Antibodies against siglec-10 and use thereof for immunotherapy

Abstract

The present invention provides compositions comprising anti-Siglec-10 antibodies and nucleic acid molecules encoding the same, and methods for treating or preventing a disease or disorder using the same.

Description

[0001] Attorney Docket No.206193-0150-00WO

[0002] TITLE OF THE INVENTION

[0003] Antibodies Against Siglec-10 and Use Thereof for Immunotherapy

[0004] CROSS REFERENCE TO RELATED APPLICATIONS

[0005] This application claims priority to U.S. Provisional Application No. 63 / 750,096, filed January 27, 2025, which is hereby incorporated by reference in its entirety.

[0006] REFERENCE TO A SEQUENCE LISTING SUBMITTED AS AN XML FILE

[0007] The present application hereby incorporates by reference the entire contents of the XML file named “206193-0150-00WO_SequenceListing” in XML format, which was created on January 26, 2026, and is 389,892 bytes in size.

[0008] BACKGROUND OF THE INVENTION

[0009] Cancers manipulate several immunological mechanisms to ensure a permissive local microenvironment that promotes tumor progression. Glycosylation is frequently cited as hallmark of cancer. Altered surface glycosylation of tumor / infected cells appears as a key feature of cancer and different infectious diseases. Sialylated glycans found on both glycoproteins and glycolipids are recognized by Siglecs, a family of lectins that are expressed on the surface of many immune cell subtypes. The interaction of cancer cells / infected cells bound sialic acid with Siglecs can thus modulate immune cell phenotype and allow them to escape the immune system.

[0010] For example, pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers, characterized by immune evasion and resistance to immunotherapy. Tumor-associated macrophages (TAMs) in the PDAC microenvironment exhibit impaired phagocytic activity, contributing to tumor progression.

[0011] There remains a need in the art for novel cancer therapeutics that effectively treat cancer by reducing the ability of cancer cells to evade the immune system. The present invention satisfies this unmet need.Attorney Docket No.206193-0150-P1US

[0012] SUMMARY OF THE INVENTION

[0013] In some embodiments, the invention relates to a Siglec-10 binding molecule, comprising a Siglec-10 antibody, a Siglec-10 binding antibody fragment or a variant of a Siglec-10 antibody.

[0014] In some embodiments the antibody comprises an amino acid sequence selected from the group consisting of:

[0015] a) a variable heavy chain sequence comprising the CDR sequences selected from the group consisting of SEQ ID NO:77-79; SEQ ID NO:89-91; SEQ ID NO: 101-103; SEQ ID NO: 113-115; SEQ ID NO: 125-127; SEQ ID NO: 137- 139; SEQ ID NO:149-151; SEQ ID NO: 161-163; SEQ ID NO: 174-176; SEQ ID NO:186-188; SEQ ID NO: 198-200; SEQ ID NO:210-212; SEQ ID NO:222-224; SEQ ID NO:234-236; SEQ ID NO:246-248; SEQ ID NO:258- 260; SEQ ID NO:270-272; SEQ ID NO:282-284; and SEQ ID NO:294-296; b) a variable light chain sequence comprising the CDR sequences selected from the group consisting of SEQ ID NO:83-85; SEQ ID NO:95-97; SEQ ID NO: 107-109; SEQ ID NO: 119-121; SEQ ID NO: 131-133; SEQ ID NO: 143- 145; SEQ ID NO:155-157; SEQ ID NO: 167-170; SEQ ID NO: 180-182; SEQ ID NO: 192-194; SEQ ID NO:204-206; SEQ ID NO:216-218; SEQ ID NO:228-230; SEQ ID NO:240-242; SEQ ID NO:252-254; SEQ ID NO:264- 266; SEQ ID NO:276-278; SEQ ID NO:288-290; and SEQ ID NO:300-302; c) a sequence having at least 95% identity to a variable heavy chain sequence of one or more of SEQ ID NO: 1, SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 13, SEQ ID NO: 17, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 37, SEQ ID NO: 41, SEQ ID NO: 45, SEQ ID NO: 49, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 61, SEQ ID NO: 65, SEQ ID NO: 69, or SEQ ID NO: 73;

[0016] d) a sequence having at least 95% identity to a variable light chain sequence of one or more of SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 15, SEQ ID NO: 19, SEQ ID NO: 23, SEQ ID NO: 27, SEQ ID NO: 31, SEQ ID NO: 35, SEQ ID NO: 39, SEQ ID NO: 43, SEQ ID NO: 47, SEQ ID NO:Attorney Docket No.206193-0150-P1US

[0017] 51, SEQ ID NO: 55, SEQ ID NO: 59, SEQ ID NO: 63, SEQ ID NO: 67, SEQ ID NO: 71, or SEQ ID NO: 75;

[0018] e) a fragment comprising at least 80% of the full- length sequence of a variable heavy chain sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 13, SEQ ID NO: 17, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 37, SEQ ID NO: 41, SEQ ID NO: 45, SEQ ID NO: 49, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 61, SEQ ID NO: 65, SEQ ID NO: 69, or SEQ ID NO: 73; and

[0019] f) a fragment comprising at least 80% of the full-length sequence of a variable light chain sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 15, SEQ ID NO: 19, SEQ ID NO: 23, SEQ ID NO: 27, SEQ ID NO: 31, SEQ ID NO: 35, SEQ ID NO: 39, SEQ ID NO: 43, SEQ ID NO: 47, SEQ ID NO: 51, SEQ ID NO: 55, SEQ ID NO: 59, SEQ ID NO: 63, SEQ ID NO: 67, SEQ ID NO: 71, or SEQ ID NO: 75.

[0020] In some embodiments, the Siglec-10 binding molecule comprises an amino acid sequence selected from the group consisting of:

[0021] a) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO:77-79 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO:83-85;

[0022] b) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 89-91and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 95-97;

[0023] c) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 101-103 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 107-109;

[0024] d) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 113-115 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 119-121;Attorney Docket No.206193-0150-P1US

[0025] e) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 125-127 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 131-133;

[0026] f) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 137-139 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 143-145;

[0027] g) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO:97-99 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 105- 107;

[0028] h) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 149-151 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 155-157;

[0029] i) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 161-163 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 167-170;

[0030] j) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 174-176 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 180-182;

[0031] k) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 186-188 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 192-194;

[0032] l) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 198-200 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 204-206;

[0033] m) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 210-212 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 216-218;

[0034] n) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 222-224 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 228-230;Attorney Docket No.206193-0150-P1US

[0035] o) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 234-236 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 240-242;

[0036] p) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 246-248 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 252-254;

[0037] q) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 258-260 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 264-266;

[0038] r) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 270-272 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 276-278;

[0039] s) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 282-284 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 288-290; and

[0040] t) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 294-296 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 300-302.

[0041] In some embodiments, the Siglec-10 binding molecule comprises an amino acid sequence selected from the group consisting of:

[0042] a) a variable heavy chain sequence of SEQ ID NO: 1 and a variable light chain sequence of SEQ ID NO:3;

[0043] b) a variable heavy chain sequence of SEQ ID NO:5 and a variable light chain sequence of SEQ ID NO: 7;

[0044] c) a variable heavy chain sequence of SEQ ID NO: 9 and a variable light chain sequence of SEQ ID NO:11;

[0045] d) a variable heavy chain sequence of SEQ ID NO: 13 and a variable light chain sequence of SEQ ID NO: 15;

[0046] e) a variable heavy chain sequence of SEQ ID NO: 17 and a variable light chain sequence of SEQ ID NO: 19;Attorney Docket No.206193-0150-P1US

[0047] f) a variable heavy chain sequence of SEQ ID NO:21 and a variable light chain sequence of SEQ ID NO:23;

[0048] g) a variable heavy chain sequence of SEQ ID NO:25 and a variable light chain sequence of SEQ ID NO:27;

[0049] h) a variable heavy chain sequence of SEQ ID NO:29 and a variable light chain sequence of SEQ ID NO:31;

[0050] i) a variable heavy chain sequence of SEQ ID NO:33 and a variable light chain sequence of SEQ ID NO:35;

[0051] j) a variable heavy chain sequence of SEQ ID NO:37 and a variable light chain sequence of SEQ ID NO:39;

[0052] k) a variable heavy chain sequence of SEQ ID NO:41 and a variable light chain sequence of SEQ ID NO:43;

[0053] l) a variable heavy chain sequence of SEQ ID NO:45 and a variable light chain sequence of SEQ ID NO:47;

[0054] m) a variable heavy chain sequence of SEQ ID NO:49 and a variable light chain sequence of SEQ ID NO: 51;

[0055] n) a variable heavy chain sequence of SEQ ID NO:53 and a variable light chain sequence of SEQ ID NO:55;

[0056] o) a variable heavy chain sequence of SEQ ID NO: 57 and a variable light chain sequence of SEQ ID NO:59;

[0057] p) a variable heavy chain sequence of SEQ ID NO:61 and a variable light chain sequence of SEQ ID NO:63;

[0058] q) a variable heavy chain sequence of SEQ ID NO:65 and a variable light chain sequence of SEQ ID NO:67;

[0059] r) a variable heavy chain sequence of SEQ ID NO: 69 and a variable light chain sequence of SEQ ID NO:71; and

[0060] s) a variable heavy chain sequence of SEQ ID NO: 73 and a variable light chain sequence of SEQ ID NO: 75.

[0061] In some embodiments, the Siglec-10 binding molecule comprises a fusion protein comprising a Siglec-10 antibody, a Siglec-10 binding antibody fragment or a variant of a Siglec-10 antibody.Attorney Docket No.206193-0150-P1US

[0062] In some embodiments, the Siglec-10 binding molecule comprises a humanized antibody or fragment thereof.

[0063] In some embodiments, the invention comprises a nucleic acid molecule, or combination of nucleic acid molecules, comprising one or more nucleotide sequence encoding a Siglec-10 binding molecule.

[0064] In some embodiments, the nucleic acid molecule comprises one or more nucleotide sequence selected from the group consisting of:

[0065] a) a nucleotide sequence encoding a variable heavy chain sequence wherein the nucleotide sequence comprises CDR encoding sequences selected from the group consisting of SEQ ID NO:80-82; SEQ ID NO:92-94; SEQ ID NO: 104- 106; SEQ ID NO:116-118; SEQ ID NO: 128-130; SEQ ID NO: 140-142; SEQ ID NO:152-154; SEQ ID NO:164-166; SEQ ID NO: 177-179; SEQ ID NO: 189-191; SEQ ID NO: 201-203; SEQ ID NO:213-215; SEQ IDNO:225- 227; SEQ ID NO:237-239; SEQ ID NO:249-251; SEQ ID NO: 261-263; SEQ ID NO:273-275; SEQ ID NO:285-287; and SEQ ID NO:297-299; b) a nucleotide sequence encoding a variable light chain sequence wherein the nucleotide sequence comprises CDR encoding sequences selected from the group consisting of SEQ ID NO:86-88; SEQ ID NO:98-101; SEQ ID NO: 110-112; SEQ ID NO: 122-124; SEQ ID NO: 134-136; SEQ ID NO: 146- 148; SEQ ID NO:158-160; SEQ ID NO: 171-173; SEQ ID NO:183-185; SEQ ID NO: 195-197; SEQ ID NO:207-209; SEQ ID NO:219-221; SEQ ID NO:231-233; SEQ ID NO:243-245; SEQ ID NO:255-257; SEQ ID NO:267- 269; SEQ ID NO:279-281; SEQ ID NO:291-293; and SEQ ID NO:303-305; c) a nucleotide sequence having at least 95% identity to a variable heavy chain encoding sequence selected from the group consisting of SEQ ID NO:2; SEQ ID NO:6; SEQ ID NO:10; SEQ ID NO:14; SEQ ID NO:18; SEQ ID NO:22; SEQ ID NO:26; SEQ ID NO:30; SEQ ID NO:34; SEQ ID NO:38; SEQ ID NO:42; SEQ ID NO:46; SEQ ID NO:50; SEQ ID NO:54; SEQ ID NO:58; SEQ ID NO:62; SEQ ID NO:66; SEQ ID NO:70; and SEQ ID NO:74; d) a nucleotide sequence having at least 95% identity to a variable light chain encoding sequence selected from the group consisting of SEQ ID NO:4; SEQAttorney Docket No.206193-0150-P1US

[0066] ID NO:8; SEQ ID NO: 12; SEQ ID NO: 16; SEQ ID NO:20; SEQ ID NO:24; SEQ ID NO:28; SEQ ID NO:32; SEQ ID NO:36; SEQ ID NO:40; SEQ ID NO:44; SEQ ID NO:48; SEQ ID NO:52; SEQ ID NO:56; SEQ ID NO:60; SEQ ID NO:64; SEQ ID NO:68; SEQ ID NO:72; and SEQ ID NO:76; e) a fragment comprising at least 80% of the full- length sequence of a variable heavy chain encoding sequence selected from the group consisting of SEQ ID NO:2; SEQ ID NO:6; SEQ ID NO: 10; SEQ ID NO: 14; SEQ ID NO: 18; SEQ ID NO:22; SEQ ID NO:26; SEQ ID NO:30; SEQ ID NO:34; SEQ ID NO:38; SEQ ID NO:42; SEQ ID NO:46; SEQ ID NO:50; SEQ ID NO:54; SEQ ID NO:58; SEQ ID NO:62; SEQ ID NO:66; SEQ ID NO:70; and SEQ ID NO:74; and

[0067] f) a fragment comprising at least 80% of the full-length sequence of a variable light chain encoding sequence selected from the group consisting of SEQ ID NO:4; SEQ ID NO:8; SEQ ID NO: 12; SEQ ID NO: 16; SEQ ID NO:20; SEQ ID NO:24; SEQ ID NO:28; SEQ ID NO:32; SEQ ID NO:36; SEQ ID NO:40; SEQ ID NO:44; SEQ ID NO:48; SEQ ID NO:52; SEQ ID NO:56; SEQ ID NO:60; SEQ ID NO:64; SEQ ID NO:68; SEQ ID NO:72; and SEQ ID NO:76.

[0068] In some embodiments, the nucleic acid molecule(s) comprises nucleotide sequences selected from the group consisting of:

[0069] a) a first nucleotide sequence comprising SEQ ID NO: 80-82, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 86-88 encoding a variable light chain sequence;

[0070] b) a first nucleotide sequence comprising SEQ ID NO: 92-94, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 98-101 encoding a variable light chain sequence;

[0071] c) a first nucleotide sequence comprising SEQ ID NO: 104-106, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 110-112 encoding a variable light chain sequence;

[0072] d) a first nucleotide sequence comprising SEQ ID NO: 116-118, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 122-124 encoding a variable light chain sequence;Attorney Docket No.206193-0150-P1US

[0073] e) a first nucleotide sequence comprising SEQ ID NO: 128-130, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 134-136 encoding a variable light chain sequence; f) a first nucleotide sequence comprising SEQ ID NO: 140-142, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 146-148 encoding a variable light chain sequence; g) a first nucleotide sequence comprising SEQ ID NO: 152-154, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 158-160 encoding a variable light chain sequence; h) a first nucleotide sequence comprising SEQ ID NO: 164-166, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 171-173 encoding a variable light chain sequence; i) a first nucleotide sequence comprising SEQ ID NO: 177-179, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 183-185 encoding a variable light chain sequence; j) a first nucleotide sequence comprising SEQ ID NO: 189-191, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 195-197 encoding a variable light chain sequence; k) a first nucleotide sequence comprising SEQ ID NO: 201-203, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 207-209 encoding a variable light chain sequence; l) a first nucleotide sequence comprising SEQ ID NO: 213-215, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 219-221 encoding a variable light chain sequence; m) a first nucleotide sequence comprising SEQ ID NO: 225-227, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 231-233 encoding a variable light chain sequence; n) a first nucleotide sequence comprising SEQ ID NO: 237-239, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 243-245 encoding a variable light chain sequence;Attorney Docket No.206193-0150-P1US

[0074] o) a first nucleotide sequence comprising SEQ ID NO: 249-251, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 255-257 encoding a variable light chain sequence; p) a first nucleotide sequence comprising SEQ ID NO: 261-263, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 267-269 encoding a variable light chain sequence; q) a first nucleotide sequence comprising SEQ ID NO: 273-275, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 279-281 encoding a variable light chain sequence; r) a first nucleotide sequence comprising SEQ ID NO: 285-287, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 291-293 encoding a variable light chain sequence; and s) a first nucleotide sequence comprising SEQ ID NO: 297-299, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 303-305 encoding a variable light chain sequence.

[0075] In some embodiments, the nucleic acid molecule(s) comprises nucleotide sequences selected from the group consisting of:

[0076] a) a first nucleotide sequence comprising SEQ ID NO:2, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO:4 encoding a variable light chain sequence;

[0077] b) a first nucleotide sequence comprising SEQ ID NO:6, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 8 encoding a variable light chain sequence;

[0078] c) a first nucleotide sequence comprising SEQ ID NO: 10, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 12 encoding a variable light chain sequence;

[0079] d) a first nucleotide sequence comprising SEQ ID NO: 14, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 16 encoding a variable light chain sequence;Attorney Docket No.206193-0150-P1US

[0080] e) a first nucleotide sequence comprising SEQ ID NO: 18, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO:20 encoding a variable light chain sequence;

[0081] f) a first nucleotide sequence comprising SEQ ID NO:22, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO:24 encoding a variable light chain sequence;

[0082] g) a first nucleotide sequence comprising SEQ ID NO:26, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO:28 encoding a variable light chain sequence;

[0083] h) a first nucleotide sequence comprising SEQ ID NO:30, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO:32 encoding a variable light chain sequence;

[0084] i) a first nucleotide sequence comprising SEQ ID NO:34, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO:36 encoding a variable light chain sequence;

[0085] j) a first nucleotide sequence comprising SEQ ID NO:38, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO:40 encoding a variable light chain sequence;

[0086] k) a first nucleotide sequence comprising SEQ ID NO:42, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO:44 encoding a variable light chain sequence;

[0087] l) a first nucleotide sequence comprising SEQ ID NO:46, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO:48 encoding a variable light chain sequence;

[0088] m) a first nucleotide sequence comprising SEQ ID NO:50, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 52 encoding a variable light chain sequence;

[0089] n) a first nucleotide sequence comprising SEQ ID NO:54, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 56 encoding a variable light chain sequence;Attorney Docket No.206193-0150-P1US

[0090] o) a first nucleotide sequence comprising SEQ ID NO:58, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO:60 encoding a variable light chain sequence;

[0091] p) a first nucleotide sequence comprising SEQ ID NO:62, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO:64 encoding a variable light chain sequence;

[0092] q) a first nucleotide sequence comprising SEQ ID NO:66, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO:68 encoding a variable light chain sequence;

[0093] r) a first nucleotide sequence comprising SEQ ID NO:70, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO:72 encoding a variable light chain sequence; and

[0094] s) a first nucleotide sequence comprising SEQ ID NO:74, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO:76 encoding a variable light chain sequence.

[0095] In some embodiments, the invention relates to a composition comprising a Siglec-10 binding molecule.

[0096] In some embodiments, the composition further comprises at least one selected form the group consisting of a pharmaceutically acceptable excipient and an adjuvant.

[0097] In some embodiments, the invention relates to a composition comprising one or more nucleic acid molecule(s) encoding a Siglec-10 binding molecule.

[0098] In some embodiments, the invention relates to a method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering a Siglec-10 binding molecule, one or more nucleic acid molecules encoding a Siglec-10 binding molecule, or a composition comprising a Siglec-10 binding molecule or one or more nucleic acid molecules encoding a Siglec-10 binding molecule to the subject.

[0099] In some embodiments, the disease or disorder is a cancer, or a disease or disorder associated with cancer. In some embodiments, the cancer is selected from pancreatic cancer and pancreatic ductal adenocarcinoma.Attorney Docket No.206193-0150-P1US

[0100] BRIEF DESCRIPTION OF THE DRAWINGS

[0101] The following detailed description of embodiments of the invention will be better understood when read in conjunction with the appended drawings. It should be understood that the invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings.

[0102] Figure 1, comprising Figure 1A through Figure 1H, depicts PDAC cell lines expressing Siglec-10 ligands other than CD24. Figure 1A depicts the comparison of Siglec-10 and CD24 expression between normal tissues and pancreatic adenocarcinoma (PAAD) tissues from the TCGA dataset. Figure IB depicts schematic representation of the glycan ligands of Siglec-10 on N-linked and O-linked glycans, along with the enzymes involved in their formation. Figure 1C and Figure ID depict the expression levels of sialyltransferase enzymes responsible for Siglec-10 ligand formation compared between normal tissues and PAAD tissues in the TCGA dataset. Figure IE depicts a schematic overview of in vitro cancer cell killing experiments. Human monocyte-derived macrophages were differentiated into macrophages using M-CSF for three days, followed by M-CSF and IL-4 for an additional four days. PDAC cell lines were labeled with pHrodo red dye and co-cultured with macrophages in the presence of either isotype control or CD24 antibody. Phagocytosis was monitored via live cell imaging every hour, with total red area (μm2 / well) used as a measure of phagocytic activity. Figure IF depicts the evaluation of anti-CD24 antibody (olive green bars) in enhancing macrophage-mediated phagocytosis of PDAC cells (AsPC-1, PANC-1, BxPC3, and MiaPaCa-2) compared to isotype control (gray bars) (Top graph). Figure IF also depicts a time-course representation of phagocytosis in AsPC-1 and MiaPaCa-2 cells treated with anti-CD24 antibody (olive green) or isotype control (gray) (Bottom graph). Figure 1G depicts flow cytometric analysis of Siglec-10 ligand and CD24 expression in MiaPaCa-2 cells. Siglec-10 ligands were detected using a recombinant Siglec-10-Fc chimeric protein and a secondary antibody (x-axis), and CD24 was detected using a specific antibody (y-axis). Cells binding Siglec-10 are highlighted (blue box), with subsets expressing CD24 (olive green box) or lacking CD24 expression (purple box). Similar analyses were performed for AsPC-1 and BxPC-3 cells. Figure 1H depicts the quantification of Siglec-10 ligandAttorney Docket No.206193-0150-P1US

[0103] (blue bars) and CD24 (olive green bars) expression in PDAC cell lines by flow cytometry, presented as both the percentage of positive cells and median fluorescence intensity (MFI).

[0104] Figure 2, comprising Figure 2A through Figure 2B, depicts monocyte-derived macrophages expressing Siglec-10. Figure 2A depicts a flow cytometry-based analysis of monocytes for Siglec-10 expression. Figure 2B depicts a flow cytometrybased analysis of macrophages derived from monocytes for Siglec-10 expression.

[0105] Figure 3, comprising Figure 3A through Figure 3F, depicts ITGA3 and ITGBl-sialylated glycoprotein ligands of Siglec-10 glycoproteins on PDAC cells. Figure 3A depicts the experimental design for the pull-down of Siglec-10 ligands on PDAC cells. Recombinant Siglec-10 (as well as no-protein control or Siglec-5 control) Fc was allowed to bind its physiological ligands on the surface of PDAC cells, followed by an HRP-conjugated anti-Fc secondary antibody. In the presence of H2O2, HRP generated short-lived radicals that facilitated the transfer of biotin to proximal Siglec-10 ligands. Biotinylated Siglec-10 ligands were pulled down using streptavidin beads and identified by mass spectrometry. Figure 3B depicts 4,044 proteins that were identified, with enriched binding compared to a control using the anti-Fc antibody only without Siglec-10 protein. Of these, 110 proteins showed enrichment relative to a Siglec-5 control. Six proteins — CD47, CD59, CD73, ITGB6, ITGA3, and ITGB1 — were significantly overexpressed in PAAD tissues compared to normal tissues in the TCGA dataset. Figure 3C depicts response curves showing interactions between Siglec-10 and the six glycoproteins measured by surface plasmon resonance (SPR). Two concentrations (1000 nM, green; 100 nM, red) were tested for all glycoproteins, while ITGA3 was also tested at 300 nM (green) and 30 nM (red). Figure 3D depicts the binding of the SNA lectin (specific for sialic acid) to ITGA3 and ITGB 1 recombinant glycoproteins as measured by a lectin array. Sialidase-treated glycoproteins (red bars) showed significantly reduced binding compared to untreated glycoproteins (blue bars). Unpaired t-tests were used for statistical analyses. Figure 3E depicts SPR response curves comparing the binding of intact (sialylated) ITGA3 and desialylated ITGA3 to immobilized Siglec-10. Figure 3F depicts SPR response curves comparing the binding of intact (sialylated) ITGB1 and desialylated ITGB1 to immobilized Siglec-10.Attorney Docket No.206193-0150-P1US

[0106] Figure 4, comprising Figure 4A and 4B, depicts the high expression of ITGA3 and ITGAB1 in PDAC cells. Figure 4A depicts flow cytometry -based analysis of PDAC cells (MiaPaca-2 and BxPC3) that were examined for their expression of ITGA3. Figure 4B depicts flow cytometry -based analysis of PDAC cells (MiaPaca-2 and BxPC3) that were examined for their expression of ITGB1.

