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WO 2018/148585 Al 16 August 2018 (16.08.2018) W !P O PCT

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WO 2018/148585 Al 16 August 2018 (16.08.2018) 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 2018/148585 Al 16 August 2018 (16.08.2018) W !P O PCT (51) International Patent Classification: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY,TH, TJ, TM, TN, C07K 16/40 (2006.01) TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (21) International Application Number: (84) Designated States (unless otherwise indicated, for every PCT/US20 18/0 17680 kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (22) International Filing Date: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 09 February 2018 (09.02.2018) TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (25) Filing Language: English 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, (26) Publication Langi English TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (30) Priority Data: KM, ML, MR, NE, SN, TD, TG). 62/457,722 10 February 2017 (10.02.2017) US Declarations under Rule 4.17: (71) Applicant (for all designated States except AL, AT, BA, — as to applicant's entitlement to apply for and be granted a BE, BG, CH, CN, CY, CZ, DE, DK, EE, ES, FI, FR, GB, patent (Rule 4.1 7(H)) GR, HR, HU, IE, IN, IS, IT, LT, LU, LV, MC, MK, MT, — as to the applicant's entitlement to claim the priority of the NL, NO, PL, P T RO, RS, SE, SI, SK, SM, TR): GENEN- earlier application (Rule 4.17(Hi)) TECH, INC. [US/US]; 1 DNA Way, South San Francisco, CA 94080-4990 (US). Published: — with international search report (Art. 21(3)) (71) Applicant (for AL, AT, BA, BE, BG, CH, CN, CY, CZ, DE, — before the expiration of the time limit for amending the DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IN, IS, IT, LT, LU, claims and to be republished in the event of receipt of LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, amendments (Rule 48.2(h)) TR only): F. HOFFMANN-LA ROCHE AG [CH/CH]; — with sequence listing part of description (Rule 5.2(a)) Grenzacherstrasse 124, 4070 Basel (CH). (72) Inventors: CHEN, Xiaocheng; 1 DNA Way, South San Francisco, CA 94080-4990 (US). DENNIS, Mark; 1 DNA Way, South San Francisco, CA 94080-4990 (US). JACK- MAN, Janet; 1 DNA Way, South San Francisco, CA 94080-4990 (US). KOERBER, James, T.; 1 DNA Way, South San Francisco, CA 94080-4990 (US). LU, Mason; 5015 Darnell St., Houston, TX 77096 (US). MAUN, Hen¬ ry, R.; 1 DNA Way, South San Francisco, CA 94080-4990 (US). RAJAPAKSA, Kathila; 1 DNA Way, South San Francisco, CA 94080-4990 (US). RAMANUJAN, Saroja; 1 DNA Way, South San Francisco, CA 94080-4990 (US). STATON, Tracy; 1 DNA Way, South San Francisco, CA 94080-4990 (US). WU, Lawren; 1 DNA Way, South San Francisco, CA 94080-4990 (US). YI, Tangsheng; 1 DNA Way, South San Francisco, CA 94080-4990 (US). (74) Agent: ELBING, Karen, L.; Clark & Elbing LLP, 101 Federal Street, 15th Floor, Boston, MA 021 10 (US). (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, 00 (54) Title: ANTI-TRYPTASE ANTIBODIES, COMPOSITIONS THEREOF, AND USES THEREOF (57) Abstract: The invention provides compositions including anti-tryptase antibodies and pharmaceutical compositions thereof, as well as methods of using the same. ANTI-TRYPTASE ANTIBODIES, COMPOSITIONS THEREOF, AND USES THEREOF Cross-Reference to Related Applications This application claims benefit to U.S. Provisional Application No. 62/457,722, filed on February 10 , 201 7 , which is incorporated by reference herein in its entirety. Sequence Listing The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on February 9 , 201 8 , is named 50474-1 12W02_Sequence_Listing_2. 