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WO 2018/049285 Al 15 March 2018 (15.03.2018) W !P O PCT

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WO 2018/049285 Al 15 March 2018 (15.03.2018) 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 2018/049285 Al 15 March 2018 (15.03.2018) W !P O PCT (51) International Patent Classification: INC. [US/US]; 530 Fairview Avenue North, Suite 1400, A61K 38/00 (2006.01) C12Q 1/37 (2006.01) Seattle, WA 98109 (US). A61K 9/00 (2006.01) (72) Inventors: GIRARD, Emily, June; 16724 Woodside Dri (21) International Application Number: ve SE, Renton, WA 98058 (US). CORRENTI, Colin; PCT/US2017/050855 5850 57th Avenue NE, Seattle, WA 98105 (US). OLSON, James; 4733 Lake Washington Boulevard South, Seattle, (22) International Filing Date: WA 981 18 (US). NAIRN, Natalie, Winblade; 741 1 48th 09 September 2017 (09.09.2017) Avenue NE, Seattle, WA 981 15 (US). GEWE, Mesfln, (25) Filing Language: English Mulugeta; 428 218th Street SW, Bothell, WA 98021 (US). MEHLIN, Christopher; 2806 NW 61st Street, Seattle, (26) Publication Language: English WA 98107 (US). CROOK, Zachary; 18617 19th Drive (30) Priority Data: SE, Bothell, WA 98102 (US). STRONG, Roland; 1700 62/385,908 09 September 2016 (09.09.2016) US North Northlake Way #209, Seattle, WA 98103 (US). 62/432,487 09 December 20 16 (09. 12.20 16) US PRESNELL, Scott, Ronald; 2902 North Puget Sound Av 62/447,869 18 January 2017 (18.01.2017) US enue, Tacoma, WA 98407 (US). 62/5 10,710 24 May 2017 (24.05.2017) US (74) Agent: HOLZAPFEL, Keli, L. et al; Wilson Sonsini (71) Applicants: FRED HUTCHINSON CANCER Goodrich & Rosati, 650 Page Mill Road, Palo Alto, CA RESEARCH CENTER [US/US]; 1100 Fairview Avenue 94304-1050 (US). North, Seattle, WA 98109 (US). BLAZE BIOSCIENCE, (54) Title: STABLE PEPTIDES AND METHODS OF USE THEREOF hit FIG. 1 (57) Abstract: Peptides that are stable to denaturation and degradation by reducing agents, proteases, temperature, and low pH envi © ronments are disclosed. Pharmaceutical compositions and uses for peptides, peptide- active agent conjugates, and peptide-detectable agent conjugates comprising such peptides are also disclosed. Peptide compositions, peptide conjugate compositions, and pharmaceu 00 tical compositions can be formulated for various routes of delivery, such as oral delivery, and for deliver to various compartments of o the body. Peptides of this disclosure are stable and display enhanced pharmacokinetics after such delivery. o [Continued on nextpage] WO 2018/049285 Al llll II II 11III II I II III 11II II I III II I II (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). Published: STABLE PEPTIDES AND METHODS OF USE THEREOF CROSS REFERENCE [0001] This application claims the benefit of U.S. Provisional Patent Application No. 62/385,908, filed September 9, 2016, U.S. Provisional Patent Application No. 62/432,487, filed December 9, 2016, U.S. Provisional Patent Application No. 62/447,869, filed January 18, 2017, and U.S. Provisional Patent Application No. 62/510,710, filed May 24, 2017, the disclosures of which are incorporated herein in their entireties. BACKGROUND [0002] Peptides and proteins can be degraded in the body by specific and non-specific mechanisms. Biologic environments that are reducing can lead to unfolding of proteins and peptides by breaking disulfide bridges. Enzymes such as proteases that are prevalent in various organs and cellular compartments can digest peptides and proteins by clipping peptide bonds. Low pH environments in various organs and cellular compartments can promote denaturation of proteins and peptides. As a result, peptide and protein therapeutics face significant stability challenges after administration in vivo. Poor stability of peptide and proteins can lead to diminished pharmacokinetics and reduced efficacy. Moreover, low thermal and solution stability of peptides and proteins can lead to denaturation and/or precipitation, thus resulting in a short shelf-life or requiring special storage methods such as refrigeration. SUMMARY [0003] In various aspects the present disclosure provides a method of delivering a peptide to a target tissue, the method comprising: administering the peptide to a subject; and delivering the peptide to the target tissue, wherein the peptide has at least one of the following characteristics: (a) at least 70% the peptide remains intact after exposure to dithiothreitol (DTT) at a concentration of from 10 mM and a temperature of at least 23°C for at least 30 minutes; (b) at least 70% of the