[0107] Figure 5, comprising Figure 5A through Figure 5K, depicts the overexpression of ITGA3 and ITGB1 in PDAC tissues and their association with poor survival in PDAC. Figure 5 A depicts flow cytometric analysis of ITGA3 expression on PDAC cell lines (HS766T, AsPC-1, and PANC-1) along the x-axis. Figure 5B depicts the comparative expression of ITGA3 in PAAD tissues versus normal tissues in the TCGA dataset. Figure 5C depicts flow cytometric analysis of ITGB1 expression on PDAC cell lines (HS766T, AsPC-1, and PANC-1) along the x-axis. Figure 5D depicts the comparative expression of ITGB1 in PAAD tissues versus normal tissues in the TCGA dataset. Figure 5E depicts the survival analysis of pancreatic tumor patients in the TCGA dataset showing the correlation between CD24 expression on overall survival. Figure 5F depicts the survival analysis of pancreatic tumor patients in the TCGA dataset showing the correlation between ITGA3 expression on overall survival. Figure 5G depicts the survival analysis of pancreatic tumor patients in the TCGA dataset showing the correlation between ITGB1 expression on overall survival. Figure 5H depicts Single-cell RNA-seq analysis of publicly available datasets using BBrowser software. Clusters representing distinct cell types were categorized into normal (blue clusters) and PDAC (orange clusters). Figure 51 depicts ITGA3 expression levels in epithelial cell clusters from normal tissues (blue bar) and PDAC tissues (orange bar). The intensity of red represents the expression of ITGA3, with darker shades indicating higher expression levels. Figure 5J depicts pathway analysis comparing ITGA3hland ITGA3lowepithelial cells in PDAC tissues to identify upregulated and downregulated pathways. Figure 5K depicts ITGB1 expression levels in epithelial cell clusters from normal tissues (blue bar) and PDAC tissues (orange bar). The intensity of red represents the expression of ITGB1, with darker shades indicating higher expression levels.

[0108] Figure 6, comprising Figure 6A through Figure 6D, depicts the expression of Siglec-10 and Siglec-10 ligand forming enzymes associated with the expression ofAttorney Docket No.206193-0150-P1US

[0109] ITGA3 and ITGB1. Figure 6A depicts the Spearman r correlation analysis in TCGA of Siglec-10 with ITGA3. Figure 6B depicts the Spearman r correlation analysis in TCGA of ITGA3 with Siglec-10 ligand forming enzymes; ST3GAL1 and B3GNT3. Figure 6C depicts the Spearman r correlation analysis in TCGA of Siglec-10 with ITGB1. Figure 6D depicts the Spearman r correlation analysis in TCGA of ITGB1 with Siglec-10 ligand forming enzymes; ST3GAL1 andB3GNT3.

[0110] Figure 7, comprising Figure 7A through 7D, depicts the high expression of ITGA3 and ITGB1 in PDAC epithelial cells. Figure 7A depicts the ITGB1 high vs low pathway analysis for the overexpression of ITGA3 and ITGB1 in PDAC tissues for Figure 5. Figure 7B depicts single cell RNA seq analysis from publicly available dataset (PMID:36781852) using BBrowser software. Each cluster representing different cell types. Figure 7C depicts ITGA3 expression examination on epithelial cell cluster in PDAC tissue. Figure 7D depicts pathway analysis for ITGA3 high vs low expression in epithelial cells from PDAC tissue from cluster represented in Figure 7C.

[0111] Figure 8, comprising Figure 8A through Figure 8G, depicts how ITGA3-and ITGBl-expressing PDAC cells evade macrophage-mediated phagocytosis. Figure 8A (top panel) depicts a schematic representation of the experimental setup to enrich for ITGA3lowor ITGBllowPDAC cells. Columns coated with anti-ITGA3 or anti-ITGBl antibodies were used to isolate ITGA3lowor ITGBllowcells (cells passing through the columns without binding), respectively. Cells passing through uncoated columns (expressing high levels of ITGA3 or ITGB1) were used as controls. Figure 8A (bottom panels) depict representative flow cytometry analysis showing ITGA3 or ITGB1 expression levels on ITGA3lowor ITGBllowcells compared to controls, using MIA PaCa-2 PDAC cells. Figure 8B depicts a schematic representation of the experimental setup to test the phagocytic capacity of monocyte-derived macrophages targeting control cells (enriched with ITGA3hlcells) or ITGA3lowcells (n = 4-6). Figure 8C and Figure 8D depict Phagocytosis of control and ITGA3lowMIA PaCa-2 (c) or PANCI (d) PDAC cells by macrophages from different donors. Top: Representative images where increased red indicates higher phagocytosis. Bottom left: Live imaging results (each symbol represents data from one donor). Bottom right: Area under the curve (AUC) data compiled from multiple donors. Statistical significance was assessed using ratio paired t-tests. Figure 8EAttorney Docket No.206193-0150-P1US

[0112] depicts a schematic representation of the experimental setup to test the phagocytic capacity of monocyte-derived macrophages targeting control cells (enriched with ITGB1hicells) or ITGBllowcells (n = 4-6). Figure 8F and Figure 8G depict Phagocytosis of control and ITGB110" MIA PaCa-2 or PANCI PDAC cells by macrophages from different donors. Top: Representative images showing phagocytosis (increased red indicates higher phagocytosis). Bottom left: Live imaging results (each symbol represents data from one donor). Bottom right: AUC data compiled from multiple donors.

[0113] Figure 9, comprising Figure 9A through Figure 91, depicts the development of Siglec-10 blocking antibodies to enhance the phagocytosis of PDAC cells by macrophages in vitro. Figure 9A depicts a model illustrating the mechanism of Siglec-10-mediated inhibition of macrophage phagocytosis. Siglec-10 expressed on macrophages binds to its glycan ligands on PDAC cells, which are present on multiple proteins such as ITGA3, ITGB1, and CD24. This interaction induces inhibitory signaling in macrophages, suppressing phagocytosis (left panel). Blocking Siglec-10 with an antibody prevents inhibitory signaling, thereby enhancing macrophage phagocytic ability (right panel). Figure 9B depicts the screening of recombinant antibodies from the top clones for Siglec-10 binding using ELISA. Binding to immobilized Siglec-10 (blue) and Siglec-5 (gray) proteins is shown. Figure 9C depicts flow cytometric analysis of clone selectivity, showing binding to CHO-K1 cells expressing either Siglec-10 (blue) or Siglec-5 (gray). Figure 9D depicts area under the curve (AUC) analysis of an in vitro phagocytosis assay to screen the ability of Siglec-10 antibody clones, as well as the commercially available antibodies against CD24 and Siglec-10, to enhance the phagocytic activity of macrophages against AsPC-1 PDAC cells. Figure 9E depicts AUC analysis of the in vitro phagocytosis assay for the top-performing Siglec-10 antibody clone using macrophages differentiated from the monocytes of four donors. Statistical significance was determined using Friedman's ANOVA test. Figure 9F depicts a timecourse analysis of the in vitro phagocytosis assay for the top Siglec-10 blocking antibody clone (68A11A1, blue) compared to the isotype control (gray). Results are based on n=4 independent experiments. Figure 9G depicts ELISA-based binding analysis of the 68A11A1 recombinant antibody to immobilized recombinant Siglec-10 and Siglec-5 proteins at different dilutions. Figure 9H depicts the evaluation of the ability of anti-Attorney Docket No.206193-0150-P1US

[0114] CD24 or recombinant Siglec-10 antibody (clone 68A11 Al) to enhance macrophage-mediated phagocytosis of several PDAC cell lines (AsPC-1, MIA PaCa-2, and PANC-1). Phagocytosis was normalized to the isotype control for each antibody and conducted using macrophages differentiated from monocytes of 5-8 healthy donors. Each symbol represents data from an individual donor, and statistical analyses were performed using ratio paired t-tests compared to the isotype control. Figure 91 depicts a representative image of the killing assays (red indicates increased killing).

[0115] Figure 10, comprising Figure 10A through Figure 10H, depicts blocking Siglec-10 interactions, enhances macrophage-mediated phagocytosis and reduces PDAC tumor size in vivo. Figure 10A depicts the experimental design for subcutaneous tumor development and Siglec-10 antibody treatment. A total of 2 million AsPC-1 cells were subcutaneously injected into immunodeficient NSG mice. After 7 days, when tumors reached ~45 mm3, mice were randomized into treatment groups. On the indicated days, approximately 3 million monocyte-derived macrophages were injected intravenously along with 200 pg of either isotype control or Siglec-10 antibody. Tumor size was measured on the specified days using a Vernier caliper. On the final day, tumors were excised for RNA-seq analysis. Figure 10B depicts measurement of tumor volume over time in mice treated with isotype control (pink dots) or Siglec-10 antibody (blue dots). Data represents n=10 mice per group. Figure 10C through Figure 10E depicts tumor assessment on day 31 after tumor induction and treatment with reference to tumor volume, tumor weight, and representative tumor images from mice treated with isotype control (grey dots) or Siglec-10 antibody (blue dots). Data represents n=10 mice per group. Figure 10F through Figure 10H depict heatmaps showing differential gene expression in FACS-sorted human macrophages from tumors of subcutaneous PDAC-bearing mice treated with Siglec-10 antibody, highlighting: immune activation pathways (Figure 1 OF), phagocytosis-related genes (Figure 10G), and metabolism-related genes (Figure 10H). Red represents higher expression while blue represents lower expression.

[0116] Figure 11 depicts a gating strategy for sorting the human tumor associated macrophages from mouse subcutaneous tumor. Single cell suspension from mouse subcutaneous tumor was used to obtain human monocytes derived macrophages injectedAttorney Docket No.206193-0150-P1US

[0117] 12hr intravenously for RNA seq analysis. Mouse BV711-CD45’ and Human APC-CD45+cells were sorted for RNA seq analysis.

[0118] DETAILED DESCRIPTION

[0119] The present invention relates to sialic acid receptor antibodies, fragments thereof, variants thereof, or a nucleic acid molecule encoding the same, and methods of use to enhance macrophage phagocytosis of cancer cells in a subject in need thereof.

[0120] In one aspect, the present invention relates to a composition that can be used to increase or enhance an immune response, i.e., create a more effective immune response, by administering sialic acid receptor antibodies, fragments thereof, variants thereof, or a nucleic acid molecule encoding the same. In one embodiment, the sialic acid receptor antibody is an antibody against Siglec-10. In one embodiment, the composition enhances macrophage phagocytosis of cancer cells in a subject in need thereof. In some embodiments, the cancer cells are pancreatic ductal adenocarcinoma (PDAC) cells.

[0121] In one aspect, the present invention relates to methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a sialic acid receptor antibody, fragment thereof, variant thereof, or a nucleic acid molecule encoding the same. In some embodiments, the sialic acid receptor antibody is an antibody against Siglec-10. In one embodiment, the disease or disorder is cancer. In one embodiment, the disease or disorder is pancreatic ductal adenocarcinoma.

[0122] Definitions

[0123] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, exemplary methods and materials are described.

[0124] As used herein, each of the following terms has the meaning associated with it in this section.Attorney Docket No.206193-0150-P1US

[0125] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0126] “About” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, or ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[0127] “Antibody” may mean an antibody of classes IgG, IgM, IgA, IgD or IgE, or fragments, fragments or derivatives thereof, including Fab, F(ab')2, Fd, and single chain antibodies, and derivatives thereof. The antibody may be an antibody isolated from the serum sample of mammal, a polyclonal antibody, affinity purified antibody, or mixtures thereof which exhibits sufficient binding specificity to a desired epitope, or a sequence derived therefrom.

[0128] “Antigen” refers to proteins that have the ability to generate an immune response in a host. An antigen may be recognized and bound by an antibody. An antigen may originate from within the body or from the external environment.

[0129] “CDRs” are defined as the complementarity determining region amino acid sequences of an antibody which are the hypervariable regions of immunoglobulin heavy and light chains. See, e.g., Kabat et al., Sequences of Proteins of Immunological Interest, 4th Ed., U. S. Department of Health and Human Services, National Institutes of Health (1987). There are three heavy chain and three light chain CDRs (or CDR regions) in the variable portion of an immunoglobulin. Thus, “CDRs” as used herein refers to all three heavy chain CDRs, or all three light chain CDRs (or both all heavy and all light chain CDRs, if appropriate). The structure and protein folding of the antibody may mean that other residues are considered part of the antigen binding region and would be understood to be so by a skilled person. See for example Chothia et al., (1989) Conformations of immunoglobulin hypervariable regions; Nature 342, p 877-883.

[0130] “Antibody fragment” or “fragment of an antibody” as used interchangeably herein refers to a portion of an intact antibody comprising the antigenbinding site or variable region. The portion does not include the constant heavy chain domains (i.e. CH2, CH3, or CH4, depending on the antibody isotype) of the Fc region ofAttorney Docket No.206193-0150-P1US

[0131] the intact antibody. Examples of antibody fragments include, but are not limited to, Fab fragments, Fab' fragments, Fab'-SH fragments, F(ab')2fragments, Fd fragments, Fv fragments, diabodies, single-chain Fv (scFv) molecules, single-chain polypeptides containing only one light chain variable domain, single-chain polypeptides containing the three CDRs of the light-chain variable domain, single-chain polypeptides containing only one heavy chain variable region, and single-chain polypeptides containing the three CDRs of the heavy chain variable region.

[0132] “Adjuvant” as used herein means any molecule added to the vaccine described herein to enhance the immunogenicity of the antigen.

[0133] “Coding sequence” or “encoding nucleic acid” as used herein may refer to the nucleic acid (RNA or DNA molecule) that comprise a nucleotide sequence which encodes an antibody as set forth herein. The coding sequence may also comprise a DNA sequence which encodes an RNA sequence. The coding sequence may further include initiation and termination signals operably linked to regulatory elements including a promoter and polyadenylation signal capable of directing expression in the cells of an individual or mammal to whom the nucleic acid is administered. The coding sequence may further include sequences that encode signal peptides.

[0134] “Complement” or “complementary” as used herein may mean a nucleic acid may have Watson-Crick (e.g., A-T / U and C-G) or Hoogsteen base pairing between nucleotides or nucleotide analogs of nucleic acid molecules.

[0135] A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate.

[0136] In contrast, a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health.

[0137] A disease or disorder is “alleviated” if the severity of a sign or symptom of the disease or disorder, the frequency with which such a sign or symptom is experienced by a patient, or both, is reduced.Attorney Docket No.206193-0150-P1US

[0138] “Encoding” refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as a gene, a cDNA, or an mRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (i.e., rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom. Thus, a gene encodes a protein if transcription and translation of mRNA corresponding to that gene produces the protein in a cell or other biological system. Both the coding strand, the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in sequence listings, and the non-coding strand, used as the template for transcription of a gene or cDNA, can be referred to as encoding the protein or other product of that gene or cDNA.

[0139] An “effective amount” of a compound is that amount of compound which is sufficient to provide an effect to the subject or system to which the compound is administered.

[0140] “Expression vector” refers to a vector comprising a recombinant polynucleotide comprising expression control sequences operatively linked to a nucleotide sequence to be expressed. An expression vector comprises sufficient cis-acting elements for expression; other elements for expression can be supplied by the host cell or in an in vitro expression system. Expression vectors include all those known in the art, such as cosmids, plasmids (e.g., naked or contained in liposomes) and viruses (e.g., lentiviruses, retroviruses, adenoviruses, and adeno-associated viruses) that incorporate the recombinant polynucleotide.

[0141] “Feedback mechanism” as used herein may refer to a process performed by either software or hardware (or firmware), which process receives and compares the impedance of the desired tissue (before, during, and / or after the delivery of pulse of energy) with a present value, preferably current, and adjusts the pulse of energy delivered to achieve the preset value. A feedback mechanism may be performed by an analog closed loop circuit.

[0142] “Fragment” may mean a polypeptide fragment of an antibody that is function, i.e., can bind to desired target and have the same intended effect as a full length antibody. A fragment of an antibody may be 100% identical to the full length exceptAttorney Docket No.206193-0150-P1US

[0143] missing at least one amino acid from the N and / or C terminal, in each case with or without signal peptides and / or a methionine at position 1. Fragments may comprise 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more percent of the length of the particular full length antibody, excluding any heterologous signal peptide added. The fragment may comprise a fragment of a polypeptide that is 95% or more, 96% or more, 97% or more, 98% or more or 99% or more identical to the antibody and additionally comprise an N terminal methionine or heterologous signal peptide which is not included when calculating percent identity. Fragments may further comprise an N terminal methionine and / or a signal peptide such as an immunoglobulin signal peptide, for example an IgE or IgG signal peptide. The N terminal methionine and / or signal peptide may be linked to a fragment of an antibody.

[0144] A fragment of a nucleic acid sequence that encodes an antibody may be 100% identical to the full length except missing at least one nucleotide from the 5' and / or 3' end, in each case with or without sequences encoding signal peptides and / or a methionine at position 1. Fragments may comprise 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more percent of the length of the particular full length coding sequence, excluding any heterologous signal peptide added. The fragment may comprise a fragment that encode a polypeptide that is 95% or more, 96% or more, 97% or more, 98% or more or 99% or more identical to the antibody and additionally optionally comprise sequence encoding an N terminal methionine or heterologous signal peptide which is not included when calculating percent identity. Fragments may further comprise coding sequences for an N terminal methionine and / or a signal peptide such as an immunoglobulin signal peptide, for example an IgE or IgG signal peptide. The coding sequence encoding the N terminal methionine and / or signal peptide may be linked to a fragment of coding sequence.Attorney Docket No.206193-0150-P1US

[0145] “Genetic construct” as used herein refers to the DNA or RNA molecules that comprise a nucleotide sequence which encodes a protein, such as an antibody. The genetic construct may also refer to a DNA molecule which transcribes an RNA. The coding sequence includes initiation and termination signals operably linked to regulatory elements including a promoter and polyadenylation signal capable of directing expression in the cells of the individual to whom the nucleic acid molecule is administered. As used herein, the term “expressible form” refers to gene constructs that contain the necessary regulatory elements operable linked to a coding sequence that encodes a protein such that when present in the cell of the individual, the coding sequence will be expressed.

[0146] “Homologous” refers to the sequence similarity or sequence identity between two polypeptides or between two nucleic acid molecules. When a position in both of the two compared sequences is occupied by the same base or amino acid monomer subunit, e g., if a position in each of two DNA molecules is occupied by adenine, then the molecules are homologous at that position. The percent of homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences divided by the number of positions compared X 100. For example, if 6 of 10 of the positions in two sequences are matched or homologous then the two sequences are 60% homologous. By way of example, the DNA sequences ATTGCC and TATGGC share 50% homology. Generally, a comparison is made when two sequences are aligned to give maximum homology.

[0147] “Identical” or “identity” as used herein in the context of two or more nucleic acids or polypeptide sequences means that the sequences have a specified percentage of residues that are the same over a specified region. The percentage can be calculated by optimally aligning the two sequences, comparing the two sequences over the specified region, determining the number of positions at which the identical residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the specified region, and multiplying the result by 100 to yield the percentage of sequence identity. In cases where the two sequences are of different lengths or the alignment produces one or more staggered ends and the specified region of comparison includes only a single sequence, the residues of the single sequence are included in the denominator but not the numeratorAttorney Docket No.206193-0150-P1US

[0148] of the calculation. When comparing DNA and RNA, thymine (T) and uracil (U) can be considered equivalent. Identity can be performed manually or by using a computer sequence algorithm such as BLAST or BLAST 2.0.

[0149] “Isolated” means altered or removed from the natural state. For example, a nucleic acid or a peptide naturally present in a living animal is not “isolated,” but the same nucleic acid or peptide partially or completely separated from the coexisting materials of its natural state is “isolated.” An isolated nucleic acid or protein can exist in substantially purified form, or can exist in a non-native environment such as, for example, a host cell.

[0150] In the context of the present invention, the following abbreviations for the commonly occurring nucleic acid bases are used. “A” refers to adenosine, “C” refers to cytosine, “G” refers to guanosine, “T” refers to thymidine, and “U” refers to uridine.

[0151] Unless otherwise specified, a “nucleotide sequence encoding an amino acid sequence” includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. The phrase nucleotide sequence that encodes a protein or an RNA may also include introns to the extent that the nucleotide sequence encoding the protein may in some version contain an intron(s).

[0152] “Impedance” as used herein may be used when discussing the feedback mechanism and can be converted to a current value according to Ohm's law, thus enabling comparisons with the preset current.

[0153] “Immune response” as used herein may mean the activation of a host’s immune system, e.g., that of a mammal, in response to the introduction of one or more nucleic acids and / or peptides. The immune response can be in the form of a cellular or humoral response, or both.

[0154] The terms “patient,” “subject,” “individual,” and the like are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In some embodiments, the patient, subject or individual is a human.

[0155] “Parenteral” administration of a composition includes, e.g., subcutaneous (s.c ), intravenous (i.v.), intramuscular (i.m.), or intradermal injection, or infusion techniques.Attorney Docket No.206193-0150-P1US

[0156] “Nucleic acid” or “oligonucleotide” or “polynucleotide” as used herein may mean at least two nucleotides covalently linked together. The depiction of a single strand also defines the sequence of the complementary strand. Thus, a nucleic acid also encompasses the complementary strand of a depicted single strand. Many variants of a nucleic acid may be used for the same purpose as a given nucleic acid. Thus, a nucleic acid also encompasses substantially identical nucleic acids and complements thereof. A single strand provides a probe that may hybridize to a target sequence under stringent hybridization conditions. Thus, a nucleic acid also encompasses a probe that hybridizes under stringent hybridization conditions.

[0157] Nucleic acids may be single stranded or double stranded or may contain portions of both double stranded and single stranded sequence. The nucleic acid may be DNA, both genomic and cDNA, RNA, or a hybrid, where the nucleic acid may contain combinations of deoxyribo- and ribo-nucleotides, and combinations of bases including uracil, adenine, thymine, cytosine, guanine, inosine, xanthine hypoxanthine, isocytosine and isoguanine. Nucleic acids may be obtained by chemical synthesis methods or by recombinant methods.

[0158] “Operably linked” as used herein may mean that expression of a gene is under the control of a promoter with which it is spatially connected. A promoter may be positioned 5' (upstream) or 3' (downstream) of a gene under its control. The distance between the promoter and a gene may be approximately the same as the distance between that promoter and the gene it controls in the gene from which the promoter is derived. As is known in the art, variation in this distance may be accommodated without loss of promoter function.

[0159] A “peptide,” “protein,” or “polypeptide” as used herein can mean a linked sequence of amino acids and can be natural, synthetic, or a modification or combination of natural and synthetic.

[0160] “Promoter” as used herein may mean a synthetic or naturally-derived molecule which is capable of conferring, activating or enhancing expression of a nucleic acid in a cell. A promoter may comprise one or more specific transcriptional regulatory sequences to further enhance expression and / or to alter the spatial expression and / or temporal expression of same. A promoter may also comprise distal enhancer or repressorAttorney Docket No.206193-0150-P1US

[0161] elements, which can be located as much as several thousand base pairs from the start site of transcription. A promoter may be derived from sources including viral, bacterial, fungal, plants, insects, and animals. A promoter may regulate the expression of a gene component constitutively or differentially with respect to cell, the tissue or organ in which expression occurs or, with respect to the developmental stage at which expression occurs, or in response to external stimuli such as physiological stresses, pathogens, metal ions, or inducing agents. Representative examples of promoters include the bacteriophage T7 promoter, bacteriophage T3 promoter, SP6 promoter, lac operator-promoter, tac promoter, SV40 late promoter, SV40 early promoter, RSV-LTR promoter, CMV IE promoter, SV40 early promoter or SV 40 late promoter and the CMV IE promoter.

[0162] As used herein, the term “promoter / regulatory sequence” means a nucleic acid sequence which is required for expression of a gene product operably linked to the promoter / regulatory sequence. In some instances, this sequence may be the core promoter sequence and in other instances, this sequence may also include an enhancer sequence and other regulatory elements which are required for expression of the gene product. The promoter / regulatory sequence may, for example, be one which expresses the gene product in a tissue specific manner.

[0163] A “constitutive” promoter is a nucleotide sequence which, when operably linked with a polynucleotide which encodes or specifies a gene product, causes the gene product to be produced in a cell under most or all physiological conditions of the cell.