9 .18_ST25 and is 108,967 bytes in size. Field of the Invention The invention relates to anti-tryptase antibodies, pharmaceutical compositions, and methods of using the same. Background Human tryptase beta is a trypsin-like serine protease that is abundant in mast cells and, to a lesser extent, in basophils. Human tryptase beta (of which there are three subtypes, tryptase beta 1, tryptase beta 2 , and tryptase beta 3) produced by the TPSAB1 and TPSB2 loci is the predominant active tryptase produced by human mast cells. These two loci produce four tryptase isoforms; TPSAB1 produces tryptase alpha and tryptase beta 1, while TPSB2 produces tryptase beta 2 and tryptase beta 3 . Tryptase alpha, as well as other isoforms such as tryptase gamma, tryptase delta, and tryptase epsilon are largely inactive. The proteolytically processed, active tryptase beta is stored in the secretory granules of mast cells as a tetramer in complex with heparin. Mast cell degranulation, which can be caused by IgE- dependent stimuli (e.g. , allergens), or non-lgE-dependent stimuli (e.g., substance P or active tryptase), leads to release of tryptase beta along with other granule enzymes and histamine. Previous studies have observed increased mast cell numbers in bronchial smooth muscle and epithelium of asthma patients, as well as increased levels of tryptase beta in broncoalveolar lavage fluid . In addition, tryptase contributes to airway bronchoconstriction and hyperresponsiveness, and has also been suggested to play a role in fibrosis and extracellular matrix turnover, which are hallmarks of the airway remodeling process. Tryptase has been suggested to be involved in various diseases and disorders, including asthma and other pulmonary, inflammatory, autoimmune, and fibrotic disorders, for which there remains a need for improved therapeutics, including therapeutic anti-tryptase antagonists, and methods of treatment. There have been attempts to develop small molecule tryptase inhibitors (see, e.g. , Cairns, J.A., 2005, Pulmonary Pharmacology & Therapeutics 18:55-66); however, to our knowledge, no biologic tryptase antagonistic therapeutics, especially anti-tryptase antagonistic antibodies, have been reported. Summary of the Invention The present invention relates to anti-tryptase antibodies and pharmaceutical compositions thereof, as well as methods of using the same. In one aspect, the invention features an isolated antibody that binds to human tryptase beta 1, or an antigen-binding fragment thereof, wherein the antibody comprises the following six hypervariable regions (HVRs): (a) an HVR-H1 comprising the amino acid sequence of DYGMV (SEQ ID NO: 7); (b) an HVR-H2 comprising the amino acid sequence of FISSGSSTVYYADTMKG (SEQ ID NO: 2); (c) an HVR- H3 comprising the amino acid sequence of RNYDDWYFDV (SEQ ID NO: 8); (d) an HVR-L1 comprising the amino acid sequence of SASSSVTYMY (SEQ ID NO: 4); (e) an HVR-L2 comprising the amino acid sequence of RTSDLAS (SEQ ID NO: 5); and (f) an HVR-L3 comprising the amino acid sequence of QHYHSYPLT (SEQ ID NO: 6). In some embodiments, the antibody is defined by the six HVRs comprising the amino acid sequence of SEQ ID NO: 7 , 2 , 8 , 4 , 5 , and 6 . In some embodiments, the antibody further comprises S43, P46, and W47 in the light chain variable (VL) domain framework region L2 (FR-L2) (Kabat numbering). In some embodiments, the antibody comprises (a) a heavy chain variable (VH) domain comprising an amino sequence having at least 90%, at least 95%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 9 ; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 90%, at least 95%, or at least 99% identity to the amino acid sequence of SEQ ID NO: 10 ; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the antibody further comprises the following VH domain framework regions (FRs): (a) an FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO: 11) ; (b) an FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWVA (SEQ ID NO: 12); (c) an FR-H3 comprising the amino acid sequence of RFTISRDNSKNTLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 13); and (d) an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 9 . In some embodiments, the antibody further comprises the following VL domain FRs: (a) an FR-L1 comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 15); (b) an FR-L2 comprising the amino acid sequence of WYQQKPGKSPKPWIY (SEQ ID NO: 16); (c) an FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 17); and (d) an FR-L4 comprising the amino acid sequence of FGQGTKVEIK (SEQ ID NO: 18). In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 10 . In some embodiments, the antibody comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 76 and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 77.
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