peptide remains intact after exposure to reduced glutathione (GSH) at a concentration of 10 mM and a temperature of at least 23°C for at least 30 minutes; (c) at least 70% of the peptide remains intact after exposure to trypsin at a concentration of 500 U/ml and a temperature of at least 23°C for at least 30 minutes; (d) at least 70% of the peptide remains intact after exposure to pepsin at a concentration of 500 U/ml and a temperature of at least 37°C for at least 30 minutes; (e) at least 70% of the peptide remains intact after exposure to simulated gastric fluid (SGF; pH 1.05; 2% (w/v) sodium chloride in 0.7% (v/v) hydrochloric acid) and a temperature of at least 23°C for at least 30 minutes; (f) at least 70% of the peptide remains intact after exposure to a pH of 1.05 and a temperature of at least 23°C for at least 30 minutes; (g) at least 70% of the peptide remains intact after exposure to the combination of simulated gastric fluid (SGF; pH 1.05; 2% (w/v) sodium chloride in 0.7% (v/v) hydrochloric acid) with 500 U/ml pepsin, 100 mM Tris, and 10 mM DTT (SPTD) and a temperature of at least 23°C for at least 30 minutes; (h) at least 70% of the peptide remains intact after exposure to at least 70°C for at least 60 minutes; (i) at least 70% of the peptide remains intact after exposure to at least 100°C for at least 60 minutes; or ( ) at least 10% of the peptide remains intact after passage through the mouth, stomach, small intestine, or the large intestine. [0004] In various aspects, the present disclosure provides a method of delivering a peptide to a target tissue, the method comprising: administering the peptide to a subject; and delivering the peptide to the target tissue, wherein the peptide has at least one of the following characteristics: (a) at least 70%, 72%, 75%, 78%, 80%, 82%, 85, 88%, 90%, 92%, 95%, 98%, or 99% of the peptide remains intact after exposure to dithiothreitol (DTT) at a concentration of from 5 mM to 10 mM and a temperature of at least 23°C, 37°C, or 39°C for at least 5, 10, 15, 20, 30, or 60 minutes; (b) at least 70%, 72%, 75%, 78%, 80%, 82%, 85, 88%, 90%, 92%, 95%, 98%, or 99% of the peptide remains intact after exposure to reduced glutathione (GSH) at a concentration of from 5 mM to 10 mM and a temperature of at least 23°C, 37°C, or 39°C for at least 5, 10, 15, 20, 30, or 60 minutes; (c) at least 70%, 72%, 75%, 78%, 80%, 82%, 85, 88%, 90%, 92%, 95%, 98%, or 99% of the peptide remains intact after exposure to trypsin at a concentration of 0.5 U/ml to 5000 U/ml and a temperature of at least 23°C, 37°C, or 39°C for at least 5, 10, 15, 20, 30, or 60 minutes; (d) at least 70%, 72%, 75%, 78%, 80%, 82%, 85, 88%, 90%, 92%, 95%, 98%, or 99% of the peptide remains intact after exposure to pepsin at a concentration of 0.5 U/ml to 5000 U/ml and a temperature of at least 23°C, 37°C, or 39°C for at least 5, 10, 15, 20, 30, or 60 minutes; (e) at least 70%, 72%, 75%, 78%, 80%, 82%, 85, 88%, 90%, 92%, 95%, 98%, or 99% of the peptide remains intact after exposure to simulated gastric fluid (SGF; pH 1.05; 2% (w/v) sodium chloride in 0.7% (v/v) hydrochloric acid) and a temperature of at least 23°C, 37°C, or 39°C for at least 5, 10, 15, 20, 30, or 60 minutes; (f) at least 70%, 72%, 75%, 78%, 80%, 82%, 85, 88%, 90%, 92%, 95%, 98%, or 99% of the peptide remains intact after exposure to a pH of from 1-2, 2-3, 3-4, or 4-5 and a temperature of at least 23°C, 37°C, or 39°C for at least 5, 10, 15, 20, 30, or 60 minutes; (g) at least 70%, 72%, 75%, 78%, 80%, 82%, 85, 88%, 90%, 92%, 95%, 98%, or 99% of the peptide remains intact after exposure to the combination of simulated gastric fluid (SGF; pH 1.05; 2% (w/v) sodium chloride in 0.7% (v/v) hydrochloric acid) with 0.5 U/ml to 5000 U/ml pepsin, 100 mM Tris, and 10 mM DTT and a temperature of at least 23°C, 37°C, or 39°C for at least 5, 10, 15, 20, 30, or 60 minutes; (h) at least 70%, 72%, 75%, 78%, 80%, 82%, 85, 88%, 90%, 92%, 95%, 98%, or 99% of the peptide remains intact after exposure to at least 70°C for at least 5, 10, 15, 20, 30, or 60 minutes; (i) at least 1%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 72%, 75%, 78%, 80%, 82%, 85, 88%, 90%, 92%, 95%, 98%, or 99% of the peptide remains intact after exposure to at least 100°C for at least 5, 10, 15, 20, 30, or 60 minutes; or (j) at least 70%, 72%, 75%, 78%, 80%, 82%, 85, 88%, 90%, 92%, 95%, 98%, or 99% of the peptide remains intact after passage through the mouth, stomach, small intestine, or the large intestine.
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