[0164] An “inducible” promoter is a nucleotide sequence which, when operably linked with a polynucleotide which encodes or specifies a gene product, causes the gene product to be produced in a cell substantially only when an inducer which corresponds to the promoter is present in the cell.

[0165] A “tissue-specific” promoter is a nucleotide sequence which, when operably linked with a polynucleotide encodes or specified by a gene, causes the gene product to be produced in a cell substantially only if the cell is a cell of the tissue type corresponding to the promoter.

[0166] “Signal peptide” and “leader sequence” are used interchangeably herein and refer to an amino acid sequence that can be linked at the amino terminus of a protein set forth herein. Signal peptides / leader sequences typically direct localization of a protein.Attorney Docket No.206193-0150-P1US

[0167] Signal peptides / leader sequences used herein may facilitate secretion of the protein from the cell in which it is produced. Signal peptides / leader sequences are often cleaved from the remainder of the protein, often referred to as the mature protein, upon secretion from the cell. Signal peptides / leader sequences are linked at the N terminus of the protein.

[0168] “Stringent hybridization conditions” as used herein may mean conditions under which a first nucleic acid sequence (e.g., probe) will hybridize to a second nucleic acid sequence (e.g., target), such as in a complex mixture of nucleic acids. Stringent conditions are sequence dependent and will be different in different circumstances.

[0169] Stringent conditions may be selected to be about 5-10°C lower than the thermal melting point (Tm) for the specific sequence at a defined ionic strength pH. The Tmmay be the temperature (under defined ionic strength, pH, and nucleic concentration) at which 50% of the probes complementary to the target hybridize to the target sequence at equilibrium (as the target sequences are present in excess, at Tm, 50% of the probes are occupied at equilibrium). Stringent conditions may be those in which the salt concentration is less than about 1.0 M sodium ion, such as about 0.01-1.0 M sodium ion concentration (or other salts) at pH 7.0 to 8.3 and the temperature is at least about 30°C for short probes (e g., about 10-50 nucleotides) and at least about 60°C for long probes (e.g., greater than about 50 nucleotides). Stringent conditions may also be achieved with the addition of destabilizing agents such as formamide. For selective or specific hybridization, a positive signal may be at least 2 to 10 times background hybridization. Exemplary stringent hybridization conditions include the following: 50% formamide, 5x SSC, and 1% SDS, incubating at 42°C, or, 5x SSC, 1% SDS, incubating at 65°C, with wash in 0.2x SSC, and 0.1% SDS at 65°C.

[0170] “Subject” and “patient” as used herein interchangeably refers to any vertebrate, including, but not limited to, a mammal (e.g., cow, pig, camel, llama, horse, goat, rabbit, sheep, hamsters, guinea pig, cat, dog, rat, and mouse, a non-human primate (for example, a monkey, such as a cynomolgous or rhesus monkey, chimpanzee, etc) and a human). In some embodiments, the subject may be a human or a non-human. The subject or patient may be undergoing other forms of treatment.

[0171] “Substantially complementary” as used herein may mean that a first sequence is at least 60%, 65%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,Attorney Docket No.206193-0150-P1US

[0172] 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the complement of a second sequence over a region of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more nucleotides or amino acids, or that the two sequences hybridize under stringent hybridization conditions.

[0173] “Substantially identical” as used herein may mean that a first and second sequence are at least 60%, 65%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical over a region of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100 or more nucleotides or amino acids, or with respect to nucleic acids, if the first sequence is substantially complementary to the complement of the second sequence.

[0174] “Synthetic antibody” as used herein refers to an antibody that is encoded by the recombinant nucleic acid sequence described herein and is generated in a subject.

[0175] “Treatment” or “treating,” as used herein can mean protecting of a subject from a disease through means of preventing, suppressing, repressing, or completely eliminating the disease. Preventing the disease involves administering a vaccine of the present invention to a subject prior to onset of the disease. Suppressing the disease involves administering a vaccine of the present invention to a subject after induction of the disease but before its clinical appearance. Repressing the disease involves administering a vaccine of the present invention to a subject after clinical appearance of the disease.

[0176] A “therapeutic” treatment is a treatment administered to a subject who exhibits signs or symptoms of a disease or disorder, for the purpose of diminishing or eliminating the frequency or severity of those signs or symptoms.

[0177] As used herein, “treating a disease or disorder” means reducing the frequency or severity, or both, of at least one sign or symptom of the disease or disorder experienced by a patient.

[0178] The phrase “therapeutically effective amount,” as used herein, refers to an amount that is sufficient or effective to prevent or treat (delay or prevent the onset of,Attorney Docket No.206193-0150-P1US

[0179] prevent the progression of, inhibit, decrease or reverse) a disease or disorder, including alleviating signs and / or symptoms of such diseases and disorders.

[0180] To “treat” a disease or disorder as the term is used herein, means to reduce the frequency or severity of at least one sign or symptom of a disease or disorder experienced by a subject.

[0181] “Variant” used herein with respect to a nucleic acid means (i) a portion or fragment of a referenced nucleotide sequence; (ii) the complement of a referenced nucleotide sequence or portion thereof; (iii) a nucleic acid that is substantially identical to a referenced nucleic acid or the complement thereof; or (iv) a nucleic acid that hybridizes under stringent conditions to the referenced nucleic acid, complement thereof, or a sequences substantially identical thereto.

[0182] Variant can further be defined as a peptide or polypeptide that differs in amino acid sequence by the insertion, deletion, or conservative substitution of amino acids, but retain at least one biological activity. Representative examples of “biological activity” include the ability to be bound by a specific antibody or to promote an immune response. Variant can also mean a protein with an amino acid sequence that is substantially identical to a referenced protein with an amino acid sequence that retains at least one biological activity. A conservative substitution of an amino acid, i.e., replacing an amino acid with a different amino acid of similar properties (e.g., hydrophilicity, degree and distribution of charged regions) is recognized in the art as typically involving a minor change. These minor changes can be identified, in part, by considering the hydropathic index of amino acids, as understood in the art. Kyte et al., J. Mol. Biol. 157:105-132 (1982). The hydropathic index of an amino acid is based on a consideration of its hydrophobicity and charge. It is known in the art that amino acids of similar hydropathic indexes can be substituted and still retain protein function. In one aspect, amino acids having hydropathic indexes of ±2 are substituted. The hydrophilicity of amino acids can also be used to reveal substitutions that would result in proteins retaining biological function. A consideration of the hydrophilicity of amino acids in the context of a peptide permits calculation of the greatest local average hydrophilicity of that peptide, a useful measure that has been reported to correlate well with antigenicity and immunogenicity. Substitution of amino acids having similar hydrophilicity values canAttorney Docket No.206193-0150-P1US

[0183] result in peptides retaining biological activity, for example immunogenicity, as is understood in the art. Substitutions can be performed with amino acids having hydrophilicity values within ±2 of each other. Both the hydrophobicity index and the hydrophilicity value of amino acids are influenced by the particular side chain of that amino acid. Consistent with that observation, amino acid substitutions that are compatible with biological function are understood to depend on the relative similarity of the amino acids, and particularly the side chains of those amino acids, as revealed by the hydrophobicity, hydrophilicity, charge, size, and other properties.

[0184] A variant may be a nucleic acid sequence that is substantially identical over the full length of the full gene sequence or a fragment thereof. The nucleic acid sequence may be 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical over the full length of the gene sequence or a fragment thereof. A variant may be an amino acid sequence that is substantially identical over the full length of the amino acid sequence or fragment thereof. The amino acid sequence may be 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical over the full length of the amino acid sequence or a fragment thereof.

[0185] A “vector” is a composition of matter which comprises an isolated nucleic acid and which can be used to deliver the isolated nucleic acid to the interior of a cell. Numerous vectors are known in the art including, but not limited to, linear polynucleotides, polynucleotides associated with ionic or amphiphilic compounds, plasmids, and viruses. Thus, the term “vector” includes an autonomously replicating plasmid or a virus. The term should also be construed to include non-plasmid and non-viral compounds which facilitate transfer of nucleic acid into cells, such as, for example, polylysine compounds, liposomes, and the like. Examples of viral vectors include, but are not limited to, adenoviral vectors, adeno-associated virus vectors, retroviral vectors, and the like.

[0186] Ranges: throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should beAttorney Docket No.206193-0150-P1US

[0187] considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0188]

[0189] Provided herein are antibodies or antibodydike molecules which specifically bind to Siglec-10. In one embodiment, the invention provides immunogenic compositions comprising the antibodies or antibody-like molecules which specifically bind to Siglec-10, a fragment thereof, a variant thereof, or a nucleic acid molecule encoding the same of the invention.

[0190] Therefore, in some embodiments, the invention provides compositions comprising one or more antibody that specifically binds to Siglec-10, a fragment thereof, or a variant thereof, or a nucleic acid molecule encoding the same. In some embodiments, the antibody that binds to Siglec-10 is a humanized antibody.

[0191] In some embodiments, the invention provides methods of treating or preventing a disease or disorder comprising administering to a subject an antibody or antibody-like molecule which specifically binds to Siglec-10, a fragment thereof, a variant thereof, or a nucleic acid molecule encoding the same of the invention. In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is pancreatic ductal adenocarcinoma (PDAC).

[0192] Antibody compositions

[0193] In one embodiment, the invention relates to compositions comprising at least one Siglec-10 antibody, or a fragment or variant thereof.

[0194] In one embodiment, the anti-siglec-10 antibody, or fragment thereof comprises a heavy chain variable region having an amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 13, SEQ ID NO: 17, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 37, SEQ ID NO: 41, SEQ ID NO: 45, SEQ ID NO: 49, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 61,Attorney Docket No.206193-0150-P1US

[0195] SEQ ID NO: 65, SEQ ID NO: 69, or SEQ ID NO: 73 or a fragment or variant thereof. In one embodiment, the anti-siglec-10 antibody, or fragment thereof comprises a light chain variable region having an amino acid sequence of SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 15, SEQ ID NO: 19, SEQ ID NO: 23, SEQ ID NO: 27, SEQ ID NO: 31, SEQ ID NO: 35, SEQ ID NO: 39, SEQ ID NO: 43, SEQ ID NO: 47, SEQ ID NO: 51, SEQ ID NO: 55, SEQ ID NO: 59, SEQ ID NO: 63, SEQ ID NO: 67, SEQ ID NO: 71, or SEQ ID NO: 75, or a fragment or variant thereof.

[0196] In one embodiment, the antibody comprises a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO:77-79 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO:83-85. In one embodiment, the antibody comprises a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO:89-91 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO:95-97. In one embodiment, the antibody comprises a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 101-103 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 107-109. In one embodiment, the antibody comprises a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 113-115 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 119-121. In one embodiment, the antibody comprises a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 125-127 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 131-133. In one embodiment, the antibody comprises a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 137-139 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 143-146. In one embodiment, the antibody comprises a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 149-151 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 155-157. In one embodiment, the antibody comprises a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 161-163 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 167-170. In one embodiment, the antibody comprises a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 174-176 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 180-182. In one embodiment,Attorney Docket No.206193-0150-P1US

[0197] the antibody comprises a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 186-188 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 192-194. In one embodiment, the antibody comprises a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 198-200 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO:204-206. In one embodiment, the antibody comprises a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO:210-212 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO:216-218. In one embodiment, the antibody comprises a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO:222-224 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO:228-230. In one embodiment, the antibody comprises a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO:234-236 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO:240-242. In one embodiment, the antibody comprises a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO:246-248 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO:252-254. In one embodiment, the antibody comprises a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO:258-260 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO:264-266. In one embodiment, the antibody comprises a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO:270-272 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO:276-278. In one embodiment, the antibody comprises a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO:282-284 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO:288-290. In one embodiment, the antibody comprises a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO:294-296 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO:300-302.

[0198] In one embodiment, the antibody comprises a variable heavy chain sequence of SEQ ID NO: 1 and a variable light chain sequence of SEQ ID NO: 3. In one embodiment, the antibody comprises a variable heavy chain sequence of SEQ ID NO: 5 and a variable light chain sequence of SEQ ID NO:7. In one embodiment, the antibodyAttorney Docket No.206193-0150-P1US

[0199] comprises a variable heavy chain sequence of SEQ ID NO:9 and a variable light chain sequence of SEQ ID NO: 11. In one embodiment, the antibody comprises a variable heavy chain sequence of SEQ ID NO: 13 and a variable light chain sequence of SEQ ID NO: 15. In one embodiment, the antibody comprises a variable heavy chain sequence of SEQ ID NO: 17 and a variable light chain sequence of SEQ ID NO: 19. In one embodiment, the antibody comprises a variable heavy chain sequence of SEQ ID NO:21 and a variable light chain sequence of SEQ ID NO:23. In one embodiment, the antibody comprises a variable heavy chain sequence of SEQ ID NO:25 and a variable light chain sequence of SEQ ID NO: 27. In one embodiment, the antibody comprises a variable heavy chain sequence of SEQ ID NO: 29 and a variable light chain sequence of SEQ ID NO: 31. In one embodiment, the antibody comprises a variable heavy chain sequence of SEQ ID NO: 33 and a variable light chain sequence of SEQ ID NO: 35. In one embodiment, the antibody comprises a variable heavy chain sequence of SEQ ID NO: 37 and a variable light chain sequence of SEQ ID NO: 39. In one embodiment, the antibody comprises a variable heavy chain sequence of SEQ ID NO: 41 and a variable light chain sequence of SEQ ID NO: 43. In one embodiment, the antibody comprises a variable heavy chain sequence of SEQ ID NO: 45 and a variable light chain sequence of SEQ ID NO: 47. In one embodiment, the antibody comprises a variable heavy chain sequence of SEQ ID NO: 49 and a variable light chain sequence of SEQ ID NO: 51. In one embodiment, the antibody comprises a variable heavy chain sequence of SEQ ID NO: 53 and a variable light chain sequence of SEQ ID NO: 55. In one embodiment, the antibody comprises a variable heavy chain sequence of SEQ ID NO: 57 and a variable light chain sequence of SEQ ID NO: 59. In one embodiment, the antibody comprises a variable heavy chain sequence of SEQ ID NO: 61 and a variable light chain sequence of SEQ ID NO: 63. In one embodiment, the antibody comprises a variable heavy chain sequence of SEQ ID NO: 65 and a variable light chain sequence of SEQ ID NO: 67. In one embodiment, the antibody comprises a variable heavy chain sequence of SEQ ID NO: 69 and a variable light chain sequence of SEQ ID NO: 71. In one embodiment, the antibody comprises a variable heavy chain sequence of SEQ ID NO: 73 and a variable light chain sequence of SEQ ID NO: 75.Attorney Docket No.206193-0150-P1US

[0200] In some embodiments, a variant of an amino acid sequence as described herein comprises at least about 60% identity, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, 99% or higher identity over a specified region when compared to a defined amino acid sequence. In some embodiments, a variant of an amino acid sequence as described herein comprises at least about 60% identity, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, 99% or higher identity over the full length of variable heavy chain having an amino acid sequence of one or more of SEQ ID NO: 1, SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 13, SEQ ID NO: 17, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 37, SEQ ID NO: 41, SEQ ID NO: 45, SEQ ID NO: 49, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 61, SEQ ID NO: 65, SEQ ID NO: 69, or SEQ ID NO: 73, or over the full length of variable light chain having an amino acid sequence of one or more of SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 15, SEQ ID NO: 19, SEQ ID NO: 23, SEQ ID NO: 27, SEQ ID NO: 31, SEQ ID NO: 35, SEQ ID NO: 39, SEQ ID NO: 43, SEQ ID NO: 47, SEQ ID NO: 51, SEQ ID NO: 55, SEQ ID NO: 59, SEQ ID NO: 63, SEQ ID NO: 67, SEQ ID NO: 71, or SEQ ID NO: 75.

[0201] In some embodiments, the variant of SEQ ID NO: 1, SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 13, SEQ ID NO: 17, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 37, SEQ ID NO: 41, SEQ ID NO: 45, SEQ ID NO: 49, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 61, SEQ ID NO: 65, SEQ ID NO: 69, or SEQ ID NO: 73, comprises 100% identity to all three CDR regions of SEQ ID NO: 1, SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 13, SEQ ID NO: 17, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 37, SEQ ID NO: 41, SEQ ID NO: 45, SEQ ID NO: 49, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 61, SEQ ID NO: 65, SEQ ID NO: 69, or SEQ ID NO: 73. In some embodiments, the variant of SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 15, SEQ ID NO: 19, SEQ ID NO: 23, SEQ ID NO: 27, SEQ ID NO: 31, SEQ ID NO: 35, SEQ ID NO: 39, SEQ ID NO: 43, SEQ ID NO: 47, SEQ ID NO: 51, SEQ ID NO: 55, SEQ ID NO: 59,Attorney Docket No.206193-0150-P1US

[0202] SEQ ID NO: 63, SEQ ID NO: 67, SEQ ID NO: 71, or SEQ ID NO: 75 comprises 100% identity to all three CDR regions of SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 15, SEQ ID NO: 19, SEQ ID NO: 23, SEQ ID NO: 27, SEQ ID NO: 31, SEQ ID NO: 35, SEQ ID NO: 39, SEQ ID NO: 43, SEQ ID NO: 47, SEQ ID NO: 51, SEQ ID NO: 55, SEQ ID NO: 59, SEQ ID NO: 63, SEQ ID NO: 67, SEQ ID NO: 71, or SEQ ID NO: 75.

[0203] As used herein, the term "antibody" or "immunoglobulin" refers to proteins (including glycoproteins) of the immunoglobulin (Ig) superfamily of proteins. An antibody or immunoglobulin (Ig) molecule may be tetrameric, comprising two identical light chain polypeptides and two identical heavy chain polypeptides. The two heavy chains are linked together by disulfide bonds, and each heavy chain is linked to a light chain by a disulfide bond. Each full-length Ig molecule contains at least two binding sites for a specific target or antigen.

[0204] A sialic acid-binding receptor antibody, or antigen-binding fragment thereof, includes, but is not limited to a polyclonal antibody, a monoclonal fusion proteins, antibodies or fragments thereof, chimerized or chimeric fusion proteins, antibodies or fragments thereof, humanized fusion proteins, antibodies or fragments thereof, deimmunized humfusion proteins, antibodies or fragments thereof, fully humfusion proteins, antibodies or fragments thereof, single chain antibody, single chain Fv fragment (scFv), Fv, Fd fragment, Fab fragment, Fab' fragment, F(ab')2fragment, diabody or antigen- binding fragment thereof, minibody or antigen-binding fragment thereof, triabody or antigen- binding fragment thereof, domain fusion proteins, antibodies or fragments thereof, camelid fusion proteins, antibodies or fragments thereof, dromedary fusion proteins, antibodies or fragments thereof, phage-displayed fusion proteins, antibodies or fragments thereof, or antibody, or antigen- binding fragment thereof, identified with a repetitive backbone array (e.g. repetitive antigen display).

[0205] The immune system produces several different classes of Ig molecules (isotypes), including IgA, IgD, IgE, IgG, and IgM, each distinguished by the particular class of heavy chain polypeptide present: alpha (a) found in IgA, delta (8) found in IgD, epsilon (s) found in IgE, gamma (y) found in IgG, and mu (p) found in IgM. There are at least five different y heavy chain polypeptides (isotypes) found in IgG. In contrast, thereAttorney Docket No.206193-0150-P1US

[0206] are only two light chain polypeptide isotypes, referred to as kappa (K) and lambda (X) chains. The distinctive characteristics of antibody isotypes are defined by sequences of the constant domains of the heavy chain.

[0207] An IgG molecule comprises two light chains (either K or X form) and two heavy chains (y form) bound together by disulfide bonds. The K and X forms of IgG light chain each contain a domain of relatively variable amino acid sequences, called the variable region (variously referred to as a " VL-," " VK-," or " Vx-region") and a domain of relatively conserved amino acid sequences, called the constant region (Ct-region).

[0208] Similarly, each IgG heavy chain contains a variable region (Vn-region) and one or more conserved regions: a complete IgG heavy chain contains three constant domains (" CHI-,"11CH2-," and " CiG-regions") and a hinge region. Within each VL- or Vn-region, hypervariable regions, also known as complementarity-determining regions (" CDR"), are interspersed between relatively conserved framework regions (" FR"). Generally, the variable region of a light or heavy chain polypeptide contains four FRs and three CDRs arranged in the following order along the polypeptide: NH2-FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4-COOH. Together the CDRs and FRs determine the three-dimensional structure of the IgG binding site and thus, the specific target protein or antigen to which that IgG molecule binds. Each IgG molecule is dimeric, able to bind two antigen molecules. Cleavage of a dimeric IgG with the protease papain produces two identical antigen-binding fragments (" Fab"') and an " Fc" fragment or Fc domain, so named because it is readily crystallized.

[0209] As used throughout the present disclosure, the term "antibody" further refers to a whole or intact antibody (e.g., IgM, IgG, IgA, IgD, or IgE) molecule that is generated by any one of a variety of methods that are known in the art and described herein. The term "antibody" includes a polyclonal antibody, a monoclonal antibody, a chimerized or chimeric antibody, a humanized antibody, a deimmunized human antibody, and a fully human antibody. The antibody can be made in or derived from any of a variety of species, e.g., mammals such as humans, non-human primates (e.g., monkeys, baboons, or chimpanzees), horses, cattle, pigs, sheep, goats, dogs, cats, rabbits, guinea pigs, gerbils, hamsters, rats, and mice. The antibody can be a purified or a recombinant antibody.Attorney Docket No.206193-0150-P1US

[0210] As used herein, the term "epitope" refers to the site on a protein that is bound by an antibody. " Overlapping epitopes" include at least one (e.g., two, three, four, five, or six) common amino acid residue(s).

[0211] The antibodies and fragments thereof can be, in some embodiments, "chimeric." Chimeric antibodies and antigen-binding fragments thereof comprise portions from two or more different species (e.g., mouse and human). Chimeric antibodies can be produced with mouse variable regions of desired specificity spliced onto human constant domain gene segments (see, for example, U. S. Patent No. 4,816,567). In this manner, non-human antibodies can be modified to make them more suitable for human clinical application (e.g., methods for treating or preventing a complement associated disorder in a human subject).

[0212] The monoclonal antibodies of the present disclosure include "humanized" forms of the non-human (e.g., mouse) antibodies. Humanized or CDR-grafted mAbs are particularly useful as therapeutic agents for humans because they are not cleared from the circulation as rapidly as mouse antibodies and do not typically provoke an adverse immune reaction. Methods of preparing humanized antibodies are generally well known in the art. For example, humanization can be essentially performed following the method of Winter and co-workers (see, e g., Jones et al. (1986) Nature 321:522-525; Riechmann et al. (1988) Nature 332:323-327; and Verhoeyen et al. (1988) Science 239: 1534-1536), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Also see, e.g., Staelens et al. (2006) Mol Immunol 43:1243-1257. In some embodiments, humanized forms of non-human (e.g., mouse) antibodies are human antibodies (recipient antibody) in which hypervariable (CDR) region residues of the recipient antibody are replaced by hypervariable region residues from a non- human species (donor antibody) such as a mouse, rat, rabbit, or non-human primate having the desired specificity, affinity, and binding capacity. In some instances, framework region residues of the human immunoglobulin are also replaced by corresponding non-human residues (so called "back mutations"). In addition, phage display libraries can be used to vary amino acids at chosen positions within the antibody sequence. The properties of a humanized antibody are also affected by the choice of the human framework.Attorney Docket No.206193-0150-P1US

[0213] Furthermore, humanized and chimerized antibodies can be modified to comprise residues that are not found in the recipient antibody or in the donor antibody in order to further improve antibody properties, such as, for example, affinity or effector function.

[0214] Fully human antibodies are also provided in the disclosure. The term "human antibody" includes antibodies having variable and constant regions (if present) derived from human germline immunoglobulin sequences. Human antibodies can include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, the term "human antibody" does not include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences (i.e., humanized antibodies). Fully human or human antibodies may be derived from transgenic mice carrying human antibody genes (carrying the variable (V), diversity (D), joining (J), and constant (C) exons) or from human cells. For example, it is now possible to produce transgenic animals (e.g., mice) that are capable, upon immunization, of producing a full repertoire of human antibodies in the absence of endogenous immunoglobulin production. (See, e.g., Jakobovits et al. (1993) Proc. Natl. Acad. Sci. USA 90:2551;

[0215] Jakobovits et al. (1993) Nature 362:255-258; Bruggemann et al. (1993) Year in Immunol.

