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WO 2018/190719 A2 18 October 2018 (18.10.2018) W !P O PCT

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WO 2018/190719 A2 18 October 2018 (18.10.2018) 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 2018/190719 A2 18 October 2018 (18.10.2018) W !P O PCT (51) International Patent Classification: Not classified (21) International Application Number: PCT/NL20 18/050234 (22) International Filing Date: 13 April 2018 (13.04.2018) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 2018708 13 April 2017 (13.04.2017) NL 2019166 03 July 2017 (03.07.2017) NL (71) Applicant: ADURO BIOTECH HOLDINGS, EUROPE B.V. [NL/NL]; Kloosterstraat 9 RX1 101, 5349 AB Oss (NL). (72) Inventors: VAN EENENNAAM, Hans; c/o Klooster straat 9 RX1 101, 5349 AB Oss (NL). VAN ELSAS, An- drea; c/o Kloosterstraat 9 RX1 101, 5349 AB Oss (NL). = VOETS, Erik; c/o Kloosterstraat 9 RX1 101, 5349 AB Oss = (NL). VINK, Paul; c/o Kloosterstraat 9 RX1 101, 5349 AB = Oss (NL). HULSIK, David Lutje; c/o Kloosterstraat 9 = RX1 101, 5349 AB Oss (NL). = (74) Agent: JANSEN, CM.; V.O., Camegieplein 5, 25 17 KJ = Den Haag (NL). (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, N 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: — without international search report and to be republished ® upon receipt of that report (Rule 48.2(g)) 00 (54) Title: ANTI-SIRP ALPHA ANTIBODIES (57) Abstract: The present invention relates to anti-SIRPa antibodies, as well as use of these antibodies in the treatment of diseases u a cancer and infectious disease. ANTI-SIRP alpha ANTIBODIES [00 The present application claims the benefit of Netherlands Patent Application 2018708, filed April 13, 2017, and of Netherlands Patent Application 2019166, filed July 3, 2017, each of which is hereby incorporated by reference in its entirety including all tables, figures, and claims. FIELD OF THE INVENTION [0002] The present invention relates to anti-SIRPa antibodies, as well as use of these antibodies in the treatment of diseases. BACKGROUND OF THE INVENTION [0003] Signal regulatory protein alpha (SIRP ) is membrane glycoprotein from the SIRP family. Members of the SIRP family share certain common structural motifs. These include a transmembrane segment and an N-terminal extracellular domain that contains three Ig-like loops connected by three pairs of disulfide bonds. The C-terminal intracellular domain, however, differs between SIRP family members. SIRPa has an extended intracellular domain containing four tyrosine residues that form two immunoreceptor tyrosine-based inhibitory motifs (ITIMs), while SIRP contains a lysine residue in the transmembrane domain followed by a short intracellular tail lacking ITIMs serving as a receptor for DAP12. Eight SIRPa single nucleotide polymorphisms have been identified, with the most prevalent being SIRPaVl and SIRPaV2 (Takenaka et al., Nat. Immunol. 2007, 8:1313-23). [0004] "Eat-me" signals (i.e. "altered self") are extracellular players specifically produced by and displayed on the surface of apoptotic cells, but not healthy cells, and are key to the initiation of phagocytosis by activating phagocytic receptors and subsequent signaling cascades. Eat-me signals require extracellular trafficking in order to be displayed on apoptotic cells. A particular category of eat-me signals is provided by membrane-anchored proteins such as phosphatidylserine (PtdSer) and calreticulin (CRT). Externalized PtdSer binds to its receptors on phagocytes to facilitate clearance of apoptotic cells (a process known as efferocytosis). Likewise, CRT is upregulated on the surface of apoptotic cells and binds to LDL-receptor-related protein 1 (LRPl ) on the phagocyte thereby mediating engulfment. [0005] SIRPa is broadly expressed on phagocytes (e.g., macrophages, granulocytes, and dendritic cells) and acts as an inhibitory receptor through its interaction with a transmembrane protein CD47. This interaction mediates a response referred to as the "don't eat me" signal. This interaction negatively regulates effector function of innate