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A61K9/00 (2006.01) G01N 2 7/447 (2006.01) Chusetts 02139 (US) ( (51) International Patent Classification: (74) Agent: SCARR, Rebecca B. et al.; McNeill Baur PLLC, C07K 16/28 (2006.01) A61K 35/00 (2006.01) 125 Cambridge Park Drive, Suite 301, Cambridge, Massa¬ A61K9/00 (2006.01) G01N 2 7/447 (2006.01) chusetts 02139 (US). A61K9/19 (2006.01) C07K 19/00 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection av ailable) . AE, AG, AL, AM, PCT/US2020/036035 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, (22) International Filing Date: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, 04 June 2020 (04.06.2020) HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, (25) Filing Language: English 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, (26) Publication Language: English OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (30) Priority Data: SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, TJ, TM, TN, TR, 62/857,364 05 June 2019 (05.06.2019) US TT, TZ, UA, UG, US, UZ, VC, VN, WS, ZA, ZM, ZW. 62/906,862 27 September 2019 (27.09.2019) US (84) Designated States (unless otherwise indicated, for every (71) Applicant: SEATTLE GENETICS, INC. [US/US]; kind of regional protection available) . ARIPO (BW, GH, 21823 30th Drive SE, Bothell, Washington 98021 (US). GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (72) Inventors: LEISKE, Danielle; c/o Seattle Genetics, Inc., TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, SE, 21823 30th Drive Bothell, Washington 98021 (US). EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, CUNNINGHAM, Elise; c/o Seattle Genetics, Inc., 21823 MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, 30th Drive SE, Bothell, Washington 98021 (US). JIANG, TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, Shan; c/o Seattle Genetics, Inc., 21823 30th Drive SE, KM, ML, MR, NE, SN, TD, TG). Bothell, Washington 98021 (US). WESTENDORF, Lori; c/o Seattle Genetics, Inc., 21823 30th Drive SE, Bothell, Published: Washington 98021 (US). FELDHAUS, Michael; c/o Seat¬ — with international search report (Art. 21(3)) tle Genetics, Inc., 21823 30th Drive SE, Bothell, Washing¬ — before the expiration of the time limit for amending the ton 98021 (US). COSGRAVE, Eoin Francis James; c/o claims and to be republished in the event of receipt of Seattle Genetics, Inc., 21823 30th Drive SE, Bothell, Wash¬ amendments (Rule 48.2(h)) ington 98021 (US). EAKIN, Catherine Marie; c/o Seattle — with sequence listing part of description (Rule 5.2(a)) Genetics, Inc., 21823 30th Drive SE, Bothell, Washington 98021 (US). (54) Title: MASKED ANTIBODY FORMULATIONS (57) Abstract: Formulations comprising masked antibodies are pro¬ vided. In some embodiments there is reduced aggregation of the ts, in MASKED ANTIBODY FORMULATIONS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of priority of US Provisional Application No. 62/857,364, filed June 5, 2019, and US Provisional Application No. 62/906,862, filed September 27, 2019, each of which is incorporated by reference herein in its entirety for any purpose. FIELD OF THE INVENTION [0002] The present invention relates to the field of antibody formulations. In particular, the present invention relates to formulations of masked antibodies with reduced aggregation. In some embodiments, the masked antibodies comprise anti-CD47 antibodies. BACKGROUND [0003] Current antibody-based therapeutics may have less than optimal selectivity for the intended target. Although monoclonal antibodies are typically specific for binding to their intended targets, most target molecules are not specific to the disease site and may be present in cells or tissues other than the disease site. [0004] Several approaches have been described for overcoming these off-target effects by engineering antibodies to have a cleavable linker attached to an inhibitory or masking domain that inhibits antibody binding (see, e.g., W02003/068934, W02004/009638, WO 2009/025846, W02101/081 173 and WO2014103973). The linker can be designed to be cleaved by enzymes that are specific to certain tissues or pathologies, thus enabling the antibody to be preferentially activated in desired locations. Masking moieties can act by binding directly to the binding site of an antibody or can act indirectly via steric hindrance. Various masking moieties, linkers, protease sites and formats of assembly have been proposed. The extent of masking may vary between different formats as may the compatibility of masking moieties with expression, purification, conjugation, or pharmacokinetics of antibodies. [0005] The present invention relates to formulations of masked antibodies with reduced aggregation. In some embodiments, the masked antibodies comprise a first coiled-coil domain linked to a