[0216] 7:33; and Duchosal et al. (1992) Nature 355:258.) Transgenic mice strains can be engineered to contain gene sequences from unrearranged human immunoglobulin genes. The human sequences may code for both the heavy and light chains of human antibodies and would function correctly in the mice, undergoing rearrangement to provide a wide antibody repertoire similar to that in humans. The transgenic mice can be immunized with the target protein (to create a diverse array of specific antibodies and their encoding RNA. Nucleic acids encoding the antibody chain components of such antibodies may then be cloned from the animal into a display vector. Typically, separate populations of nucleic acids encoding heavy and light chain sequences are cloned, and the separate populations then recombined on insertion into the vector, such that any given copy of the vector receives a random combination of a heavy and a light chain. The vector is designed to express antibody chains so that they can be assembled and displayed on the outer surface of a display package containing the vector. For example, antibody chainsAttorney Docket No.206193-0150-P1US

[0217] can be expressed as fusion proteins with a phage coat protein from the outer surface of the phage. Thereafter, display packages can be screened for display of antibodies binding to a target.

[0218] Thus, in some embodiments, the disclosure provides, e.g., humanized, deimmunized or primatized antibodies comprising one or more of the complementarity determining regions (CDRs) of the mouse monoclonal antibodies described herein, which retain the ability (e.g., at least 50, 60, 70, 80, 90, or 100%, or even greater than 100%) of the mouse monoclonal antibody counterpart to bind to its antigen.

[0219] In addition, human antibodies can be derived from phage-display libraries (Hoogenboom et al. (1991) J. Mol. Biol. 227:381; Marks et al. (1991) J. Mol. Biol, 222:581-597; and Vaughan et al. (1996) Nature Biotech 14:309 (1996)). Synthetic phage libraries can be created which use randomized combinations of synthetic human antibody V-regions. By selection on antigen fully human antibodies can be made in which the V-regions are very human-like in nature. See, e.g., U. S. Patent Nos. 6,794,132, 6,680,209, 4,634,666, and Ostberg et al. (1983), Hybridoma 2:361- 367, the contents of each of which are incorporated herein by reference in their entirety.

[0220] For the generation of human antibodies, also see Mendez et al. (1998) Nature Genetics 15: 146-156 and Green and Jakobovits (1998) J. Exp. Med. 188:483-495, the disclosures of which are hereby incorporated by reference in their entirety. Human antibodies are further discussed and delineated in U. S. Patent Nos.: 5,939,598; 6,673,986; 6,1 14,598; 6,075, 181; 6, 162,963; 6,150,584; 6,713,610; and 6,657, 103 as well as U. S. Patent Application Publication Nos. 2003- 0229905 Al, 2004-0010810 Al, US 2004-0093622 Al, 2006-0040363 Al, 2005-0054055 Al, 2005-0076395 Al, and 2005-0287630 Al. See also International Publication Nos. WO 94 / 02602, WO 96 / 34096, and WO 98 / 24893, and European Patent No. EP 0463 151 Bl. The disclosures of each of the above-cited patents, applications, and references are hereby incorporated by reference in their entirety.

[0221] In an alternative approach, others, including GenPharm International, Inc., have utilized a "minilocus" approach. In the minilocus approach, an exogenous Ig locus is mimicked through the inclusion of pieces (individual genes) from the Ig locus. Thus, one or more VH genes, one or more DH genes, one or more JH genes, a mu constantAttorney Docket No.206193-0150-P1US

[0222] region, and a second constant region (preferably a gamma constant region) are formed into a construct for insertion into an animal. This approach is described in, e.g., U. S. Patent Nos.: 5,545,807; 5,545,806; 5,625,825; 5,625, 126; 5,633,425; 5,661,016;

[0223] 5,770,429; 5,789,650; and 5,814,318; 5,591,669; 5,612,205; 5,721,367; 5,789,215;

[0224] 5,643,763; 5,569,825; 5,877,397; 6,300,129; 5,874,299; 6,255,458; and 7,041,871, the disclosures of which are hereby incorporated by reference. See also European Patent No.

[0225] 0 546073 Bl, International Patent Publication Nos. WO 92 / 03918, WO 92 / 22645, WO 92 / 22647, WO 92 / 22670, WO 93 / 12227, WO 94 / 00569, WO 94 / 25585, WO 96 / 14436, WO 97 / 13852, and WO 98 / 24884, the disclosures of each of which are hereby incorporated by reference in their entirety. See further Taylor et al. (1992) Nucleic Acids Res. 20: 6287; Chen et al. (1993) Int. Immunol. 5: 647; Tuaillon et al. (1993) Proc. Natl. Acad. Sci. USA 90: 3720-4; Choi et al. (1993) Nature Genetics 4: 1 17; Lonberg et al. (1994) Nature 368: 856-859; Taylor et al. (1994) International Immunology 6: 579-591; Tuaillon et al. (1995) J. Immunol. 154: 6453- 65; Fishwild et al. (1996) Nature Biotechnology 14: 845; and Tuaillon et al. (2000) Eur. J. Immunol. 10: 2998-3005, the disclosures of each of which are hereby incorporated by reference in their entirety.

[0226] In some embodiments, de-immunized antibodies or antigen-binding fragments thereof are provided. De-immunized antibodies or antigen-binding fragments thereof are antibodies that have been modified so as to render the antibody or antigenbinding fragment thereof non- immunogenic, or less immunogenic, to a given species (e.g., to a human). De-immunization can be achieved by modifying the fusion proteins, antibodies or fragments thereof utilizing any of a variety of techniques known to those skilled in the art (see, e.g., PCT Publication Nos. WO 04 / 108158 and WO 00 / 34317). For example, fusion proteins, antibodies or fragments thereof may be de-immunized by identifying potential T cell epitopes and / or B cell epitopes within the amino acid sequence of the fusion proteins, antibodies or fragments thereof and removing one or more of the potential T cell epitopes and / or B cell epitopes from the fusion proteins, antibodies or fragments thereof, for example, using recombinant techniques. The modified antibody or antigen- binding fragment thereof may then optionally be produced and tested to identify antibodies or antigen-binding fragments thereof that have retained one or more desired biological activities, such as, for example, binding affinity, but haveAttorney Docket No.206193-0150-P1US

[0227] reduced immunogenicity. Methods for identifying potential T cell epitopes and / or B cell epitopes may be carried out using techniques known in the art, such as, for example, computational methods (see e.g., PCT Publication No. WO 02 / 069232), in vitro or in silico techniques, and biological assays or physical methods (such as, for example, determination of the binding of peptides to MHC molecules, determination of the binding of peptide: MHC complexes to the T cell receptors from the species to receive the fusion proteins, antibodies or fragments thereof, testing of the protein or peptide parts thereof using transgenic animals with the MHC molecules of the species to receive the antibody or antigen- binding fragment thereof, or testing with transgenic animals reconstituted with immune system cells from the species to receive the fusion proteins, antibodies or fragments thereof, etc.). In various embodiments, the de- immunized antibodies described herein include de-immunized antigen-binding fragments, Fab, Fv, scFv, Fab' and F(ab')2, monoclonal antibodies, murine antibodies, engineered antibodies (such as, for example, chimeric, single chain, CDR-grafted, humanized, fully human antibodies, and artificially selected antibodies), synthetic antibodies and semi-synthetic antibodies.

[0228] In some embodiments, the present disclosure also provides antibodies, or antigen-binding fragments thereof, which are variants of a peptide, protein or antibody described herein. In some embodiments, such a variant peptide, protein or antibody maintains the binding or inhibitory ability of the parent peptide, protein or antibody. Methods to prepare variants of known proteins, peptides or antibodies are known in the art. In some embodiments, such a variant comprises at least a single amino acid substitution, deletion, insertion, or other modification. In some embodiments, fusion proteins, antibodies or fragments thereof described herein comprises two or more (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more) amino acid modifications (e.g., amino acid substitutions, deletions, or additions). In some embodiments, fusion proteins, antibodies or fragments thereof described herein does not contain an amino acid modification in a CDR. In some embodiments, fusion proteins, antibodies or fragments thereof described herein does contain one or more (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) amino acid modifications in a CDR.Attorney Docket No.206193-0150-P1US

[0229] As used herein, the term "antibody fragment", "antigen-binding fragment", "antigen binding fragment", or similar terms refer to fragment of an antibody that retains the ability to bind to an antigen wherein the antigen binding fragment may optionally include additional compositions not part of the original antibody (e.g. different framework regions or mutations) as well as the fragment(s) from the original antibody. Examples include, but are not limited to, a single chain antibody, a single chain Fv fragment (scFv), an Fd fragment, an Fab fragment, an Fab' fragment, or an F(ab')2fragment. An scFv fragment is a single polypeptide chain that includes both the heavy and light chain variable regions of the antibody from which the scFv is derived. In addition, diabodies (Poljak (1994) Structure 2(12): 1121-1123; Hudson et al. (1999) J. Immunol. Methods 23(1-2): 177-189, the disclosures of each of which are incorporated herein by reference in their entirety), minibodies, triabodies (Schoonooghe et al. (2009) BMC Biotechnol 9:70), and domain antibodies (also known as "heavy chain immunoglobulins" or camelids; Holt et al. (2003) Trends Biotechnol 21(1 l):484-490), (the disclosures of each of which are incorporated herein by reference in their entirety) that bind to a complement component protein can be incorporated into the compositions, and used in the methods, described herein. In some embodiments, any of the antigen binding fragments described herein may be included under "antigen binding fragment thereof or equivalent terms, when referring to fragments related to an antibody, whether such fragments were actually derived from the antibody or are antigen binding fragments that bind the same epitope or an overlapping epitope or an epitope contained in the antibody's epitope. An antigen binding fragment thereof may include antigen-binding fragments that bind the same, or overlapping, antigen as the original antibody and wherein the antigen binding fragment includes a portion (e.g. one or more CDRs, one or more variable regions, etc.) that is a fragment of the original antibody.

[0230] In some embodiments, the fragment of SEQ ID NO: 1, SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 13, SEQ ID NO: 17, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 37, SEQ ID NO: 41, SEQ ID NO: 45, SEQ ID NO: 49, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 61, SEQ ID NO: 65, SEQ ID NO: 69, or SEQ ID NO: 73 comprises at least all three CDR regions of SEQ ID NO: 1, SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 13, SEQ ID NO: 17, SEQ ID NO: 21, SEQAttorney Docket No.206193-0150-P1US

[0231] ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 37, SEQ ID NO: 41, SEQ ID NO: 45, SEQ ID NO: 49, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 61, SEQ ID NO: 65, SEQ ID NO: 69, or SEQ ID NO: 73. In some embodiments, the fragment of SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 15, SEQ ID NO: 19, SEQ ID NO: 23, SEQ ID NO: 27, SEQ ID NO: 31, SEQ ID NO: 35, SEQ ID NO: 39, SEQ ID NO: 43, SEQ ID NO: 47, SEQ ID NO: 51, SEQ ID NO: 55, SEQ ID NO: 59, SEQ ID NO: 63, SEQ ID NO: 67, SEQ ID NO: 71, or SEQ ID NO: 75 comprises at least all three CDR regions of SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 15, SEQ ID NO: 19, SEQ ID NO: 23, SEQ ID NO: 27, SEQ ID NO: 31, SEQ ID NO: 35, SEQ ID NO: 39, SEQ ID NO: 43, SEQ ID NO: 47, SEQ ID NO: 51, SEQ ID NO: 55, SEQ ID NO: 59, SEQ ID NO: 63, SEQ ID NO: 67, SEQ ID NO: 71, or SEQ ID NO: 75. In some embodiments, the fragment of the sialic acid-binding receptor comprises an scFv antibody fragment that comprises a heavy chain of SEQ ID NO: 1, SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 13, SEQ ID NO: 17, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 37, SEQ ID NO: 41, SEQ ID NO: 45, SEQ ID NO: 49, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 61, SEQ ID NO: 65, SEQ ID NO: 69, or SEQ ID NO: 73, or all three CDR regions of SEQ ID NO: 1, SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 13, SEQ ID NO: 17, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 37, SEQ ID NO: 41, SEQ ID NO: 45, SEQ ID NO: 49, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 61, SEQ ID NO: 65, SEQ ID NO: 69, or SEQ ID NO: 73 and a light chain of SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 15, SEQ ID NO: 19, SEQ ID NO: 23, SEQ ID NO: 27, SEQ ID NO: 31, SEQ ID NO: 35, SEQ ID NO: 39, SEQ ID NO: 43, SEQ ID NO: 47, SEQ ID NO: 51, SEQ ID NO: 55, SEQ ID NO: 59, SEQ ID NO: 63, SEQ ID NO: 67, SEQ ID NO: 71, or SEQ ID NO: 75 or all three CDR regions of SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 15, SEQ ID NO: 19, SEQ ID NO: 23, SEQ ID NO: 27, SEQ ID NO: 31, SEQ ID NO: 35, SEQ ID NO: 39, SEQ ID NO: 43, SEQ ID NO: 47, SEQ ID NO: 51, SEQ ID NO: 55, SEQ ID NO: 59, SEQ ID NO: 63, SEQ ID NO: 67, SEQ ID NO: 71, or SEQ ID NO: 75.

[0232] In some embodiments, the heavy chain or light chain of an antibody described herein can include one or more leader sequences. The leader sequence mayAttorney Docket No.206193-0150-P1US

[0233] comprise signal peptide. The signal peptide can be an immunoglobulin (Ig) signal peptide, for example, but not limited to, an IgG signal peptide and an IgE signal peptide. In some embodiments, the signal peptide comprises a sequence selected from SEQ ID NO: 382, 384, 386, 388, 390, 392, 394, 396, 398, 400, or SEQ ID NO: 402.

[0234] In some embodiments, the antibodies described herein comprise an altered or mutated sequence that leads to altered stability or half-life compared to parent antibodies. This includes, for example, an increased stability or half- life for higher affinity or longer clearance time in vitro or in vivo, or a decreased stability or half-life for lower affinity or quicker removal. Additionally, the antibodies described herein may contain one or more (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) amino acid substitutions, deletions, or insertions that result in altered post-translational modifications, including, for example, an altered glycosylation pattern (e.g., the addition of one or more sugar components, the loss of one or more sugar components, or a change in composition of one or more sugar components.

[0235] In some embodiments, the antibodies described herein comprise reduced (e.g. or no) effector function. Altered effector functions include, for example, a modulation in one or more of the following activities: antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), apoptosis, binding to one or more Fc- receptors, and pro-inflammatory responses. Modulation refers to an increase, decrease, or elimination of an effector function activity exhibited by a subject antibody containing an altered constant region as compared to the activity of the unaltered form of the constant region. In particular embodiments, modulation includes situations in which an activity is abolished or completely absent.

[0236] Antibodies with altered or no effector functions may be generated by engineering or producing antibodies with variant constant, Fc, or heavy chain regions; recombinant DNA technology and / or cell culture and expression conditions may be used to produce antibodies with altered function and / or activity. For example, recombinant DNA technology may be used to engineer one or more amino acid substitutions, deletions, or insertions in regions (such as, for example, Fc or constant regions) that affect antibody function including effector functions. Alternatively, changes in post-translational modifications, such as, e.g., glycosylation patterns, may be achieved byAttorney Docket No.206193-0150-P1US

[0237] manipulating the cell culture and expression conditions by which the antibody is produced. Suitable methods for introducing one or more substitutions, additions, or deletions into an Fc region of an antibody are well known in the art and include, e.g., standard DNA mutagenesis techniques as described in, e.g., Sambrook et al. (1989) " Molecular Cloning: A Laboratory Manual, 2nd Edition," Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N. Y.; Harlow and Lane (1988), supra; Borrebaek (1992), supra; Johne et al. (1993), supra; PCT publication no. WO 06 / 53301; and U. S. patent no.

[0238] 7,704,497.

[0239] Nucleic Acid Molecules

[0240] Provided herein are polynucleotides that encode the Siglec-10 antibodies, or fragments thereof, of the invention. In some embodiments, the polynucleotide also comprises a sequence encoding a signal peptide operably linked at the 5' end of the encoding sequence. In some embodiments, the polynucleotide also comprises a sequence encoding a linker sequence.

[0241] In one embodiment, the nucleic acid molecule encodes an antibody comprising a heavy chain variable region having an amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 13, SEQ ID NO: 17, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 37, SEQ ID NO: 41, SEQ ID NO: 45, SEQ ID NO: 49, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 61, SEQ ID NO: 65, SEQ ID NO: 69, or SEQ ID NO: 73; a light chain variable region having an amino acid sequence of SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 15, SEQ ID NO: 19, SEQ ID NO: 23, SEQ ID NO: 27, SEQ ID NO: 31, SEQ ID NO: 35, SEQ ID NO: 39, SEQ ID NO: 43, SEQ ID NO: 47, SEQ ID NO: 51, SEQ ID NO: 55, SEQ ID NO: 59, SEQ ID NO: 63, SEQ ID NO: 67, SEQ ID NO: 71, or SEQ ID NO: 75; a sequence having at least 95% identity to a heavy chain variable region having an amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 13, SEQ ID NO: 17, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 37, SEQ ID NO: 41, SEQ ID NO: 45, SEQ ID NO: 49, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 61, SEQ ID NO: 65, SEQ ID NO: 69, or SEQ ID NO: 73; a sequence having at least 95% identity to a light chain variable region having an amino acid sequence of SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 15, SEQAttorney Docket No.206193-0150-P1US

[0242] ID NO: 19, SEQ ID NO: 23, SEQ ID NO: 27, SEQ ID NO: 31, SEQ ID NO: 35, SEQ ID NO: 39, SEQ ID NO: 43, SEQ ID NO: 47, SEQ ID NO: 51, SEQ ID NO: 55, SEQ ID NO: 59, SEQ ID NO: 63, SEQ ID NO: 67, SEQ ID NO: 71, or SEQ ID NO: 75; a fragment comprising at least 80% of the full- length sequence of a heavy chain variable region having an amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 13, SEQ ID NO: 17, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 37, SEQ ID NO: 41, SEQ ID NO: 45, SEQ ID NO: 49, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 61, SEQ ID NO: 65, SEQ ID NO: 69, or SEQ ID NO: 73; a fragment comprising at least 80% of the full- length sequence of a light chain variable region having an amino acid sequence of SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 15, SEQ ID NO: 19, SEQ ID NO: 23, SEQ ID NO: 27, SEQ ID NO: 31, SEQ ID NO: 35, SEQ ID NO: 39, SEQ ID NO: 43, SEQ ID NO: 47, SEQ ID NO: 51, SEQ ID NO: 55, SEQ ID NO: 59, SEQ ID NO: 63, SEQ ID NO: 67, SEQ ID NO: 71, or SEQ ID NO: 75, or a combination thereof.

[0243] In one embodiment, the nucleic acid molecule comprises nucleotide sequences encoding the variable heavy chain CDR sequences of SEQ ID NO: 1, SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 13, SEQ ID NO: 17, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 37, SEQ ID NO: 41, SEQ ID NO: 45, SEQ ID NO: 49, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 61, SEQ ID NO: 65, SEQ ID NO: 69, or SEQ ID NO: 73. In one embodiment, the nucleic acid molecule comprises nucleotide sequences encoding the variable light chain CDR sequences of SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 15, SEQ ID NO: 19, SEQ ID NO: 23, SEQ ID NO: 27, SEQ ID NO: 31, SEQ ID NO: 35, SEQ ID NO: 39, SEQ ID NO: 43, SEQ ID NO: 47, SEQ ID NO: 51, SEQ ID NO: 55, SEQ ID NO: 59, SEQ ID NO: 63, SEQ ID NO: 67, SEQ ID NO: 71, or SEQ ID NO: 75.

[0244] In one embodiment, the nucleic acid molecule comprises SEQ ID NO:80-82; SEQ ID NO:86-88; SEQ ID NO:92-94; SEQ ID NO:98-100; SEQ ID NO: 104-106; SEQ ID NO: 110-112; SEQ ID NO: 116-118; SEQ ID NO: 122-124; SEQ ID NO: 128-130; SEQ ID NO: 134- 136; SEQ ID NO: 140- 142; SEQ ID NO: 146- 148; SEQ ID NO: 152- 154; SEQ ID NO: 158- 160; SEQ ID NO: 164- 166; SEQ ID NO: 171 - 173; SEQ ID NO: 177- 179; SEQ ID NO: 183 - 185; SEQ ID NO: 189- 191; SEQ ID NO: 195 - 197; SEQ ID NO: 201 -203;Attorney Docket No.206193-0150-P1US

[0245] SEQ ID NO:207-209; SEQ ID NO:213-215; SEQ ID NO:219-221; SEQ ID NO:225-227; SEQ ID NO:231-233; SEQ ID NO: 237-239; SEQ ID NO: 243-245; SEQ ID NO: 249-251; SEQ ID NO: 255-257; SEQ ID NO: 261-263; SEQ ID NO: 267-269; SEQ ID NO: 273-275; SEQ ID NO: 279-281; SEQ ID NO: 285-287; SEQ ID NO: 291-293; SEQ ID NO: 297-299; or SEQ ID NO: 303-305..

[0246] In one embodiment, the nucleic acid molecule comprises SEQ ID NO:2; SEQ ID NO:4; SEQ ID NO:6; SEQ ID NO:8; SEQ ID NO: 10; SEQ ID NO: 12; SEQ ID NO:14; SEQ ID NO:16; SEQ ID NO:18; SEQ ID NO:20; SEQ ID NO:24; SEQ ID NO:26; SEQ ID NO:28; SEQ ID NO:30; SEQ ID NO:32; SEQ ID NO:34; SEQ ID NO:36; SEQ ID NO:38; SEQ ID NO:40; SEQ ID NO:42; SEQ ID NO:44; SEQ ID NO:46; SEQ ID NO:48; SEQ ID NO:50; SEQ ID NO:52; SEQ ID NO:54; SEQ ID NO:56; SEQ ID NO:58; SEQ ID NO:60; SEQ ID NO:62; SEQ ID NO:64; SEQ ID NO:66; SEQ ID NO:68; SEQ ID NO:70; SEQ ID NO:72; SEQ ID NO:74; or SEQ ID NO:76.

[0247] In some embodiments, a variant of a nucleotide sequence as described herein comprises at least about 60% identity, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher identity over a specified region when compared to a defined nucleotide sequence. In some embodiments, a variant of a nucleotide sequence as described herein comprises at least about 60% identity, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, 99% or higher identity over the full length of a nucleotide sequence. In some embodiments, the variant of SEQ ID NO:2; SEQ ID NO:4; SEQ ID NO:6; SEQ ID NO:8; SEQ ID NO:10; SEQ ID NO:12; SEQ ID NO:14; SEQ ID NO:16; SEQ ID NO:18; SEQ ID NO:20; SEQ ID NO:24; SEQ ID NO:26; SEQ ID NO:28; SEQ ID NO:30; SEQ ID NO:32; SEQ ID NO:34; SEQ ID NO:36; SEQ ID NO:38; SEQ ID NO:40; SEQ ID NO:42; SEQ ID NO:44; SEQ ID NO:46; SEQ ID NO:48; SEQ ID NO:50; SEQ ID NO:52; SEQ ID NO:54; SEQ ID NO:56; SEQ ID NO:58; SEQ ID NO:60; SEQ ID NO:62; SEQ ID NO:64; SEQ ID NO:66; SEQ ID NO:68; SEQ ID NO:70; SEQ IDAttorney Docket No.206193-0150-P1US

[0248] NO:72; SEQ ID NO:74; or SEQ ID NO:76comprises 100% identity to all three CDR regions of SEQ ID NO:2; SEQ ID NO: 4; SEQ ID NO:6; SEQ ID NO:8; SEQ ID NO: 10; SEQ ID NO: 12; SEQ ID NO: 14; SEQ ID NO: 16; SEQ ID NO: 18; SEQ ID NO:20; SEQ ID NO:24; SEQ ID NO 26; SEQ ID NO:28; SEQ ID NO:30; SEQ ID NO:32; SEQ ID NO 34; SEQ ID NO:36; SEQ ID NO:38; SEQ ID NO:40; SEQ ID NO:42; SEQ ID NO:44; SEQ ID NO:46; SEQ ID NO:48; SEQ ID NO:50; SEQ ID NO:52; SEQ ID NO:54; SEQ ID NO:56; SEQ ID NO:58; SEQ ID NO:60; SEQ ID NO:62; SEQ ID NO:64; SEQ ID NO:66; SEQ ID NO:68; SEQ ID NO:70; SEQ ID NO:72; SEQ ID NO:74; or SEQ ID NO:76. Therefore, in some embodiments, the variability is in a region outside of a CDR-encoding region.