immune cells such as host cell phagocytosis. As CD47 is often present on tumor cells, this "don't eat me" signal is thought to contribute to the resistance of tumors to phagocyte-dependent clearance. Despite the similarities in the extracellular domains of SIRPa and SIRPpi functional differences exist among the SIRP family members. For example, SIRP does not bind CD47 at detectable levels and so does not mediate the "don't eat me" signal. Instead, SIRPpi is involved in the activation of myeloid cells. [0006] Disruption of CD47-SIRPa signalling (e.g., by antagonistic monoclonal antibodies that bind to either CD47 or SIRPa) reportedly results in enhanced phagocytosis of both solid and hematopoietic tumor cells, including increased phagocytosis of glioblastoma cells in vitro and significant anti-tumor activity in vivo. SUMMARY OF THE INVENTION [0007] In a first aspect, the invention provides anti-SIRPa antibodies and antigen binding fragments thereof comprising the structural and functional features specified below. [0008] In various embodiments, the invention provides an antibody or antigen binding fragment thereof that binds to human SIRPa comprising one, two, or all three of (i), (ii) and (iii): (i) a heavy chain variable region CDRl comprising the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence differing from SEQ ID NO: 1 by 1, 2, 3, or more conservative substitutions; (ii) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence differing from SEQ ID NO: 2 by 1, 2, 3, or more conservative substitutions; and/or (iii) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence differing from SEQ ID NO: 3 by 1, 2, 3, or more conservative substitutions. [0009] In various other embodiments, the invention provides an antibody or antigen binding fragment thereof that binds to human SIRPa comprising one, two, or all three of (i), (ii) and (iii): (i) a heavy chain variable region CDRl comprising the amino acid sequence of SEQ ID NO: 69 or an amino acid sequence differing from SEQ ID NO: 1 by 1, 2, 3, or more conservative substitutions; (ii) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 70 or an amino acid sequence differing from SEQ ID NO: 2 by 1, 2, 3, or more conservative substitutions; and/or (iii) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 7 1 or an amino acid sequence differing from SEQ ID NO: 3 by 1, 2, 3, or more conservative substitutions. [0010] In certain embodiments, the antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: 75 or an amino acid sequence at least 90%, 95%, 97%, 98%, or 99% similar or identical thereto, SEQ ID NO: 78 or an amino acid sequence at least 90%, 95%, 97%, 98%, or 99% similar or identical thereto, SEQ ID NO: 80 or an amino acid sequence at least 90%, 95%, 97%, 98%, or 99% similar or identical thereto, SEQ ID NO: 82 or an amino acid sequence at least 90%, 95%, 97%, 98%, or 99% similar or identical thereto, SEQ ID NO: 84 or an amino acid sequence at least 90%, 95%, 97%, 98%, or 99% similar or identical thereto, SEQ ID NO: 86 or an amino acid sequence at least 90%, 95%, 97%, 98%, or 99% similar or identical thereto, SEQ ID NO: 88 or an amino acid sequence at least 90%, 95%, 97%, 98%, or 99% identical thereto, SEQ ID NO: 102 or an amino acid sequence at least 90%, 95%, 97%, 98%, or 99% identical thereto, SEQ ID NO: 7 or an amino acid sequence at least 90%, 95%, 97%, 98%', or 99% similar or identical thereto, SEQ ID NO: 10 or an amino acid sequence at least 90%, 95%, 97%, 98%, or 99% similar or identical thereto. SEQ ID NO: 12 or an amino acid sequence at least 90%, 95%, 97%, 98%, or 99% similar or identical thereto, SEQ ID NO: 14 or an amino acid sequence at least 90%, 95%, 97%, 98%, or 99% similar or identical thereto, SEQ ID NO: 16 or an amino acid sequence at least 90%, 95%, 97%, 98%, or 99% similar or identical thereto, SEQ ID NO: 8 or an amino acid sequence at least 90%, 95%, 97%, 98%, or 99% similar or identical thereto, and SEQ ID NO: 30 or an amino acid sequence at least 90%, 95%, 97%, 98%, or 99% similar or identical thereto.
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