73 or 74. In other embodiments, the IgG2 constant region module comprises at least 60, 70, 75, 80, 85, 90, 95, or 99% identity with one or more of SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 51, SEQ ID NO: 66 or SEQ ID NO: 67. In one embodiment, the light chain variable region module comprises at least 60, 70, 75, 80, 85, 90, 95, or 99% identity with a light chain variable region of an antibody in Table 4. In one embodiment, the light chain variable region module comprises at least 60, 70, 75, 80, 85, 90, 95, or 99% identity with SEQ ID NO: 38 or 18. In one embodiment, the heavy chain module comprises at least 60, 70, 75, 80, 85, 90, 95, or 99% identity to the heavy chain framework regions of SEQ ID NOS: 4 1 or 47. In one embodiment, the heavy chain module comprises at least 60, 70, 75, 80, 85, 90, 95, or 99% identity to one or more of, e.g., one, two, three, or all of, the heavy chain framework region 1, e.g., HC FR1, heavy chain framework region 2, e.g., HC FR2, heavy chain framework region 3, e.g., HC FR3, or heavy chain framework region 4, e.g., HC FR4. The heavy chain framework regions are depicted in Figures 15A. In one embodiment, the light chain module comprises at least 60, 70, 75, 80, 85, 90, 95, or 99% identity to the light chain framework regions of SEQ ID NOS: 4 1 or 47. In one embodiment, the light chain module comprises at least 60, 70, 75, 80, 85, 90, 95, or 99% identity to one or more of, e.g., one, two, three, or all of, the light chain framework region 1, e.g., LC FR1, light chain framework region 2, e.g., LC FR2, light chain framework region 3, e.g., LC FR3, or light chain framework region 4, e.g., LC FR4. The heavy chain framework regions are depicted in Figures 15B. In one embodiment, one or more, e.g., one, two, or three, of the CDRs of the heavy chain module differ from the corresponding heavy chain CDRs of an antibody in Table 4 by 1, 2, 3, 4, 5, 6, 7 or more residues. In one embodiment, one or more, e.g., one, two, or three, of the CDRs of the light chain module differ from the corresponding light chain CDRs of an antibody in Table 4 by 1, 2, 3, 4, 5, 6, 7 or more residues. In one embodiment, the composition has increased ocular retention when administered, e.g., intravitreally, to a subject compared with the ocular retention of the agent when it is not covalently attached to the OHLE polypeptide, e.g., effective antibody or effective fragment thereof. In one embodiment, the ocular retention of the composition in the vitreous, aqueous humor, retina, choroid, iris ciliary body, lens, sclera, conjunctiva, and/or cornea is increased. In one embodiment, the retention is increased as indicated by an increase in the half life of at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. In one embodiment, the increase in half life is measured in an assay described herein, e.g., a rabbit pharmacokinetic (PK) model described herein, e.g., in Example 21. In one embodiment, the half life of the composition in the vitreous of a subject is at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 21, 22, 23, 24, or 25 days when the composition is administered intravitreally to the subject. In another aspect, the invention relates to an engineered agent or composition that includes an effective sequence from an IL-6 antibody described herein (e.g., EBI-029, EBI-030, and/or EBI-03 1) that improves ocular retention of the agent. In one embodiment, the OHLE polypeptide binds IL-6, e.g., with an affinity that is at least 50% of that of an antibody from Table 4. In one embodiment, the OHLE polypeptide does not substantially bind to IL-6, e.g., or binds with an affinity that is less than 20%, 10%, or 5% of that of an antibody from Table 4.
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