[0249] In one embodiment, the nucleic acid molecule comprises a nucleotide sequence having at least 95% identity to SEQ ID NO:2; SEQ ID NO:4; SEQ ID NO:6; SEQ ID NO:8; SEQ ID NO: 10; SEQ ID NO: 12; SEQ ID NO: 14; SEQ ID NO: 16; SEQ ID NO: 18; SEQ ID NO:20; SEQ ID NO:24; SEQ ID NO:26; SEQ ID NO:28; SEQ ID NO:30; SEQ ID NO:32; SEQ ID NO:34; SEQ ID NO:36; SEQ ID NO:38; SEQ ID NO:40; SEQ ID NO:42; SEQ ID NO:44; SEQ ID NO:46; SEQ ID NO:48; SEQ ID NO:50; SEQ ID NO:52; SEQ ID NO:54; SEQ ID NO:56; SEQ ID NO:58; SEQ ID NO:60; SEQ ID NO:62; SEQ ID NO:64; SEQ ID NO:66; SEQ ID NO:68; SEQ ID NO:70; SEQ ID NO:72; SEQ ID NO:74; or SEQ ID NO:76.

[0250] In some embodiments, a fragment of a nucleotide sequence as described herein comprises at least about 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the full-length sequence of a defined nucleotide sequence. In some embodiments, a fragment of a nucleotide sequence as described herein comprises at least about 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, or 99% of the full length nucleotide sequence. In some embodiments, the fragment of SEQ ID NO:2; SEQ ID NO:4; SEQ ID NO:6; SEQ ID NO:8; SEQ ID NO:10; SEQ ID NO:12; SEQ ID NO:14; SEQ IDNO:16; SEQ ID NO: 18; SEQ ID NO:20; SEQ ID NO:24; SEQ ID NO:26; SEQ ID NO:28; SEQAttorney Docket No.206193-0150-P1US

[0251] ID NO:30; SEQ ID NO 32; SEQ ID NO:34; SEQ ID NO:36; SEQ ID NO:38; SEQ ID NO:40; SEQ ID NO:42; SEQ ID NO:44; SEQ ID NO:46; SEQ ID NO:48; SEQ ID NO:50; SEQ ID NO:52; SEQ ID NO:54; SEQ ID NO:56; SEQ ID NO:58; SEQ ID NO:60; SEQ ID NO:62; SEQ ID NO:64; SEQ ID NO:66; SEQ ID NO:68; SEQ ID NO:70; SEQ ID NO:72; SEQ ID NO:74; or SEQ ID NO:76 comprises at least all three CDR regions of SEQ ID NO:2; SEQ ID NO:4; SEQ ID NO:6; SEQ ID NO:8; SEQ ID NO:10; SEQ ID NO:12; SEQ ID NO:14; SEQ ID NO:16; SEQ ID NO:18; SEQ ID NO:20; SEQ ID NO:24; SEQ ID NO:26; SEQ ID NO:28; SEQ ID NO:30; SEQ ID NO:32; SEQ ID NO:34; SEQ ID NO:36; SEQ ID NO:38; SEQ ID NO:40; SEQ ID NO:42; SEQ ID NO:44; SEQ ID NO:46; SEQ ID NO:48; SEQ ID NO:50; SEQ ID NO:52; SEQ ID NO:54; SEQ ID NO:56; SEQ ID NO:58; SEQ ID NO:60; SEQ ID NO:62; SEQ ID NO:64; SEQ ID NO:66; SEQ ID NO:68; SEQ ID NO:70; SEQ ID NO:72; SEQ ID NO:74; or SEQ ID NO:76.

[0252] In one embodiment, the nucleic acid molecule comprises a fragment comprising at least 80% of the full- length sequence of SEQ ID NO:2; SEQ ID NO:4; SEQ ID NO:6; SEQ ID NO:8; SEQ ID NO: 10; SEQ ID NO: 12; SEQ ID NO: 14; SEQ ID NO: 16; SEQ ID NO: 18; SEQ ID NO:20; SEQ ID NO:24; SEQ ID NO:26; SEQ ID NO:28; SEQ ID NO:30; SEQ ID NO:32; SEQ ID NO:34; SEQ ID NO:36; SEQ ID NO:38; SEQ ID NO:40; SEQ ID NO:42; SEQ ID NO:44; SEQ ID NO:46; SEQ ID NO:48; SEQ ID NO:50; SEQ ID NO:52; SEQ ID NO:54; SEQ ID NO:56; SEQ ID NO:58; SEQ ID NO:60; SEQ ID NO:62; SEQ ID NO:64; SEQ ID NO:66; SEQ ID NO:68; SEQ ID NO:70; SEQ ID NO:72; SEQ ID NO:74; or SEQ ID NO:76.

[0253] The nucleic acid sequence encoding the heavy chain or light chain of an antibody described herein can include one or more leader sequences. The leader sequence can encode a signal peptide. The signal peptide can be an immunoglobulin (Ig) signal peptide, for example, but not limited to, an IgG signal peptide and an IgE signal peptide. In some embodiments, the leader sequence is selected from the group consisting of SEQ ID NO: 383, 385, 387, 389, 391, 393, 395, 397, 399, 401, or SEQ ID NO: 403.

[0254] The isolated nucleic acid may comprise any type of nucleic acid, including, but not limited to DNA, cDNA, and RNA. For example, in one embodiment, the composition comprises an isolated DNA molecule, including for example, an isolatedAttorney Docket No.206193-0150-P1US

[0255] cDNA molecule, encoding a protein inhibitor or functional fragment thereof. In one embodiment, the composition comprises an isolated RNA molecule encoding a protein inhibitor or a functional fragment thereof.

[0256] The nucleic acid molecules of the present invention can be modified to improve stability in serum or in growth medium for cell cultures. Modifications can be added to enhance stability, functionality, and / or specificity and to minimize immunostimulatory properties of the nucleic acid molecule of the invention. For example, in order to enhance the stability, the 3 ’-residues may be stabilized against degradation, e.g., they may be selected such that they consist of purine nucleotides, particularly adenosine or guanosine nucleotides. Alternatively, substitution of pyrimidine nucleotides by modified analogues, e.g., substitution of uridine by 2’-deoxythymidine is tolerated and does not affect function of the molecule.

[0257] The present invention also includes a vector in which the isolated nucleic acid of the present invention is inserted. The art is replete with suitable vectors that are useful in the present invention.

[0258] Therefore, in another aspect, the invention relates to a vector, comprising the nucleotide sequence of the invention or the construct of the invention. The choice of the vector will depend on the host cell in which it is to be subsequently introduced. In some embodiments, the vector of the invention is an expression vector. Suitable host cells include a wide variety of prokaryotic and eukaryotic host cells. In specific embodiments, the expression vector is selected from the group consisting of a viral vector, a bacterial vector and a mammalian cell vector. Prokaryote- and / or eukaryote-vector based systems can be employed for use with the present invention to produce polynucleotides, or their cognate polypeptides. Many such systems are commercially and widely available.

[0259] The vectors of the present invention may also be used for nucleic acid immunization, using standard gene delivery protocols. Methods for gene delivery are known in the art. See, e.g., U. S. Pat. Nos. 5,399,346, 5,580,859, 5,589,466, incorporated by reference herein in their entireties.

[0260] The isolated nucleic acid of the invention can be cloned into a number of types of vectors. For example, the nucleic acid can be cloned into a vector including, but not limited to a plasmid, a phagemid, a phage derivative, an animal virus, and a cosmid.Attorney Docket No.206193-0150-P1US

[0261] Vectors of particular interest include expression vectors, replication vectors, probe generation vectors, and sequencing vectors.

[0262] Further, the vector may be provided to a cell in the form of a viral vector. Viral vector technology is well known in the art and is described, for example, in Sambrook et al. (2012, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York), and in other virology and molecular biology manuals. Viruses, which are useful as vectors include, but are not limited to, retroviruses, adenoviruses, adeno-associated viruses, herpes viruses, and lentiviruses. In general, a suitable vector contains an origin of replication functional in at least one organism, a promoter sequence, convenient restriction endonuclease sites, and one or more selectable markers, (e.g., WO 01 / 96584; WO 01 / 29058; and U. S. Pat. No. 6,326,193).

[0263] Further, the expression vector may be provided to a cell in the form of a viral vector. Viral vector technology is well known in the art and is described, for example, in Sambrook et al. (2012), and in Ausubel et al. (1997), and in other virology and molecular biology manuals. Viruses, which are useful as vectors include, but are not limited to, retroviruses, adenoviruses, adeno-associated viruses, herpes viruses, and lentiviruses. In general, a suitable vector contains an origin of replication functional in at least one organism, a promoter sequence, convenient restriction endonuclease sites, and one or more selectable markers. (See, e.g., WO 01 / 96584; WO 01 / 29058; and U. S. Pat. No. 6,326,193.

[0264] By way of illustration, the vector in which the nucleic acid sequence is introduced can be a plasmid, which is or is not integrated in the genome of a host cell when it is introduced in the cell. Illustrative, non-limiting examples of vectors in which the nucleotide sequence of the invention or the gene construct of the invention can be inserted include a tet-on inducible vector for expression in eukaryote cells.

[0265] The vector may be obtained by conventional methods known by persons skilled in the art (Sambrook et al., 2012). In a particular embodiment, the vector is a vector useful for transforming animal cells.

[0266] In one embodiment, the recombinant expression vectors may also contain nucleic acid molecules, which encode a peptide or protein of invention, described elsewhere herein.Attorney Docket No.206193-0150-P1US

[0267] A number of viral based systems have been developed for gene transfer into mammalian cells. For example, retroviruses provide a convenient platform for gene delivery systems. A selected gene can be inserted into a vector and packaged in retroviral particles using techniques known in the art. The recombinant virus can then be isolated and delivered to cells of the subject either in vivo or ex vivo. A number of retroviral systems are known in the art. In some embodiments, adenovirus vectors are used. A number of adenovirus vectors are known in the art. In one embodiment, lentivirus vectors are used.

[0268] For example, vectors derived from retroviruses such as the lentivirus are suitable tools to achieve long-term gene transfer since they allow long-term, stable integration of a transgene and its propagation in daughter cells. Lentiviral vectors have the added advantage over vectors derived from onco-retroviruses such as murine leukemia viruses in that they can transduce non-proliferating cells, such as hepatocytes. They also have the added advantage of low immunogenicity. In one embodiment, the composition includes a vector derived from an adeno-associated virus (AAV). Adeno-associated viral (AAV) vectors have become powerful gene delivery tools for the treatment of various disorders. AAV vectors possess a number of features that render them ideally suited for gene therapy, including a lack of pathogenicity, minimal immunogenicity, and the ability to transduce postmitotic cells in a stable and efficient manner. Expression of a particular gene contained within an AAV vector can be specifically targeted to one or more types of cells by choosing the appropriate combination of AAV serotype, promoter, and delivery method.

[0269] In some embodiments, the vector also includes conventional control elements which are operably linked to the transgene in a manner which permits its transcription, translation and / or expression in a cell transfected with the plasmid vector or infected with the virus produced by the invention. As used herein, “operably linked” sequences include both expression control sequences that are contiguous with the gene of interest and expression control sequences that act in trans or at a distance to control the gene of interest. Expression control sequences include appropriate transcription initiation, termination, promoter and enhancer sequences; efficient RNA processing signals such as splicing and polyadenylation (poly A) signals; sequences that stabilize cytoplasmicAttorney Docket No.206193-0150-P1US

[0270] mRNA; sequences that enhance translation efficiency (i.e., Kozak consensus sequence); sequences that enhance protein stability; and when desired, sequences that enhance secretion of the encoded product. A great number of expression control sequences, including promoters which are native, constitutive, inducible and / or tissue-specific, are known in the art and may be utilized.

[0271] A promoter may be one naturally associated with a gene or polynucleotide sequence, as may be obtained by isolating the 5' non-coding sequences located upstream of the coding segment and / or exon. Such a promoter can be referred to as “endogenous.” Similarly, an enhancer may be one naturally associated with a polynucleotide sequence, located either downstream or upstream of that sequence. Alternatively, certain advantages will be gained by positioning the coding polynucleotide segment under the control of a recombinant or heterologous promoter, which refers to a promoter that is not normally associated with a polynucleotide sequence in its natural environment. A recombinant or heterologous enhancer refers also to an enhancer not normally associated with a polynucleotide sequence in its natural environment. Such promoters or enhancers may include promoters or enhancers of other genes, and promoters or enhancers isolated from any other prokaryotic, viral, or eukaryotic cell, and promoters or enhancers not “naturally occurring,” i.e., containing different elements of different transcriptional regulatory regions, and / or mutations that alter expression. In addition to producing nucleic acid sequences of promoters and enhancers synthetically, sequences may be produced using recombinant cloning and / or nucleic acid amplification technology, including PCR, in connection with the compositions disclosed herein (U. S. Patent 4,683,202, U. S. Patent 5,928,906). Furthermore, it is contemplated the control sequences that direct transcription and / or expression of sequences within non-nuclear organelles such as mitochondria, chloroplasts, and the like, can be employed as well.

[0272] Naturally, it will be important to employ a promoter and / or enhancer that effectively directs the expression of the DNA segment in the cell type, organelle, and organism chosen for expression. Those of skill in the art of molecular biology generally know how to use promoters, enhancers, and cell type combinations for protein expression, for example, see Sambrook et al. (2012). The promoters employed may be constitutive, tissue-specific, inducible, and / or useful under the appropriate conditions toAttorney Docket No.206193-0150-P1US

[0273] direct high-level expression of the introduced DNA segment, such as is advantageous in the large-scale production of recombinant proteins and / or peptides. The promoter may be heterologous or endogenous.

[0274] The recombinant expression vectors may also contain a selectable marker gene, which facilitates the selection of transformed or transfected host cells. Suitable selectable marker genes are genes encoding proteins such as G418 and hygromycin, which confer resistance to certain drugs, β-galactosidase, chloramphenicol acetyltransferase, firefly luciferase, or an immunoglobulin or portion thereof such as the Fc portion of an immunoglobulin, such as IgG. The selectable markers may be introduced on a separate vector from the nucleic acid of interest.

[0275] Additional promoter elements, e.g., enhancers, regulate the frequency of transcriptional initiation. Typically, these are located in the region 30-110 bp upstream of the start site, although a number of promoters have recently been shown to contain functional elements downstream of the start site as well. The spacing between promoter elements frequently is flexible, so that promoter function is preserved when elements are inverted or moved relative to one another. In the thymidine kinase (tk) promoter, the spacing between promoter elements can be increased to 50 bp apart before activity begins to decline. Depending on the promoter, it appears that individual elements can function either cooperatively or independently to activate transcription.

[0276] One example of a suitable promoter is the immediate early cytomegalovirus (CMV) promoter sequence. This promoter sequence is a strong constitutive promoter sequence capable of driving high levels of expression of any polynucleotide sequence operatively linked thereto. Another example of a suitable promoter is Elongation Growth Factor -la (EF-la). However, other constitutive promoter sequences may also be used, including, but not limited to the simian virus 40 (SV40) early promoter, mouse mammary tumor virus (MMTV), human immunodeficiency virus (HIV) long terminal repeat (LTR) promoter, MoMuLV promoter, an avian leukemia virus promoter, an Epstein-Barr virus immediate early promoter, a Rous sarcoma virus promoter, as well as human gene promoters such as, but not limited to, the actin promoter, the myosin promoter, the hemoglobin promoter, and the creatine kinase promoter. Further, the invention should not be limited to the use of constitutiveAttorney Docket No.206193-0150-P1US

[0277] promoters. Inducible promoters are also contemplated as part of the invention. The use of an inducible promoter provides a molecular switch capable of turning on expression of the polynucleotide sequence which it is operatively linked when such expression is desired or turning off the expression when expression is not desired. Examples of inducible promoters include, but are not limited to a metallothionine promoter, a glucocorticoid promoter, a progesterone promoter, and a tetracycline promoter.

[0278] Enhancer sequences found on a vector also regulates expression of the gene contained therein. Typically, enhancers are bound with protein factors to enhance the transcription of a gene. Enhancers may be located upstream or downstream of the gene it regulates. Enhancers may also be tissue-specific to enhance transcription in a specific cell or tissue type. In one embodiment, the vector of the present invention comprises one or more enhancers to boost transcription of the gene present within the vector.

[0279] Pharmaceutical Compositions

[0280] The present invention also provides pharmaceutical compositions comprising one or more of the compositions described herein. Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for administration to a treatment site. The pharmaceutical compositions may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, and / or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents.

[0281] Administration of the compositions of this invention may be carried out, for example, by parenteral, by intravenous, subcutaneous, intramuscular, or intraperitoneal injection, or by infusion or by any other acceptable systemic method.

[0282] As used herein, “additional ingredients” include, but are not limited to, one or more of the following: excipients; surface active agents; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents; coloring agents; preservatives; physiologically degradable compositions such as gelatin;Attorney Docket No.206193-0150-P1US

[0283] aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; emulsifying agents; antioxidants; antibiotics; antifungal agents; stabilizing agents; and pharmaceutically acceptable polymeric or hydrophobic materials. Other “additional ingredients” that may be included in the pharmaceutical compositions of the invention are known in the art and described, for example in Genaro, ed. (1985, Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, PA), which is incorporated herein by reference.

[0284] Method of Delivery of the Composition

[0285] The present invention also relates to a method of delivering the composition to the subject in need thereof. The method of delivery can include, administering the composition to the subject. Administration can include, but is not limited to, DNA injection with and without in vivo electroporation, liposome mediated delivery, and nanoparticle facilitated delivery.

[0286] The mammal receiving delivery of the composition may be human, primate, non-human primate, cow, cattle, sheep, goat, antelope, bison, water buffalo, bison, bovids, deer, hedgehogs, elephants, llama, alpaca, mice, rats, and chicken.

[0287] The composition may be administered by different routes including orally, parenterally, sublingually, transdermally, rectally, transmucosally, topically, via inhalation, via buccal administration, intrapleurally, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intranasal, intranasal, intrathecal, and intraarticular or combinations thereof. For veterinary use, the composition may be administered as a suitably acceptable formulation in accordance with normal veterinary practice. The veterinarian can readily determine the dosing regimen and route of administration that is most appropriate for a particular animal. The composition may be administered by traditional syringes, needleless injection devices, "microprojectile bombardment gone guns", or other physical methods such as electroporation (“EP”), “hydrodynamic method”, or ultrasound.

[0288] Treatment MethodsAttorney Docket No.206193-0150-P1US

[0289] In one embodiment, the invention provides a method for treatment or prevention of a disease or disorder. In one embodiment, the invention provides a method for treatment or prevention of cancer.

[0290] The following are non-limiting examples of cancers that can be diagnosed or treated by the disclosed methods and compositions: pancreatic ductal adenocarcinoma, pancreatic cancer, acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, appendix cancer, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain and spinal cord tumors, brain stem glioma, brain tumor, breast cancer, bronchial tumors, burkitt lymphoma, carcinoid tumor, central nervous system atypical teratoid / rhabdoid tumor, central nervous system embryonal tumors, central nervous system lymphoma, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, cerebral astrocytoma / malignant glioma, cervical cancer, childhood visual pathway tumor, chordoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous cancer, cutaneous t-cell lymphoma, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, ewing family of tumors, extracranial cancer, extragonadal germ cell tumor, extrahepatic bile duct cancer, extrahepatic cancer, eye cancer, fungoides, gallbladder cancer, gastric (stomach) cancer, gastrointestinal cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (gist), germ cell tumor, gestational cancer, gestational trophoblastic tumor, glioblastoma, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, histiocytosis, hodgkin lymphoma, hypopharyngeal cancer, hypothalamic and visual pathway glioma, hypothalamic tumor, intraocular (eye) cancer, intraocular melanoma, islet cell tumors, kaposi sarcoma, kidney (renal cell) cancer, langerhans cell cancer, langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocvtoma of bone and osteosarcoma, medulloblastoma, medulloepithelioma, melanoma, merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer with occult primary, mouth cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis, myelodysplastic syndromes, myelodysplastic / myeloproliferative diseases, myelogenous leukemia, myeloid leukemia, myeloma, myeloproliferative disorders, nasal cavity and paranasalAttorney Docket No.206193-0150-P1US

[0291] sinus cancer, nasopharyngeal cancer, neuroblastoma, non-hodgkin lymphoma, non-small cell lung cancer, oral cancer, oral cavity cancer, oropharyngeal cancer, osteosarcoma and malignant fibrous histiocytoma, osteosarcoma and malignant fibrous histiocytoma of bone, ovarian, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal parenchymal tumors of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, primary central nervous system cancer, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, renal pelvis and ureter cancer, respiratory tract carcinoma involving the nut gene on chromosome 15, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, sezary syndrome, skin cancer (melanoma), skin cancer (nonmelanoma), skin carcinoma, small cell lung cancer, small intestine cancer, soft tissue cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, supratentorial primitive neuroectodermal tumors and pineoblastoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, visual pathway and hypothalamic glioma, vulvar cancer, waldenstrom macroglobulinemia, and wilms tumor.

[0292] EXPERIMENTAL EXAMPLES

[0293] The invention is further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples, but rather, should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

[0294] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make andAttorney Docket No.206193-0150-P1US

[0295] utilize the present invention and practice the claimed methods. The following working examples therefore are not to be construed as limiting in any way the remainder of the disclosure.

[0296]

[0297] e 1: ec- in interactions enhances

[0298]

[0299] mediated phagocytosis of pancreatic cancer.

[0300] There is an urgent need to identify novel immunological targets to improve the survival rates of patients with Pancreatic Ductal Adenocarcinoma (PDAC). This cancer is particularly challenging, with a five-year survival rate post-diagnosis of 12% and resistance to immunotherapy (Siegel et al., 2020, CA Cancer JC7zn;70(l):7-30; Siegel et a 1., 2023, CA Cancer J Clin; 73(1): 17 -48; Timmer et al., 2021, Cancers (Basel), 13(16). PDAC resistance to immunotherapy is thought to arise from various mechanisms within the tumor microenvironment (TME). Notably, tumor-associated macrophages (TAMs), a major immune infiltrate in the TME, contribute significantly to treatment resistance by promoting an immunosuppressive microenvironment and by lacking the ability to eliminate cancer cells through phagocytosis (Beatty et al., 2017, Am Soc Clin Oncol Educ Book; 37:267-78; Clark et al., 2007, Cancer Res;67(19):9518-27; Helm et al., 2014, Int J Cancer; 135(4): 843 -61). Therefore, there is a growing interest in rejuvenating macrophages’ capacity for phagocytosis and thus targeted destruction of PDAC cells. This has been pursued via blocking the 'do not eat me signal' conveyed by CD47 on cancer cells, however the outcomes have not always been optimal (Matlung et al., 2017, Immunol Rev; 276(1): 145-64; Veillette et al., 2018, Trends Immunol;

[0301] 39(3):173-84; Weiskopf et al., 2016, J Clin Invest;126(7):2610-20; Willingham et al., 2012, Proc Natl Acad Sci USA; 109(17):6662-7), highlighting the need for novel strategies to achieve this goal.

[0302] One promising area in stimulating TAMs’ ability to phagocytose PDAC cells lies in the field of glyco-immunology. Recent advances in this emerging field have shown that glycans play a pivotal role in modulating key immunological functions during disease. This recognition that glycans significantly influence immunological functions has led to an understanding that many tumor cells exploit aberrant glycosylation patterns to evade immune responses (Rodriguez et al, 2018, Nat Rev Immunol; 18(3):204-l 1). ForAttorney Docket No.206193-0150-P1US

[0303] instance, cancer cells often upregulate sialoglycans (glycans containing sialic acid) on their cell surface proteins to suppress immune surveillance (Rodrigues et al., 2018, Cancers (Basel),' 10(6)). Sialic acid on cancer cell glycoproteins binds to Siglecs, inhibitory receptors present on various immune cells, including TAMs. This binding trigger inhibitory signaling in TAMs, diminishing their ability to phagocytose cancer cells (Gu et al., 2023, Front Immunol,' 14:1183285; Laubli et al., 2022, Cancer Immunol Res,' 10(12): 1423-32; Marciel et al., 2023, Adv Cancer Res,' 157:123-55; Saini et al., 2022, EBioMedicine, 86:104354; Stanczak et al., 2023, Mol Aspects Med,' 90: 101112; Yu et al., 2023, Cancer Biol Med,' 20(5):369-84; Zhou et al., 2023, Biology.’ (Basel),' 12 (6)). Thus, Siglecs on TAMs function as ‘glyco-immune checkpoints,’ akin to the PD1 checkpoint on CD8+T cells. Targeting the interactions between Siglecs on TAMs and sialic acid on cancer cells therefore holds significant potential for enhancing the ability of macrophages to phagocytose cancer cells, including in PDAC.