heavy chain variable region of the antibody and a second coiled-coil domain linked to a light chain variable region of the antibody. The presence of these potentially hydrophobic coiled-coil polypeptide sequences can lead to aggregation during storage. In some embodiments, the present formulations may result in reduced aggregation of the masked antibodies. SUMMARY [0006] The present disclosure addresses formulating masked antibodies that comprise a removable masking agent (e.g., a coiled coil masking agent) that prevents binding of the antibodies to their intended targets until the masking agent is cleaved off or otherwise removed. In other words, the masking agent masks the antigen binding portion of the antibody so that it cannot interact with its targets. In certain therapeutic uses, the masking agent can be removed (e.g., cleaved) by one or more molecules (e.g., proteases) that are present in an in vivo environment after administration of the masked antibody to a patient. In other, for example non- therapeutic, uses, a masking agent could be removed by adding one or more proteases to the medium in which the antibody is being used. Removal of the masking agent restores the ability of the antibodies to bind to their targets, thus enabling specific targeting of the antibodies. In some embodiments herein, the antibodies are CD47 antibodies. [0007] The presence of coiled coil masking agents, for example, could increase the chances of aggregation of the antibodies during storage prior to use. Thus, the present disclosure addresses formulations of masked antibodies that may reduce aggregation of the masked antibodies during storage. [0008] In some embodiments, an aqueous formulation is provided, wherein the aqueous formulation comprises a masked antibody comprising a first masking domain comprising a first coiled-coil domain, wherein the first masking domain is linked to a heavy chain variable region of an antibody and a second masking domain comprising a second coiled-coil domain, wherein the second masking domain is linked to a light chain variable region of the antibody, wherein the first coiled-coil domain comprises the sequence VDELQAEVDQLEDENY ALKTKVAQLRKKVEKL (SEQ ID NO: 2), and the second coiled- coil domain comprises the sequence VAQLEEKVKTLRAENYELKSEVQRLEEQVAQL (SEQ ID NO: 1), and wherein the formulation comprises a buffer, and wherein the pH of the formulation is from 3.5 to 4.5. [0009] In some embodiments, an aqueous formulation is provided, wherein the aqueous formulation comprises a masked antibody comprising a first masking domain comprising a first coiled-coil domain, wherein the first masking domain is linked to a heavy chain variable region of an antibody and a second masking domain comprising a second coiled-coil domain, wherein the second masking domain is linked to a light chain variable region of the antibody, wherein the the first coiled-coil domain comprises the sequence VAQLEEKVKTLRAENYELKSEVQRLEEQVAQL (SEQ ID NO: 1), and the second coiled- coil domain comprises the sequence VDELQAEVDQLEDENYALKTKVAQLRKKVEKL (SEQ ID NO: 2), and wherein the formulation comprises a buffer, and wherein the pH of the formulation is from 3.5 to 4.5. [0010] In some embodiments, the buffer is selected from acetate, succinate, lactate, and glutamate. In some embodiments, the concentration of the buffer is from 10 mM to 100 mM, or from 10 mM to 80 mM, or from 10 mM to 70 mM, or from 10 mM to 60 mM, or from 10 mM to 50 mM, or from 10 mM to 40 mM, or from 20 mM to 100 mM, or from 20 mM to 80 mM, or from 20 mM to 70 mM, or from 20 mM to 60 mM, or from 20 mM to 50 mM, or from 20 mM to 40 mM. [0011] In some embodiments, the formulation comprises at least one cryoprotectant. In some embodiments, at least one cryoprotectant is selected from sucrose, trehalose, mannitol, and glycine. In some embodiments, the total cryoprotectant concentration in the aqueous formulation is 6-12% w/v. [0012] In some embodiments, the formulation comprises sucrose or trehalose. In some embodiments, the formulation comprises mannitol and trehalose, or glycine and trehalose. [0013] In some embodiments, the formulation comprises at least one excipient selected from glycerol, polyethylene glycol (PEG), hydroxypropyl beta-cyclodextrin (HPBCD), polysorbate 20 (PS20), polysorbate 80 (PS80), and poloxamer 188 (PI 88). [0014] In some embodiments, the formulation does not comprise added salt. In some embodiments, the formulation does not comprise added NaCl, KC1, or MgC12. [0015] In some embodiments, the concentration of the masked antibody in the formulation is from 1 to 30 mg/mL, or from 5 to 30 mg/mL, or from 10 to 30 mg/mL, or from 5 to 25 mg/mL, or from 5 to 20 mg/mL, or from 10 to 20 mg/mL, or from 10 to 25 mg/mL, or from 15 to 25 mg/mL.
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