[0304] Among the various Siglec-sialic acid interactions, the binding between Siglec-10 on TAMs and sialic acid on CD24 of cancer cells is a key interaction that inhibits TAMs’ ability to phagocytose ovarian and breast cancer cells. This interaction involves the sialic acid-containing ligand CD24 on cancer cells (akin to PD-L1 on cancer cells) and the sialic acid-binding receptor Siglec-10 on TAMs (akin to PD-1 on T cells). This interaction triggers an inhibitory signal, mediated by SHP-1 and SHP-2, which inhibits macrophage-mediated phagocytosis. This interaction has been studied primarily in ovarian and breast cancers (Barkal et al., 2019, Nature,' 572(7769):392-6). In these cancers, blockade of CD24, using an antibody, enhanced the ability of TAMs to phagocytose ovarian and breast cancer cells (Barkal et al., 2019, Nature,' 572(7769):392-6), indicating that blocking the Siglec-10 interactions improved TAMs’ ability to phagocytose cancer cells. However, it remains unknown whether blocking Siglec-10 interactions can reinvigorate macrophage-mediated phagocytosis against PDAC cells.

[0305] In this study, we investigate the role of Siglec-10 interactions in PDAC immune evasion from macrophage-mediated phagocytosis. Unlike ovarian and breast cancers, where CD24 is a key ligand for Siglec-10, we found that while most PDAC cells bind to Siglec-10 — indicating the presence of sialic acid ligands — these cells do not predominantly express CD24. This suggests that PDAC cells engage Siglec-10 primarilyAttorney Docket No.206193-0150-P1US

[0306] through other glycoproteins. Using affinity pulldown and mass spectrometry, we identified the glycoprotein ligands of Siglec-10 on PDAC cells as the two subunits of integrin a3pi (ITGA3 and ITGB1), which have not previously been implicated in PDAC immune evasion. We then confirmed that ITGA3 and ITGB1 contribute to PDAC cell resistance to macrophage phagocytosis using in vitro immune-killing assays against PDAC cells. Since we found that Siglec-10 on macrophages interacts with multiple glycoproteins on PDAC cells, we hypothesized that directly targeting Siglec-10 would be a more effective approach than targeting its ligands. To test this, we developed novel antibodies targeting Siglec-10 and evaluated their ability to enhance macrophage phagocytosis of PDAC cells. Disrupting Siglec-10 interactions using these antibodies significantly increased macrophage-mediated phagocytosis of human PDAC cells in vitro and reduced tumor size in a PDAC xenograft mouse model engrafted with human macrophages.

[0307] PDAC cells bind to Siglec-10 through sialic acid expressed on proteins other than CD24.

[0308] To investigate the potential links between Siglec-10 or CD24 expression and PDAC progression, we first analyzed TCGA data on gene expression of pancreatic adenocarcinoma (PAAD) tissues and normal tissues. Siglec-10 expression, but not CD24 expression, is significantly higher in PAAD tissues compared to normal tissues (Figure 1A). Sialic acids are added to glycoproteins, such as CD24 and others, through the action of several glycan-related enzymes, including several sialyltransferases (Figure IB). We therefore examined whether the expression of these glycan-related genes is enriched in PAAD tissues. Indeed, multiple genes involved in the production of sialic acid ligands for Siglec-10 were significantly upregulated in PAAD compared to normal tissues (Figure 1C and Figure ID). These findings suggest that Siglec-10-sialic acid interactions may play a role in PDAC progression.

[0309] Interactions between sialic acid-containing ligands (e.g., CD24) on cancer cells and Siglec-10 on macrophages are known to inhibit macrophage-mediated phagocytosis and blocking CD24 enhances macrophage-mediated phagocytosis against breast and ovarian cancer cells (Barkal et al., 2019, Nature, 572(7769):392-6). To test whether blocking CD24 could enhance macrophage phagocytosis of PDAC cells, weAttorney Docket No.206193-0150-P1US

[0310] used a blocking antibody previously shown to enhance phagocytosis in breast and ovarian cancers (Barkal et al., 2019, Nature, 572(7769):392-6). Monocytes isolated from PBMCs of healthy donors were differentiated into macrophages (Martinez et al., 2012, Curr Protoc Immunol, Chapter 14:14 28 1-14 28 3), leading to high Siglec-10 expression (Figure 2). These macrophages were co-cultured with phRhodo-labeled human PDAC cells from several cell lines in the presence of either an isotype control or anti-CD24 antibody. The CD24 blocking antibody failed to significantly or consistently enhance macrophage phagocytosis against PDAC cells (Figure IF).

[0311] Several factors may explain why blocking CD24 did not significantly or consistently enhance macrophage phagocytosis of PDAC cells. One possibility is that PDAC cells do bind to Siglec-10 on macrophages, but they do so through sialic acid expressed on other glycoproteins, instead of or in addition to CD24. To explore this possibility, we used a recombinant Siglec-10-Fc chimera protein with a BV421-conjugated secondary antibody to detect Siglec-10 ligands via flow cytometry. Several human PDAC cell lines, including MIA PaCa-2, AsPC-1, and BxPC-3 bound Siglec-10, indicating the presence of the preferred sialic acid type on their surface glycoproteins (Figure 1G; x-axis). Although some Siglec-10-binding cells did express CD24, the majority of these cells do not express CD24 (Figure 1G and Figure 1H). These data indicate that PDAC cells utilize additional glycoproteins, apart from CD24, to bind Siglec-10. This contrasts with breast and ovarian cancers, where CD24 is the primary Siglec-10-binding glycoprotein (Barkal et al., 2019, Nature,' 572(7769):392-6).

[0312] Siglec-10 binds to ITGA3 and ITGB1, the subunits of a3pi Integrin, on PDAC cells.

[0313] To identify glycoproteins on PDAC cells that bind to Siglec-10, we performed a pull-down assay using recombinant Siglec-10 and cell-membrane proteins isolated from several human PDAC cell lines. Proteins bound to Siglec-10 were identified via mass spectrometry analysis (Figure 3 A). From a total of 4,044 proteins whose binding was enriched compared to a no-protein control, 110 proteins showed enrichment compared to a Siglec-5 (a closely related Siglec used as a control). Of these, six proteins — CD47, CD59, CD73, ITGB6, ITGA3, and ITGB1 — were significantlyAttorney Docket No.206193-0150-P1US

[0314] overexpressed in PA AD tissues compared to normal tissues based on TCGA data (Figure 3B).

[0315] To determine whether these six proteins bind directly to Siglec-10, we performed surface plasmon resonance (SPR) analysis using recombinant versions of these proteins and recombinant Siglec-10. Among the six candidates, only ITGA3 and ITGB1, the subunits of a3 1 integrin, exhibited strong binding affinity to Siglec-10 (Figure 3C). To assess whether this binding is dependent on the sialic acid content of these glycoproteins, we treated ITGA3 and ITGB1 with sialidase to enzymatically remove sialic acid. The removal of sialic acid was confirmed using lectin staining with a sialic acid-specific lectin (SNA), which showed a significant reduction in sialic acid levels on ITGA3 and ITGB1 after sialidase treatment (Figure 3D). Sialidase treatment abolished the ability of ITGA3 and ITGB1 to bind to Siglec-10 (Figure 3E and Figure 3F). These findings show that Siglec-10 binds to the sialic acid on ITGA3 and ITGB1.

[0316] The expression of ITGA3 and ITGB1 on PDAC cells correlates with PDAC progression and prognosis.

[0317] Having identified ITGA3 and ITGB1 as glycoprotein ligands that interact with Siglec-10 to potentially suppress immune surveillance, we next investigated whether their expression is associated with PDAC progression and prognosis. First, we measured the cell surface expression of ITGA3 and ITGB1 on several human PDAC cell lines. High levels of ITGA3 (Figure 4A and Figure 5 A) were observed across multiple PDAC cell lines. We then analyzed TCGA data to assess the in vivo relevance of ITGA3 expression in PAAD tissues compared to normal tissues. PAAD tissues exhibited significantly higher levels of ITGA3 compared to normal tissues. Similar results were observed with ITGB1 (Figure 3C, Figure 3D, and Figure 4B). ITGA3 expression correlated with elevated Siglec-10 expression (Figure 6A) and higher levels of glycan-related genes, such as ST3GAL1 and B2GNT3, responsible for sialic acid addition to glycoproteins (Figure 6B). Similarly, ITGB1 expression correlated with increased Siglec-10 expression (Figure 3C) and elevated levels of sialic acid-related genes (Figure 3D).

[0318] Next, we investigated whether the expression of CD24 (a previously identified Siglec-10 ligand), ITGA3, and ITGB1 correlated with PDAC patient survival.Attorney Docket No.206193-0150-P1US

[0319] While CD24 expression did not correlate with survival (Figure 5E), higher expression of ITGA3 (Figure 5F) and ITGB1 (Figure 5G) was significantly associated with worse prognosis. These findings support the concept that ITGA3 and ITGB1 contribute to PDAC progression, possibly by binding to the immune-suppressing molecule Siglec-10, potentially aiding PDAC cells in evading immune-mediated surveillance.

[0320] Finally, we examined the single-cell expression of ITGA3 and ITGB1 in epithelial cells from human PDAC tissues and healthy tissues. To do this, we utilized two publicly available single-cell transcriptomic datasets of human PDAC tissues and normal tissues (Peng et al., 2019, Cell Res, 29(9):725-38; Werba et al., 2023, Nat Commun; 14(1):797). In the first dataset (Peng et al., 2019, Cell Res 29(9):725-38), PDAC tissues and normal tissues underwent single-cell analysis (Figure 5H). The single-cell expression of ITGA3 was significantly higher in PDAC epithelial cells compared to normal epithelial cells (Figure 51). Pathway analysis of ITGA3111versus ITGA3lowPDAC cells revealed differential expression of genes related to immune modulation (Figure 5J). Similarly, the single-cell expression of ITGB1 was significantly higher in PDAC epithelial cells compared to normal epithelial cells (Figure 5K). Pathway analysis of ITGBlhlversus ITGBllowPDAC cells showed altered pathways associated with immune evasion and modulation (Figure 7A). The second dataset (Werba et al., 2023, Nat Commun 14(1): 797), while lacking samples from normal tissues (Figure 7B), provided additional evidence. Analysis of ITGA3111versus ITGA3lowPDAC epithelial cells in this dataset (Figure 7C and Figure 7D) confirmed the differential expression of several cellular pathways involved in immune modulation and evasion. Together, these singlecell data from primary PDAC tissues support the role of ITGA3 and ITGB1 in promoting PDAC progression through altered immune-modulatory pathways.

[0321] ITGA3 and ITGB1 facilitate PDAC cell evasion of macrophage-mediated phagocytosis.

[0322] Given that 1) the sialic acid on ITGA3 and ITGB1 in PDAC cells binds strongly to Siglec-10, 2) ITGA3 and ITGB1 expression is associated with PDAC progression and worse prognosis, and 3) Siglec-10 interactions on macrophages inhibit their ability to phagocytose pathological cells, we next investigated whether PDAC cellsAttorney Docket No.206193-0150-P1US

[0323] with high ITGA3 or ITGB1 expression exhibit greater evasion of macrophage-mediated phagocytosis compared to cells with low expression of these glycoproteins.

[0324] We used the PDAC cell lines MIA PaCa-2 and PANC-1 and employed antibody-coated columns targeting ITGA3 or ITGB1 (Figure 8A) to enrich for ITGA3lowor ITGBllowcells, which do not bind to the columns. Flow cytometry analysis confirmed a significant enrichment of ITGA3lowandITGBllowcells compared to controls which the majority of cells express ITGA3 that passed through columns without antibodies (Figure 8 A). We then assessed the ability of PDAC cells with high (controls) and low levels of ITGA3 to evade macrophage-mediated phagocytosis using the previously described phagocytosis assay (Figure 8B). Cells expressing high levels of ITGA3 evaded macrophage-mediated phagocytosis significantly more effectively than ITGA3lowcells (Figure 8C and Figure 8D). Similarly, PDAC cells with high levels of ITGB1 also evaded macrophage-mediated phagocytosis compared to ITGBlowcells (Figure 8E through Figure 8G). These findings indicate that ITGA3 and ITGB1 significantly contribute to the immune evasion of PDAC cells by inhibiting macrophage-mediated phagocytosis, potentially through their interactions with Siglec-10.

[0325] Disrupting Siglec-10 interactions, via monoclonal antibodies, enhances macrophage-mediated phagocytosis of PDAC cells in vitro.

[0326] Our findings thus far suggest that Siglec-10 on macrophages binds to multiple glycoprotein ligands on PDAC cells, including ITGA3, ITGB1, and potentially others. This binding inhibits the phagocytic capacity of macrophages against PDAC cells (Figure 9A). Therefore, directly targeting Siglec-10 itself, rather than its individual ligands, may be necessary to enhance macrophage-mediated phagocytosis of PDAC cells. Such an approach would disrupt interactions between Siglec-10 and sialic acids across its various glycoprotein ligands. However, the lack of potent, commercially available anti-Siglec-10 antibodies has necessitated the development of these antibodies in-house.

[0327] To achieve this, we immunized mice with Siglec-10 protein, and serum titers of Siglec-10 antibodies were measured using indirect ELISA. High serum reactivity to Siglec-10 was observed in several mice, which were selected for hybridoma generation. Over 200 hybridoma clones were initially screened for antibody productionAttorney Docket No.206193-0150-P1US

[0328] using ELISA against Siglec-10 and Siglec-5 (a control). Sixteen clones were selected for subcloning, and antibodies from their culture supernatants were further analyzed using ELISA and flow cytometry (FACS). Several antibodies demonstrated high affinity for Siglec-10 in ELISA (Figure 9B). In addition, FACS confirmed the binding specificity of these antibodies to Siglec-10: CHO-K1 cells expressing Siglec-10 or Siglec-5 (as a control) were incubated with hybridoma supernatants and stained with an Alexa Fluor 488-conjugated secondary antibody. The antibodies showed significant binding to Siglec- 10-expressing cells, but not to Siglec-5 controls (Figure 9C), confirming their specificity.

[0329] The clones were then evaluated for their ability to enhance macrophage-mediated phagocytosis of PDAC cells (Figure 9D) using the same assay described in Figure IE and compared against an isotype control, an aCD24 antibody, and a commercially available aSiglec-10 antibody. Several of these clones significantly enhanced the macrophages’ ability to phagocytose PDAC cells (Figure 9D). The top five clones were further tested for their ability to enhance macrophage-mediated phagocytosis of PDAC cells using macrophages derived from the monocytes of several donors. One clone, 68A11 Al, demonstrated superior performance and was selected for recombinant expression (Figure 9E and Figure 9F). The recombinant 68A11A1 antibody displayed high specificity for Siglec-10 without cross-reactivity to Siglec-5 or other irrelevant His-tagged proteins (Figure 9G). Notably, this recombinant antibody significantly enhanced the phagocytic capacity of macrophages against multiple human PDAC cell lines compared to the antibody targeting CD24, using a similar assay as shown in Figure IE and using macrophages from multiple donors (Figure 9H). Together, these results show the successful generation and characterization of monoclonal antibodies with high affinity and specificity for Siglec-10. These antibodies enhanced macrophage-mediated phagocytosis of PDAC cells, further underscoring the critical role of Siglec-10 interactions in immune evasion by PDAC cells and their potential as therapeutic targets.

[0330] Disrupting Siglec-10 interactions enhances macrophage-mediated phagocytosis of PDAC cells and induces human macrophage activation in vivo.

[0331] Since mice lack Siglec-10 and instead express a homolog, testing a Siglec- 10 antibody in wild-type mice is not feasible. To address this, we utilizedAttorney Docket No.206193-0150-P1US

[0332] immunodeficient NSG mice engrafted with AsPC-1 human PDAC cells and human monocyte-derived macrophages. Mice were treated with either an isotype control antibody or the Siglec-10-specific antibody, clone 68A11A1. Targeting Siglec-10 significantly reduced PDAC tumor growth in vivo (Figure 10A through Figure 10E).

[0333] At the end of the experiment, tumors were collected, and human macrophages were isolated using FACS (Figure 11). Transcriptomic analysis of isolated macrophages by RNA-sequencing showed significant changes in gene expression, supporting the impact of disrupting Siglec-10 interactions on macrophage activation and enhanced phagocytic capacity (Figure 10H). In particular, macrophages from mice treated with the Siglec-10 antibody displayed significant activation of PI3K / AKT, MAPK, and AP-1 immune signaling pathways; all key pathway downstream of Siglec-10 interactions. Upregulated genes included PIK3C2A, PTEN, and PRKAA1, which regulate PI3K / AKT signaling critical for macrophage survival, metabolic reprogramming, and phagocytosis. Genes such as MAP3K1, MAP3K2, and DUSP1 modulate MAPK signaling, and their up-regulation support balanced activation and feedback inhibition for sustained immune responses. JUN and FOS, components of the AP-1 transcription complex, were upregulated, which can support immune responses. Additional upregulated genes such as NFKBIZ indicated induced immune activation. Conversely, downregulation of MAP2K2, CREB3, and PPP2R1A suggested a shift in MAPK signaling toward activation of JNK and p38 branches, favoring immune activation over ERK-mediated proliferation. Reduced expression ofMIF, an immune regulator, further alleviated inhibitory effects on macrophage activation (Figure 10F).

[0334] In addition, macrophages from mice treated with the Siglec-10 antibody showed up-regulation of several pathways related to enhanced phagocytosis. Upregulated genes including RAB5A, which controls phagosome maturation and vesicle trafficking; DOCK1, which activates Rael to drive actin remodeling essential for phagocytic cup formation; and CDC42EP3, which facilitates actin filament organization. Other upregulated genes included CD46, a complement receptor linking target recognition to enhanced phagocytosis; WASL, which promotes actin polymerization crucial for stabilizing the phagocytic cup; PLXNB1, which modulates cytoskeletal changes; and ACTN4, ARHGAP12, and ROCK2, which regulate actin dynamics andAttorney Docket No.206193-0150-P1US

[0335] cytoskeletal rearrangement for efficient engulfment of targets. Notably, genes such as FCGR2B and CFL1, which inhibit phagocytosis and actin remodeling, were downregulated, lifting constraints on macrophage function. These changes collectively indicate enhanced phagocytosis driven by improved actin remodeling, vesicle trafficking, and target recognition while reducing inhibitory signals (Figure 10G).

[0336] Finally, macrophages from mice treated with Siglec-10 showed evidence of metabolic reprogramming. Upregulation of ACADM, PDK4, and PRKAA1 indicated a shift toward fatty acid P-oxidation, a metabolic adaptation that provides energy for sustained macrophage activation and phagocytosis. Notably, downregulation of ALDOA, a glycolytic enzyme, suggested a decreased reliance on glycolysis in favor of oxidative metabolism, aligning with the energy demands of prolonged immune responses (Figure 10H). Together, these findings show that disrupting Siglec-10 interactions enhances macrophage-mediated phagocytosis ofPDAC cells in vivo, accompanied by extensive macrophage activation characterized by cytoskeletal remodeling, immune pathway activation, and metabolic reprogramming. These data establish targeting Siglec-10 interactions as a promising therapeutic target for immunotherapy in PDAC.

[0337] In this study, we identified a novel immunological interaction between a3pi integrin on PDAC cell surfaces and Siglec-10, a gly co-immune checkpoint receptor on macrophages, which facilitates immune evasion by PDAC cells. This previously unrecognized interaction suppresses macrophage-mediated immune surveillance, enabling tumor cells to evade immune clearance. Notably, we show that disrupting these interactions with monoclonal antibodies restores macrophage phagocytic capacity against PDAC cells. By tapping into glycan-based interventions, a largely underexplored avenue in cancer immunotherapy, our findings lay the foundation for innovative strategies that could enhance therapeutic outcomes for PDAC patients. With PDAC projected to account for approximately 66,440 new cases and 51,750 deaths in the United States in 2024 alone (Siegel et al., 2023, CA Cancer J Clin, 73(1): 17-48), this work addresses an urgent and critical clinical need.

[0338] In 2019, a pivotal study identified interactions between Siglec-10 and CD24 as a key 'don't eat me' signal in breast and ovarian cancers, mediating immune evasion through macrophage suppression (Barkal et al., 2019, Nature;572(7769):392-6).Attorney Docket No.206193-0150-P1US

[0339] Our findings uncover a distinct mechanism in PDAC, where a301 integrin, rather than CD24, emerges as a primary ligand for Siglec-10. These findings suggest that Siglec-10 interacts with multiple ligands on cancer cell surfaces, with these ligands varying across cancer types. Such diversity highlights the critical need to identify cancer-specific Siglec- 10 ligands. Identifying these ligands provides novel insights into how distinct cancers evade immune surveillance and could inform the development of therapeutics targeting both Siglec-10 and its ligands. This approach holds significant potential to enhance the efficacy of tailored immunotherapeutic strategies in oncology.

[0340] Integrin a301, composed of the ITGA3 and ITGB1 subunits, is a well-characterized cell surface receptor known for its roles in cell adhesion, migration, and signaling. a3pi has been implicated in tumor progression, metastasis, and resistance to therapy across various cancer types (Ganguly et al., 2022, Gastroenterology, 162(7):2032-46 el2; Li et al., 2024, Cancer Gene Ther, Miskin et al., 2021, Cancers (Basel); 13(3); Subbaram et al., 2011, Expert Opin Ther Targets,' 15(10): 1197-210; Subbaram et al., 2014, J Cell Sci;127(Pt 6); Varzavand et al., 2013, Clin Exp Metastasis', 30(4):541-52). In PDAC, ITGA3 and ITGB1 are frequently overexpressed and contribute to the disease's aggressive nature by promoting epithelial-mesenchymal transition, invasion, and survival within the dense, immunosuppressive tumor microenvironment (Hu et al., 2022, Open Med (Wars),' 17(1): 1935-43; Idichi et al., 2018, < / 7co / ar ^ / ;9(48):28849-65; Iwatate et al., 2022, PLoS One;17(6):e0268630; Jiao et al., 2019, Onco Targets Ther, 12:4141-52; Li et al., 2022, Cancers (Basel),' 14(14); Lu et al., 2016, Onco Targets Ther, 9:99-109; Zhang et al., 2024, Biochem Genet;62(4):2652-66). However, their involvement in immune evasion has remained unexplored. In this study, we identify a previously uncharacterized function for a3pi integrin, via its glycosylation, as a critical ligand for Siglec-10 on macrophages in PDAC. By interacting with Siglec-10, a3pi transmits a ‘don’t eat me’ signal, suppressing macrophage-mediated phagocytosis and facilitating immune evasion and tumor progression. These findings broaden the understanding of a3pi, extending its role beyond tumor cell behavior to include a pivotal function in immune suppression. By uncovering this mechanism of immune evasion, we highlight a3pi-Siglec-10 interactions as a promising therapeutic target to overcome immune resistance and improve outcomes for PDAC patients.Attorney Docket No.206193-0150-P1US

[0341] Current immunotherapy efforts focusing on targeting proteins and nucleic acids have revolutionized cancer treatment. However, these approaches remain insufficient to fully realize the potential of immunotherapy for many patients, including those with PDAC (Johnson et al., 2023, N Engl J Med;3 ( 6y.1529-32; Ju et al., 2024, NPJ Precis Oncol; 8(1): 199). Targeting glycomic interactions between glycans and glyco-immune checkpoints such as Siglec-10 represents a novel and complementary approach to enhance the efficacy of cancer immunotherapy (Beatson et al., 2016, Nat Immunol; Yl( 1): 1273-81; Hudak et al., 2014, Nat Chem Zfr'o / ;10(l):69-75; Jandus et al., 2014, J Clin Invest; 124(4): 1810-20; Stanczak et al., 2018, J Clin Invest;\2% 1):4912-23). Our findings underscore the therapeutic promise of disrupting Siglec-10 interactions as a strategy to restore macrophage function and enhance anti-PDAC immunity. Unlike traditional immune checkpoint inhibitors, such as those targeting PD-1 / PD-L1 interactions that primarily act on T cells, Siglec-10 targeting directly reactivates myeloid cells like macrophages, which play a pivotal role within the tumor microenvironment. This creates opportunities for combining Siglec-10 targeting with other therapies. For instance, combining it with therapies targeting immune checkpoints on T cells could further enhance anti-tumor immunity. Additionally, Siglec-10 targeting can be integrated with therapies designed to enhance macrophage-mediated phagocytosis, such as CD47-blocking antibodies, which are already in clinical development. CD47 inhibits phagocytosis by interacting with macrophage SIRPa (Matlung et al., 2017, Immunol 7?ev;276(l): 145-64; Weiskopf et al., 2016,. / ( 7 / / / / / i’c’.s7; l 26(7):26 l 0-20; Willingham et al., 2012, Proc Natl Acad Sci USd;109(17):6662-7). Since Siglec-10 and CD47 regulate phagocytosis through distinct pathways, targeting both simultaneously could produce additive or synergistic effects. Together, Siglec-targeting therapies, when combined with immune checkpoint inhibitors acting on T cells or macrophages, have the potential to significantly expand the arsenal of immunotherapeutic tools available for cancer treatment.

[0342] In our study, monoclonal antibodies against Siglec-10 restored macrophage phagocytic capacity in vitro and reduced tumor growth in vivo, providing a proof of concept for targeting this glyco-immune checkpoint. However, targeting Siglecs on myeloid cells could have broader implications for immunity by activating antigen-Attorney Docket No.206193-0150-P1US

[0343] presenting cells, potentially enhancing downstream T cell responses, indirectly (Egan et al., 2023, Cell Rep, 42(5): 112475; Mei et al., 2023, Nat Cancer, 4(9): 1273-91; Wang et al., 2022, Front Cell Dev Biol, 0:828916). In our experiments using NSG mouse models engrafted with macrophages, we focused on the role of Siglec-10 interactions in modulating phagocytosis. However, the broader impact of disrupting these interactions on overall anti-tumor immunity warrants further investigation in humanized mouse models with an intact immune system. Importantly, Siglec-sialic acid interactions serve as critical immune checkpoints to prevent autoimmunity (Varki et al., 2012, Annals of the New York Academy of Sciences; 1253: 16-36). As such, blocking Siglecs may pose a risk of inducing non-specific inflammation, similar to what has been observed with other immune checkpoint inhibitors, such as PD-1 / PD-L1 blockers (Su et al., 2020, Front Oncol, 10:554313). Notably, there are key differences between Siglecs and other immune checkpoints, including their expression patterns and functions. For example, a recent clinical trial (NCT03822208) evaluating a Siglec-3 (CD33) inhibitor reported favorable safety profiles in humans, suggesting that Siglec-targeted therapies may be well-tolerated. Nevertheless, careful evaluation of the balance between the beneficial and potentially detrimental effects of Siglec blockade is essential. If toxicity is observed when blocking Siglecs using monospecific antibodies, alternative approaches may be required.

[0344] Bispecific or trispecific antibodies targeting both Siglec-10 and its ligands, such as the a3pi integrin identified in this study, could represent a promising strategy. Such approaches could enhance immune responses by disrupting Siglec- 10-mediated immune suppression while minimizing the risk of non-specific inflammatory effects.

[0345] While our study provides significant insights into the role of Siglec-10 interactions in PDAC immune evasion, it is not without limitations. First, our in vivo experiments were conducted in NSG mouse models engrafted with human macrophages, which, although useful for studying macrophage-specific effects, lack a fully intact immune system. This limits our ability to evaluate the broader impact of Siglec-10 blockade on other immune cell types, such as T cells. Second, while we identified a3pi integrin as a critical ligand for Siglec-10 in PDAC, it is likely that additional ligands exist in other cancer types, and these remain to be explored. Third, potential off-target effects and long-term consequences of Siglec-10 blockade, such as non-specific inflammation orAttorney Docket No.206193-0150-P1US

[0346] autoimmunity, require further investigation in more complex and clinically relevant models. Despite these limitations, our findings represent a substantial advancement in understanding glyco-immune interactions in PDAC biology. By identifying a301 integrin as a novel ligand for Siglec-10 and demonstrating the therapeutic potential of disrupting this interaction, we provide a new framework for targeting immune evasion in PDAC.

[0347] METHODS

[0348] Macrophage differentiation and in vitro phagocytic assay. Macrophages were differentiated as described previously (Barkal et al., 2019, Nature, 572(7769): 392-6; Martinez, 2012, Curr Protoc Immunol Chapter 14:1428 1-14). Briefly, monocytes from healthy donors were differentiated into macrophages by culturing them for 7-9 days in Iscove's Modified Dulbecco's Medium (IMDM) supplemented with 10% AB human serum (Life Technologies). During the initial 3-4 days, macrophages were stimulated with 50 ng / mL M-CSF. Subsequently, M-CSF (50 ng / ml) and IL-4 (20 ng / mL) were added to support differentiation, and this stimulation was maintained until the macrophages were used on Days 7-9. PDAC cells were treated with TrypLE Express and labeled with pHrodo Red, SE (Thermo Fisher Scientific) according to the manufacturer’s protocol. Labeling was performed at a concentration of 250 ng / mL in PBS for 10 minutes at 37°C, followed by two washes with Dulbecco's Modified Eagle Medium (DMEM) containing 10% FBS and 100 U / mL penicillin / streptomycin. Healthy donor-derived macrophages were harvested using TrypLE Express, and 50,000 macrophages were seeded into black 96-well flat-bottom plates, allowing them to adhere for 30 minutes at 37°C. After adhesion, 50,000 pHrodo Red-labeled PDAC cells were added in serum-free IMDM. The plates were incubated at 37°C, and phagocytosis was monitored by imaging every hour using an Incucyte (Sartorius). The initial image (t = 0) was captured within 30 minutes of co-culture. Images were taken using a 20* objective with a 400 ms exposure per field. Phagocytosis was quantified by measuring the total red area (pm2) across technical replicates for each donor. Thresholds for identifying pHrodo Red-positive events were determined based on intensity measurements from labeled cells in the absence of macrophages.

[0349] Siglec-10 ligand staining by flow cytometry. Siglec-10 ligand expression was detected using recombinant chimeric proteins consisting of the Siglec-10 bindingAttorney Docket No.206193-0150-P1US

[0350] region fused to human IgG Fc domains (SigleclO-Fc, R& D Systems). To form the Siglec-10-Fc / anti-human IgG-BV421 complex, Siglec-10-Fc (2.5 pg / mL) andBV421-conjugated anti-human IgG were incubated on ice for 1 hour. PDAC cells were detached using TrypLE Express, washed, pelleted, and adjusted to a density of 1x106cells / mL. The cells were resuspended in the Siglec-10-Fc / anti-human IgG-BV421 precomplex solution along with CD24-Alexa 488 antibody. After a 30-minute incubation on ice, the cells were pelleted by centrifugation at 300 * g for 5 minutes and washed twice. Samples were analyzed using a BD FACS Symphony A3 cytometer, acquiring at least 30,000 events per sample. Data analysis was performed using FlowJo V9.

[0351] Pull-Down and mass spectrometry analysis of Siglec-10 ligands on PDAC cells. To identify Siglec-10 ligands, we employed a proximity labeling approach based on the tyramide radicalization principle (Chang et al, 2017, J Proteome

[0352] Res, 16(10):3929-41). Briefly, recombinant Siglec-10-Fc fusion protein (10 pg) was incubated with an anti-human Fc HRP conjugate (5 pg) — a monoclonal antibody against human Fc tag directly conjugated to horseradish peroxidase (HRP) — on ice for 60 minutes to facilitate complex formation. PDAC cell lines (AsPC-1, BxPC-3, MiaPaCa-2, Panc-1) were incubated with the Siglec-10-HRP complex on ice for 1 hour (20 x 106cells per reaction). After incubation, cells were washed twice with 10 mb of 140 mM NaCl in 20 mM Tris-HCl buffer (pH 8.0, TBS). The cells were then treated with 10 pM biotin tyramide and 10 mM H2O2in TBS at room temperature for 10 minutes. Following the reaction, cells were washed three times with TBS and lysed in 200 pL of lysis buffer (50 mM Tris-HCl, pH 8.0, 150 mMNaCl, 1% Nonidet P-40, 0.5% sodium deoxycholate, 0.1% SDS) supplemented with a protease inhibitor cocktail. Lysis was performed on ice for 30 minutes. A Siglec-5 control and a secondary antibody-only control were included for each cell line. The lysates were cleared by centrifugation at 15,000 x g for 30 minutes and used for the purification of biotinylated proteins.

[0353] Biotinylated proteins were purified using streptavidin-functionalized paramagnetic beads. One milligram of Dynabeads Streptavidin-MyOne Cl (Thermo Fisher Scientific) was mixed with 100 pL of cleared lysate and incubated at room temperature for 1 hour with constant shaking. The beads were collected using a magnet (DynaMag-2, Thermo Fisher Scientific) and washed extensively with D-PBS containingAttorney Docket No.206193-0150-P1US

[0354] 0.1% SDS. The samples were reduced with tris(2-carboxyethyl)phosphine, alkylated with iodoacetamide, and digested on-bead with trypsin (Promega). Tryptic digests were cleaned using BioPureSPN C18 spin columns (Nest Group) and analyzed by liquid chromatography -tandem mass spectrometry (LC-MS / MS) using a 1.5-hour LC gradient on a Thermo Q Exactive Plus mass spectrometer (Crissey et al., 2024, Autophagy, 1-13). MS data were searched with full tryptic specificity against the UniProt human proteome (downloaded on 8 / 21 / 2023) and a contaminant database using MaxQuant 2.4.7.0 (Cox et al., 2008, Nat Biotechnol, 26(12) 1367 -72). Protein and peptide false discovery rates were set at 1%. A total of 4,044 proteins were identified, which were further filtered based on a two-fold enrichment of Siglec-10 compared to the Siglec-5 control.

[0355] Surface Plasmon Resonance (SPR): Recombinant Siglec-10 Fc protein was immobilized on a protein A / G chip at three different densities (-200 RU, -600 RU, -1000 RU). One flow cell was left blank as a control to account for non-specific binding to the chip. All test proteins were desalted in running buffer and tested at two concentrations (100 nM and 1000 nM), except for ITGA3, which was tested at 30 nM and 300 nM. The association time was set to 120 seconds, the dissociation time to 600 seconds, and the flow rate to 25 pL / min. After each injection of test protein, the Siglec-10 / protein complex was dissociated from the chip using 20 mM glycine (pH 2.0), followed by the re-immobilization of fresh Siglec-10 protein.

[0356] Sialidase treatment and lectin staining. Proteins were treated with Sialidase A (Agilent) following the manufacturer’s instructions. Briefly, 5 pg of ITGA3 and ITGB1 glycoproteins were combined with 14 pL of deionized water, 4 pL of 5* Reaction Buffer, and 2 pL of Sialidase A. The reaction mixture was incubated at 37°C for 1 hour. To verify the removal of sialic acid, a lectin microarray platform was used to profile sialic acid-dependent glycan structures. This array utilizes a panel of immobilized lectins, each with known glycan structure binding specificity. Both sialidase-digested and undigested proteins were labeled with Cy3 dye (Sigma- Aldrich) and hybridized to the lectin microarray. The lectin chips were scanned for fluorescence intensity at each lectin-coated spot using an evanescent-field fluorescence scanner (Rexxam Co., Ltd.). All samples were run in triplicate, and the average fluorescence intensity of the triplicates was used for analysis. Data were normalized using the global normalization method.Attorney Docket No.206193-0150-P1US

[0357] JTGA3lowand lTGBllowPDAC cell enrichment. PDAC cells were incubated with anti-human ITGA3 and ITGB1 antibodies (Clone ASC-1 and TS2 / 16, respectively, from Thermo Fisher Scientific) at a concentration of 1 pg / mL in lx PBS at 4°C for 15 minutes. The cells were then washed twice and incubated with 20 pL of antimouse MicroBeads (Miltenyi Biotec, Cat# 130-048-402) for 15 minutes at 4°C.

[0358] Following another wash, the cells were loaded onto pre-equilibrated LS columns (Miltenyi Biotec, Cat# 130-042-401) in accordance with the manufacturer’s protocol. After extensive washing, the cells in the eluate fraction were pelleted, resuspended in DMEM supplemented with 10% FBS, and subsequently used for in vitro cell-killing assays.

[0359] Single-Cell RNA-Seq analysis: We analyzed two publicly available single-cell transcriptomic datasets of human PDAC and normal tissues (Peng et al., 2019, Cell 7?es;29(9):725-38; Werba et al., 2023, Nat Common, 14(1):797). Data analysis was performed using BBrowser 3, with the Talk2Data plugin utilized for deeper insights. The datasets were initially categorized into PDAC and normal tissue groups. ITGA3 and ITGB1 expression in epithelial cells was assessed, with gating performed on the PDAC cluster to separate cells based on high and low ITGA3 expression. Pathway analysis was subsequently conducted using BBrowser to identify biological processes associated with ITGA3 expression.

[0360] Siglec-10 monoclonal antibody production. Monoclonal antibodies targeting the extracellular domain (ECD) of Siglec-10 were developed and characterized. Ten BALB / c and C57BL / 6 mice were initially immunized with 50pg of recombinant Siglec-10 protein (GenScript), followed by four booster immunizations of 25pg each at two-week intervals. Blood samples were collected after each immunization, and serum antibody titers were assessed using indirect ELISA. For ELISA, 96-well plates were coated with Siglec-10 antigen or Siglec-5 antigen (Ipg / mL in PBS) and incubated overnight at 4°C. Plates were blocked with 1% BSA in PBS to prevent nonspecific binding. Diluted serum samples were incubated for 1 hour at 37°C, followed by washes and incubation with horseradish peroxidase (HRP)-conjugated goat anti-mouse IgG secondary antibody. The reaction was developed using tetramethylbenzidine (TMB) substrate, stopped with acid, and the absorbance was measured at 450 nm. Mice withAttorney Docket No.206193-0150-P1US

[0361] serum OD450 values exceeding 1.0 at dilutions >1:8,000 were selected for hybridoma generation. Splenocytes from selected mice were fused with SP2 / 0 myeloma cells via electrofusion. The hybridomas were cultured in HAT medium, and supernatants were screened for Siglec-10-specific antibodies using same ELISA protocol described above. Hybridoma clones were also tested for specificity by flow cytometry (FACS) using CHO-K1 cells expressing Siglec-10 or Siglec-5 (as a control). Positive hybridoma supernatants demonstrated significant fluorescence with Siglec-10-expressing cells compared to controls. For FACS, 50 pL of a CHO-K1 cell suspension (1 x 105cells per well) was incubated with hybridoma supernatants at 4°C for 30 minutes. After washing, Alexa Fluor 488-conjugated goat anti-mouse IgG secondary antibody (Jackson ImmunoResearch) was added, and samples were analyzed using a flow cytometer. Clones with high median fluorescence intensity (MFI) against Siglec-10 cells were selected for subcloning.

[0362] Selected hybridoma clones underwent limiting dilution for subcloning. Subclones were cultured, and supernatants were collected for antibody purification. Antibodies were purified using Protein A chromatography and assessed for purity by SDS-PAGE. Concentrations were determined using UV spectrophotometry. The specificity of purified antibodies was validated using the same ELISA and FACS protocols described above against both Siglec-10 and Siglec-5 (as a control). Antibodies from positive clones were sequenced. RNA was extracted from hybridoma cells using the RNeasy Isolation Kit, and antibody sequences were determined via RT-PCR using universal primers. Sequenced antibodies were expressed recombinantly in CHO-S cells and purified. Functional characterization of these recombinant antibodies was performed using the same ELISA and FACS assays described above.

[0363] In vivo mice experiments. NSG (NOD. Cg-PrkdcscldI^rg^^' / SzJ) mice were anesthetized with isoflurane, and the hair on the right flank was shaved. A 100 pL suspension of AsPC-1 cells (2 x io6cells per mouse) was prepared by mixing the cells with Matrigel and 1 x PBS at a 1:1 ratio, which was then injected subcutaneously into each mouse. After one-week, subcutaneous tumors of approximately 40 mm3had developed. The mice were randomly assigned to two groups: isotype control or Siglec-10 antibody treatment. Monocyte-derived macrophages were incubated with 200 pg of eitherAttorney Docket No.206193-0150-P1US

[0364] isotype or Siglec-10 antibody for 30 minutes. Each mouse received intravenous injections of antibody-incubated macrophages three times per week for three weeks. Tumor size was measured using a vernier caliper, and tumor volume was calculated using the formula: tumor volume = ’A (length x width2).

[0365] RNA-Seq analysis of macrophages. Subcutaneous tumors were excised from each mouse, and human CD1 lb+cells were sorted by FACS. Total RNA was extracted from the sorted human macrophages using the Single Cell RNA Purification Kit (Norgen). RNA quality was assessed using the TapeStation High Sensitivity RNA ScreenTape (Agilent). Libraries were prepared using the Low Input RNA Library Prep Kit (Takara Biosciences) with 500 ng of DNase Ltreated total RNA. Final library quality control was performed using the Bioanalyzer High Sensitivity DNA Kit (Agilent). Nextgeneration sequencing (NGS) was conducted with 100 bp paired-end reads on a NovaSeq 6000 system (Illumina) using the SP vl.5200-cycle kit. RNA-seq analysis was performed by Bencos Research Solutions. Briefly, RNA-seq data were aligned to the hg!9 human genome using the Bowtie2 algorithm, and RSEM vl.2.12 was used to estimate read counts and RPKM values with gene information from the Ensembl GRCh37.pl3 transcriptome. Raw counts were analyzed for differential expression using DESeq2, with significance thresholds set at FDR < 0.05 and additional fold change cutoffs where applicable.Attorney Docket No.206193-0150-00WO

[0366] Example 2: SEQUENCES

[0367] SEQ ID NO: 1 29F2C7 heavy chain amino acid sequence EVKLVESGGGLVQPGGSLSLSCAASGFTFTDYYMSWVRQSPGKALEWLGFIRNRPSGYTTEYSAS VKGRFTFSRDNSQNILYLQMNALRSEDSATYYCARYISLWLLGYFDVWGTGTTVTVSS SEQ ID NO: 229F2C7 heavy chain nucleic acid sequence GAGGTGAAGCTGGTGGAGTCTGGAGGAGGCTTGGTCCAGCCTGGGGGTTCTCTGAGTCTCTCCTGT GCAGCTTCTGGATTCACCTTCACTGATTACTACATGAGCTGGGTCCGCCAGTCTCCAGGGAAGGCA CTTGAGTGGTTGGGTTTTATTAGAAACAGACCTAGTGGTTACACAACAGAGTACAGTGCATCTGTG AAGGGTCGGTTCACCTTCTCCAGAGATAATTCCCAAAACATCCTCTATCTTCAAATGAATGCCCTG AGATCTGAGGACAGTGCCACTTATTACTGTGCAAGATATATATCGCTATGGTTACTCGGGTACTTC GATGTCTGGGGCACAGGGACCACGGTCACCGTCTCCTCA SEQ ID NO: 329F2C7 light chain amino acid sequence DVQITQSPSYLAASPGETITINCRTSKSISKYLAWYQEKPGRTINLLIYSGSTLQSGLPSRFSGTG SGTDFTLTISSLEPEDFAMYYCQQHNEFPLTFGAGTKLELK SEQ ID NO: 429F2C7 light chain nucleic acid sequence GATGTCCAGATAACCCAGTCTCCATCTTATCTTGCTGCATCTCCTGGAGAAACCATTACTATTAA TTGCAGGACAAGTAAGAGCATTAGCAAATATTTAGCCTGGTATCAAGAGAAACCTGGGAGAACTA TTAACCTTCTGATCTACTCTGGATCCACTTTGCAATCTGGACTTCCATCAAGGTTCAGTGGCACT GGATCTGGTACAGATTTCACTCTCACCATCAGTAGCCTGGAGCCTGAAGATTTTGCAATGTATTA CTGTCAACAGCATAATGAATTCCCGCTCACATTCGGTGCTGGGACCAAGCTGGAGCTGAAA SEQ ID NO: 534F4A2 heavy chain amino acid sequence EVKLVESGGGLVQPGGSLSLSCAASGFTFTDYYMTWVRQPPGKALEWLGFVRNKANGYTTEYSAS VKGRFTISRDNSQSILYLQMNALRAEDSATYYCARYGLRGFAYWGQGTLVTVSA SEQ ID NO: 634F4A2 heavy chain nucleic acid sequence GAGGTGAAGCTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGAGTCTCTCCTGT GCAGCTTCTGGATTCACCTTCACTGATTACTACATGACCTGGGTCCGCCAGCCTCCAGGGAAGGCA CTTGAGTGGTTGGGTTTTGTTAGAAACAAAGCTAATGGTTACACAACAGAGTACAGTGCATCTGTG AAGGGTCGGTTCACCATCTCCAGAGATAATTCCCAAAGCATCCTCTATCTTCAAATGAATGCCCTG AGAGCTGAGGACAGTGCCACTTATTACTGTGCAAGATATGGATTACGCGGATTTGCTTACTGGGGC CAAGGGACTCTGGTCACTGTCTCTGCA SEQ ID NO: 734F4A2 light chain amino acid sequence DIVMTQSPSSLAMSVGQKVTMSCESSQSLLNSSNLKNYLAWYQQKPGQSPKLLVYFASTRDSGVPD RFIGSGSGTDFTLTISVVQAEDLADYFCHQHYSAPYTFGGGTKLEIK SEQ ID NO: 834F4A2 light chain nucleic acid sequence GACATTGTGATGACACAGTCTCCATCCTCCCTGGCTATGTCAGTAGGACAGAAGGTCACTATGAGC TGCGAGTCCAGTCAGAGCCTTTTAAATAGTAGCAATCTAAAGAACTATTTGGCCTGGTACCAACAG AAACCAGGACAGTCTCCTAAACTTCTGGTATACTTTGCATCCACTAGGGACTCTGGGGTCCCTGAT CGCTTCATAGGCAGTGGATCTGGGACAGATTTCACTCTTACCATCAGCGTTGTGCAGGCTGAAGAC CTGGCAGATTACTTCTGTCACCAACATTATAGCGCTCCGTACACGTTCGGAGGGGGGACCAAGCTG GAAATAAAAAttorney Docket No.206193-0150-P1US

[0368] SEQ ID NO: 935A3G11 heavy chain amino acid sequence EVKLVESGGGLVQPGGSLSLSCAASGFTFTDYYMSWVRQPPGKALEWLGFIRNKVSGYTTDYSSS VKGRFTFSRDNSQSIVYLHMNALRAEDSATYYCTRYVSLWLLGYFDVWGTGTTVTVSS SEQ ID NO: 1035A3G11 heavy chain nucleic acid sequence GAGGTGAAACTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGAGTCTCTCCTGT GCAGCTTCTGGATTCACCTTCACTGATTACTACATGAGTTGGGTCCGCCAGCCTCCAGGGAAGGCA CTTGAGTGGTTGGGTTTTATTAGAAATAAAGTTAGTGGTTACACAACAGACTACAGTTCATCTGTG AAGGGTCGGTTCACCTTCTCCAGAGATAATTCCCAAAGCATCGTCTATCTTCATATGAATGCCCTG AGAGCTGAGGACAGTGCCACTTATTACTGTACAAGATATGTATCGCTATGGTTACTCGGGTACTTC GATGTCTGGGGCACAGGGACCACGGTCACCGTCTCCTCA SEQ ID NO: 11 35A3G11 light chain amino acid sequence DVQITQSPSYLAASPGETITINCRASKSISKYLAWYQEKPGKTNKLLIYSGSTLQSGIPSRFSGSG SGTDFTLTISSLEPEDFAMYYCQQHNEYPLTFGAGTKLELK SEQ ID NO: 1235A3G11 light chain nucleic acid sequence GATGTCCAGATAACCCAGTCTCCATCTTATCTTGCTGCATCTCCTGGAGAAACCATTACTATTAAT TGCAGGGCAAGTAAGAGCATTAGCAAATATTTAGCCTGGTATCAAGAGAAACCTGGGAAAACTAAT AAGCTTCTTATCTACTCTGGATCCACTTTGCAATCTGGAATTCCATCAAGGTTCAGTGGCAGTGGA TCTGGTACAGATTTCACTCTCACCATCAGTAGCCTGGAGCCTGAAGATTTTGCAATGTATTACTGT CAACAGCATAATGAATACCCGCTCACATTCGGTGCTGGGACCAAGCTGGAGCTGAAA SEQ ID NO: 1335B3F9 heavy chain amino acid sequence EVKLVESGGGLVQPGGSLRLSCAASGFTFTDYYMSWVRQPPGKALEWLGFIRNKVSGYTTDNSAS VKGRFTISRDDSQSIVYLQMNDLRAEDSATYYCARYVSLWLLGYFDVWGTGTTVTVSS SEQ ID NO: 1435B3F9 heavy chain nucleic acid sequence GAGGTGAAGCTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGAGGCTCTCCTGT GCAGCTTCTGGATTCACCTTCACTGATTACTACATGAGCTGGGTCCGCCAGCCCCCAGGGAAGGCA CTTGAGTGGTTGGGTTTTATTAGAAATAAAGTTAGTGGTTACACAACAGACAACAGTGCATCTGTG AAGGGTCGGTTCACCATCTCCAGAGATGATTCCCAAAGCATCGTCTATCTTCAAATGAATGACCTG AGAGCTGAGGACAGTGCCACCTATTACTGTGCAAGATATGTTTCGCTTTGGTTACTCGGGTACTTC GATGTCTGGGGCACAGGGACCACGGTCACCGTCTCCTCA SEQ ID NO: 1535B3F9 light chain amino acid sequence DVQITQSPSYLAASPGETITINCRASKSISKYLAWYQEKPGKTNKLLIYSGSTLQSGIPSRFSGSG SGTDFTLTISSLEPEDFAMYYCQQHNEYPLTFGTGTKLELK SEQ ID NO: 1635B3F9 light chain nucleic acid sequence GATGTCCAGATAACCCAGTCTCCATCTTATCTTGCTGCATCTCCTGGAGAAACCATTACTATTAA TTGCAGGGCAAGTAAGAGCATTAGCAAATATTTAGCCTGGTATCAAGAGAAACCTGGGAAAACTA ATAAGCTTCTTATCTACTCTGGATCCACTTTGCAATCTGGAATTCCATCAAGGTTCAGTGGCAGT GGATCTGGCACAGATTTCACTCTCACCATCAGTAGCCTGGAGCCTGAAGATTTTGCAATGTATTA CTGTCAACAGCATAATGAATACCCACTCACATTCGGTACTGGGACCAAGCTGGAGCTGAAA SEQ ID NO: 1736F7B3 heavy chain amino acid sequence EVKLVESGGGLVQPGGSLSLSCAASGFTFTDYYMTWVRQPPGKALEWLCFIRNKANGYTTEYSAS VKGRFTISRDNSQSILYLQVNALRAEDSATYYCATYVLRGLAYWGQGTLVTVSAAttorney Docket No.206193-0150-P1US

[0369] SEQ ID NO: 1836F7B3 heavy chain nucleic acid sequence GAGGTGAAGCTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGAGTCTCTCCTGT GCAGCTTCTGGATTCACCTTCACTGATTACTACATGACCTGGGTCCGCCAGCCTCCAGGGAAGGCA CTTGAGTGGTTGTGTTTTATTAGAAACAAAGCTAATGGTTACACAACAGAGTACAGTGCATCTGTG AAGGGTCGGTTCACCATCTCCAGAGATAATTCTCAAAGCATCCTCTATCTTCAAGTGAATGCCCTG AGAGCTGAGGACAGTGCCACTTATTACTGTGCAACATATGTCCTACGTGGGCTTGCTTACTGGGGC CAAGGGACTCTGGTCACTGTCTCTGCA SEQ ID NO: 1936F7B3 light chain amino acid sequence DIVMTQSPSSLAMSVGQKVTMSCKSSQSLLNSSNQKNYLAWYQQKPGQSPKLLVYFASTRESGVPD RFIGSGSGTNFTLTISSVQAEDLADYFCHQHYSTPLTFGAGTKLELK SEQ ID NO: 2036F7B3 light chain nucleic acid sequence GACATTGTGATGACACAGTCTCCATCCTCCCTGGCTATGTCAGTAGGACAGAAGGTCACTATGAG CTGCAAGTCCAGTCAGAGCCTTTTAAATAGTAGCAATCAAAAGAACTATTTGGCCTGGTACCAGC AGAAACCAGGACAGTCTCCTAAACTTCTGGTATACTTTGCATCCACTAGGGAATCTGGGGTCCCT GATCGCTTCATAGGCAGTGGATCTGGGACAAATTTCACTCTTACCATCAGCAGTGTGCAGGCTGA AGACCTGGCAGATTACTTCTGTCACCAACATTATAGCACTCCGCTCACGTTCGGTGCTGGGACCA AGCTGGAGCTGAAA SEQ ID NO: 21 36D6A8 heavy chain amino acid sequence EVKLVESGGGLVQPGGSLSLSCAASGFTFTDYYMSWVRQPPGKALEWLGFIRNKASGYTTEYSAS VKGRFTISRDNSQNILYLQMNALRAEDGATYYCVRYISLWLLGYFDVWGTGTTVTVSS SEQ ID NO: 2236D6A8 heavy chain nucleic acid sequence GAGGTGAAGCTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGAGTCTCTCCTGT GCAGCTTCTGGATTCACCTTCACTGATTACTACATGAGCTGGGTCCGCCAGCCTCCAGGGAAGGCA CTTGAGTGGTTGGGTTTTATTAGAAACAAAGCTAGTGGTTACACAACAGAGTACAGTGCATCTGTG AAGGGTCGGTTCACCATCTCCAGAGATAATTCCCAAAACATCCTCTATCTTCAAATGAATGCCCTG AGAGCTGAGGACGGTGCCACTTATTACTGTGTAAGATATATATCGCTATGGTTACTCGGGTACTTC GATGTCTGGGGCACAGGGACCACGGTCACCGTCTCCTCA SEQ ID NO: 2336D6A8 light chain amino acid sequence DVQITQSPSYLAASPGETITINCRASKSISKYLAWYQEKPGKTNKLLIYSGSTLQSGIPSRFSGSG SGTDFTLTISSLEPEDFAMYYCQQHNDYPLTFGAGTKLELK SEQ ID NO: 2436D6A8 light chain nucleic acid sequence GATGTCCAGATAACCCAGTCTCCATCTTATCTTGCTGCATCTCCTGGAGAAACCATTACTATTAA TTGCAGGGCAAGTAAGAGCATTAGCAAATATTTAGCCTGGTATCAAGAGAAACCTGGGAAAACTA ATAAGCTTCTTATCTATTCTGGATCCACTTTGCAATCTGGAATTCCATCAAGGTTCAGTGGCAGT GGATCTGGTACAGATTTCACTCTCACCATCAGTAGCCTGGAGCCTGAAGATTTTGCAATGTATTA CTGTCAACAGCATAATGATTATCCGCTCACATTCGGTGCTGGGACCAAGCTGGAGCTGAAA SEQ ID NO: 2554C3B11 heavy chain amino acid sequence EVKLVESGGGLVQPGGSLSLSCAASGFTFTDYYMTWVRQPPGKALEWLCFIRNKANGYTTEYSAS VKGRFTISRDNSQSILYLQVNALRAEDSATYYCATYVLRGLAYWGQGTLVTVSA SEQ ID NO: 2654C3B11 heavy chain nucleic acid sequence GAGGTGAAGCTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGAGTCTCTCCTGT GCAGCTTCTGGATTCACCTTCACTGATTACTACATGACCTGGGTCCGCCAGCCTCCAGGGAAGGCA CTTGAGTGGTTGTGTTTTATTAGAAACAAAGCTAATGGTTACACAACAGAGTACAGTGCATCTGTGAttorney Docket No.206193-0150-P1US

[0370] AAGGGTCGGTTCACCATCTCCAGAGATAATTCTCAAAGCATCCTCTATCTTCAAGTGAATGCCCTG AGAGCTGAGGACAGTGCCACTTATTACTGTGCAACATATGTCCTACGTGGGCTTGCTTACTGGGGC CAAGGGACTCTGGTCACTGTCTCTGCA SEQ ID NO: 2754C3B11 light chain amino acid sequence DIVMTQSPSSLAMSVGQKVTMSCKSSQSLLNSSNQKNYLAWYQQKPGQSPKLLVYFASTRESGVPD RFIGSGSGTNFTLTISSVQAEDLADYFCHQHYSTPLTFGAGTKLELK SEQ ID NO: 2854C3B11 light chain nucleic acid sequence GACATTGTGATGACACAGTCTCCATCCTCCCTGGCTATGTCAGTAGGACAGAAGGTCACTATGAG CTGCAAGTCCAGTCAGAGCCTTTTAAATAGTAGCAATCAAAAGAACTATTTGGCCTGGTACCAGC AGAAACCAGGACAGTCTCCTAAACTTCTGGTATACTTTGCATCCACTAGGGAATCTGGGGTCCCT GATCGCTTCATAGGCAGTGGATCTGGGACAAATTTCACTCTTACCATCAGCAGTGTGCAGGCTGA AGACCTGGCAGATTACTTCTGTCACCAACATTATAGCACTCCGCTCACGTTCGGTGCTGGGACCA AGCTGGAGCTGAAA SEQ ID NO: 2966E8F8 heavy chain amino acid sequence EVKLVESGGGLVQPGGSLSLSCAASGFTFTDYYMSWVRQPPGKALEWLCFIRNKANGYTTEYSAS VKGRFTISRDNSQSILYLQVNALRAEDSATYYCATYVLRGLAYWGQGTLVTVSA SEQ ID NO: 3066E8F8 heavy chain nucleic acid sequence GAGGTGAAGCTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGAGTCTCTCCTGT GCAGCTTCTGGATTCACCTTCACTGATTACTACATGAGCTGGGTCCGCCAGCCTCCAGGGAAGGCA CTTGAGTGGTTGTGTTTTATTAGAAACAAAGCTAATGGTTACACAACAGAGTACAGTGCATCTGTG AAGGGTCGGTTCACCATCTCCAGAGATAACTCCCAAAGCATCCTCTATCTTCAAGTGAATGCCCTG AGAGCTGAGGACAGTGCCACTTATTACTGTGCAACATATGTCCTACGTGGGCTTGCTTACTGGGGC CAAGGGACTCTGGTCACTGTCTCTGCA SEQ ID NO: 31 66E8F8 light chain amino acid sequence DIVMTQSPSSLAMSVGQKVTMSCKSSQSLLNSSNQKNYLAWYQQKPGQSPKLLVYFASTRESGVPD RFIGSGSGTDFTLTISSVQAEDLADYFCHQHYSTPLTFGAGTKLELK SEQ ID NO: 3266E8F8 light chain nucleic acid sequence GACATTGTGATGACACAGTCTCCATCCTCCCTGGCTATGTCAGTAGGACAGAAGGTCACTATGAG CTGCAAATCCAGTCAGAGCCTTTTAAATAGTAGCAATCAAAAGAACTATTTGGCCTGGTACCAGC AGAAACCAGGACAGTCTCCTAAACTTCTGGTATACTTTGCATCCACTAGGGAATCTGGGGTCCCT GATCGCTTCATAGGCAGTGGATCTGGGACAGATTTCACTCTTACCATCAGCAGTGTGCAGGCTGA GGACCTGGCAGATTACTTCTGTCACCAACATTATAGCACTCCGCTCACGTTCGGTGCTGGGACCA AGCTGGAGCTGAAA SEQ ID NO: 3368A11A1 heavy chain amino acid sequence EVKLVESGGGLVQPGGSLSLSCAASGFTFTDYYMSWVRQPPGKALEWLGFIRNKVSGYTTDYSSS VKGRFTFSRDNSQSIVYLHMNALRAEDSATYYCTRYVSLWLLGYFDVWGTGTTVTVSS SEQ ID NO: 3468A11A1 heavy chain nucleic acid sequence GAGGTGAAACTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGAGTCTCTCCTGT GCAGCTTCTGGATTCACCTTCACTGATTACTACATGAGTTGGGTCCGCCAGCCTCCAGGGAAGGCA CTTGAGTGGTTGGGTTTTATTAGAAACAAAGTTAGTGGTTACACAACAGACTACAGTTCATCTGTG AAGGGTCGGTTCACCTTCTCCAGAGATAATTCCCAAAGCATCGTCTATCTTCATATGAATGCCCTG AGAGCTGAGGACAGTGCCACTTATTACTGTACAAGATATGTATCGCTTTGGTTACTCGGGTACTTC GATGTCTGGGGCACAGGGACCACGGTCACCGTCTCCTCAAttorney Docket No.206193-0150-P1US

[0371] SEQ ID NO: 3568A11A1 light chain amino acid sequence DVQLTQSPSYLAASPGETITINCRTSKSISKYLAWYQEKPGKTNKLLIYSGSTLQSGIPSRFSGSG SGTDFTLTISSLEPEDFAMYYCQQHNEYPLTFGAGTKLELK SEQ ID NO: 3668A11A1 light chain nucleic acid sequence GATGTCCAGCTAACCCAGTCTCCATCTTATCTTGCTGCATCTCCTGGAGAAACCATTACTATTAAT TGCAGGACAAGTAAGAGCATTAGCAAATATTTAGCCTGGTATCAAGAGAAACCTGGGAAAACTAAT AAGCTTCTTATCTACTCTGGATCCACTTTGCAATCTGGAATTCCATCAAGGTTCAGTGGCAGTGGA TCTGGTACAGATTTCACTCTCACCATCAGTAGCCTGGAGCCTGAAGATTTTGCAATGTATTACTGT CAACAGCATAATGAATACCCGCTCACATTCGGTGCTGGGACCAAGCTGGAGCTGAAA SEQ ID NO: 3768B1E2 heavy chain amino acid sequence EVKLVESGGGLVQPGGSLSLSCAASGFTFTDYYMSWVRQPPGKALEWLGFIRNKASGYTTEYNAS VKGRFTISRDNSQNILYLQMNALRAEDGATYYCVRYISLWLLGYFDVWGTGTTVTVSS SEQ ID NO: 3868B1E2 heavy chain nucleic acid sequence GAGGTGAAGCTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGAGTCTCTCCTGC GCAGCTTCTGGATTCACCTTCACTGATTACTACATGAGCTGGGTCCGCCAGCCTCCAGGGAAGGCA CTTGAGTGGTTGGGTTTTATTAGAAACAAAGCTAGTGGTTACACAACAGAGTACAATGCATCTGTG AAGGGTCGGTTCACCATCTCCAGAGATAATTCCCAAAACATCCTCTATCTTCAAATGAATGCCCTG AGAGCTGAGGACGGTGCCACTTATTACTGTGTAAGATATATATCGCTATGGTTACTCGGGTACTTC GATGTCTGGGGCACAGGGACCACGGTCACCGTCTCCTCA SEQ ID NO: 3968B1E2 light chain amino acid sequence DVQITQSPSYLAASPGETITINCRASKSISKYLAWYQEKPGKTNKLLIYSGSTLQSGIPSRFSGSG SGTDFTLTISSLEPEDFAMYYCQQHNDYPLTFGAGTKLELK SEQ ID NO: 4068B1E2 light chain nucleic acid sequence GATGTCCAGATAACCCAGTCTCCATCTTATCTTGCTGCATCTCCTGGAGAAACCATTACTATTAA TTGCAGGGCAAGTAAGAGCATTAGCAAATATTTAGCCTGGTATCAAGAGAAACCTGGGAAAACTA ATAAGCTTCTTATCTATTCTGGATCCACTTTGCAATCTGGAATTCCATCAAGGTTCAGTGGCAGT GGATCTGGTACAGATTTCACTCTCACCATCAGTAGCCTGGAGCCTGAAGATTTTGCAATGTATTA CTGTCAACAGCATAATGATTATCCACTCACATTCGGTGCTGGGACCAAGCTGGAGCTGAAA SEQ ID NO: 41 56C3E6 heavy chain amino acid sequence EVNLVESGGGLVQPGDSLSLSCATSGFTFTDYYMSWVRQPPGKALEWLGFIRNKANGYTTEYSAS VKGRFTISRDNSQSILYLQMNALRPEDSATYYCASPVLRGFAYWGRGTLVTVSA SEQ ID NO: 4256C3E6 heavy chain nucleic acid sequence GAGGTGAACCTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGATTCTCTGAGTCTCTCCTGT GCAACTTCTGGATTCACCTTCACTGATTACTACATGAGCTGGGTCCGCCAGCCTCCCGGGAAGGCA CTTGAGTGGTTGGGTTTTATTAGAAACAAAGCTAATGGTTACACAACAGAGTACAGTGCATCTGTG AAGGGTCGGTTTACCATCTCCAGAGATAATTCCCAAAGCATCCTCTATCTTCAAATGAATGCCCTG AGACCTGAGGACAGTGCCACTTATTACTGTGCAAGCCCTGTACTACGGGGGTTTGCTTACTGGGGC CGAGGGACTCTGGTCACTGTCTCTGCA SEQ ID NO: 4356C3E6 light chain amino acid sequence DIQMTQSPASLSASVGETVTITCRASGNIHNYLAWYQQKQGKSPQLLVYNAKTLADGVPSRFSGSG SGTQYSLKINSLQPEDFGSYYCQHFWSTPFTFGSGTKLEIKAttorney Docket No.206193-0150-P1US

[0372] SEQ ID NO: 4456C3E6 light chain nucleic acid sequence GACATCCAGATGACTCAGTCTCCAGCCTCCCTATCTGCATCTGTGGGAGAAACTGTCACCATCACA TGTCGAGCAAGTGGGAATATTCACAATTATTTAGCATGGTATCAGCAGAAACAGGGAAAATCTCCT CAGCTCCTGGTCTATAATGCAAAAACCTTAGCAGATGGTGTGCCATCAAGGTTCAGTGGCAGTGGA TCAGGAACACAATATTCTCTCAAGATCAACAGCCTGCAGCCTGAAGATTTTGGGAGTTATTACTGT CAACATTTTTGGAGTACTCCATTCACGTTCGGCTCGGGGACAAAGTTGGAAATAAAA SEQ ID NO: 4554C2F11 heavy chain amino acid sequence EVRLVESGGGLVQPGGSLRLSCAASGFTFTDYYMSWVRQPPGKALEWLGFIRNKPSGYTTEYSAS VKGRFTISRDNSQSILYLQMNALRAEDSATYYCARYISLWLLGYLDVWGTGTTVTVSS SEQ ID NO: 4654C2F11 heavy chain nucleic acid sequence GAGGTGAGGCTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGCGTCTCTCCTGT GCAGCTTCTGGATTCACCTTCACTGATTACTACATGAGCTGGGTCCGCCAGCCTCCAGGGAAGGCA CTTGAGTGGTTGGGTTTTATTAGAAACAAACCTAGTGGTTACACAACAGAGTACAGTGCATCTGTG AAGGGTCGGTTCACCATCTCCAGAGATAATTCCCAAAGCATCCTCTATCTTCAAATGAATGCCCTG AGAGCTGAGGACAGTGCCACTTACTACTGTGCAAGATATATATCGCTATGGTTACTCGGCTACCTC GATGTCTGGGGCACAGGGACCACGGTCACCGTCTCCTCA SEQ ID NO: 4754C2F11 light chain amino acid sequence DVQITQSPSYLAASPGETIIINCRTSKSISKYLAWYQEKPGKTNKLLIYSGSTLQSGIPSRFSGSG SGTDFTLTISSLEPEDFAMYYCQQHNEYPLTFGAGTKLELN SEQ ID NO: 4854C2F11 light chain nucleic acid sequence GATGTCCAGATAACCCAGTCTCCATCTTATCTTGCTGCATCTCCTGGAGAAACCATTATTATTAAT TGCAGGACAAGTAAGAGCATTAGCAAATATTTAGCCTGGTATCAAGAGAAACCTGGGAAAACTAAT AAGCTTCTTATCTACTCTGGATCCACTTTGCAATCTGGAATTCCATCAAGGTTCAGTGGCAGTGGA TCTGGTACAGATTTCACTCTCACCATCAGTAGCCTGGAGCCTGAAGATTTTGCAATGTATTACTGT CAACAACATAATGAATACCCGCTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAT SEQ ID NO: 4922F1A9 heavy chain amino acid sequence EVQLVESGGGLVKPGGSLKLSCAASGFTFSSYAMSWVRQTPEKRLEWVATISDGGSYTYYPDNVK GRFTISRDNTKNNLYLQMSHLKSEDTAMFYCARDLSPLYYRGPMDYWGQGTSVTVSS SEQ ID NO: 5022F1A9 heavy chain nucleic acid sequence GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTAGTGAAGCCTGGAGGGTCCCTGAAACTCTCCTGT GCAGCCTCTGGATTCACTTTCAGTAGCTATGCCATGTCTTGGGTTCGCCAGACTCCGGAAAAGAGG CTGGAGTGGGTCGCAACCATTAGTGATGGTGGTAGTTACACCTACTATCCAGACAATGTAAAGGGC CGATTCACCATCTCCAGAGACAATACCAAGAACAACCTGTACCTGCAAATGAGCCATCTGAAGTCT GAGGACACAGCCATGTTTTACTGTGCAAGAGATCTGTCCCCTCTCTACTATCGTGGGCCTATGGAC TACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA SEQ ID NO: 51 22F1A9 light chain amino acid sequence DIQMTQSPASLSASLGERVSLTCRASQDIGSSLNWLQQEPDGTIKRLIYATSSLDSGVPKRFSGSR SGSDYSLTISSLESEDFVDYYCLQYASSPFT FGSGTKLEIK SEQ ID NO: 5222F1A9 light chain nucleic acid sequence GACATCCAGATGACCCAGTCTCCAGCTTCCTTATCTGCCTCTCTGGGAGAAAGAGTCAGTCTCAC TTGTCGGGCAAGTCAGGACATTGGTAGTAGCTTAAACTGGCTTCAGCAGGAACCAGATGGAACTA TTAAACGCCTGATCTACGCCACATCCAGTTTAGATTCTGGTGTCCCCAAAAGGTTCAGTGGCAGTAttorney Docket No.206193-0150-P1US

[0373] AGGTCTGGGTCAGATTATTCTCTCACCATCAGCAGCCTTGAGTCTGAAGATTTTGTAGACTATTA CTGTCTACAATATGCTAGTTCTCCATTCACGTTCGGCTCGGGGACAAAGTTGGAAATAAAA SEQ ID NO: 5331E6H8 heavy chain amino acid sequence EVKLVESGGGLVQPGGSLSLSCAASGFTFTDYYMTWVRQPPGKALEWLGFIRNKANGYTTEYSAS VKGRFTISRDNSQSILSLQMNALSAEDSATYYCASLVLRGFAYWGQGTLVTVSA SEQ ID NO: 5431E6H8 heavy chain nucleic acid sequence GAGGTGAAGCTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGAGTCTCTCCTGT GCAGCTTCTGGATTCACCTTCACTGATTACTACATGACCTGGGTCCGCCAGCCTCCAGGGAAGGCA CTTGAGTGGTTGGGTTTTATTAGAAACAAAGCTAATGGTTACACAACAGAGTACAGTGCATCTGTG AAGGGTCGGTTCACCATCTCCAGAGATAATTCCCAAAGCATCCTCTCTCTTCAAATGAATGCCCTG AGCGCTGAGGACAGTGCCACTTATTACTGTGCAAGCCTTGTACTACGGGGGTTTGCTTACTGGGGC CAAGGGACTCTGGTCACTGTCTCTGCA SEQ ID NO: 5531E6H8 light chain amino acid sequence DIVMTQSPSSLAMSVGQKVTMNCKSSQSLLNNSNQKNYLAWYQQKPGQSPKLLVYFASTRESGVPD RFIGSGSGTDFTLTLSSVQAEDLADYFCQQHYITPYTFGGGTKLEIK SEQ ID NO: 5631E6H8 light chain nucleic acid sequence GACATTGTGATGACACAGTCTCCATCCTCCCTGGCTATGTCAGTAGGACAGAAGGTCACTATGAA CTGCAAGTCCAGTCAGAGCCTTTTAAATAATAGCAATCAAAAGAACTATTTGGCCTGGTACCAGC AGAAACCAGGACAGTCTCCTAAACTTCTGGTATACTTTGCATCCACTAGGGAATCTGGGGTCCCT GATCGCTTCATAGGCAGTGGATCTGGGACAGATTTCACTCTTACCCTCAGCAGTGTGCAGGCTGA AGACCTGGCAGATTACTTCTGTCAACAACATTATATCACTCCGTACACGTTCGGAGGGGGGACCA AGCTGGAGATAAAA SEQ ID NO: 5735A3C10 heavy chain amino acid sequence EVKLVESGGGLVQPGGSLSLSCAASGFTFTDYYMSWVRQPPGKALEWLGFIRNKVSGYTTDYSSS VKGRFTFSRDNSQSIVYLHMNALRAEDSATYYCTRYVSLWLLGYFDVWGTGTTVTVSS SEQ ID NO: 5835A3C10 heavy chain nucleic acid sequence GAGGTGAAACTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGAGTCTCTCCTGT GCAGCTTCTGGATTCACCTTCACTGATTACTACATGAGTTGGGTCCGCCAGCCTCCAGGGAAGGCA CTTGAGTGGTTGGGTTTTATTAGAAATAAAGTTAGTGGTTACACAACAGACTACAGTTCATCTGTG AAGGGTCGGTTCACCTTCTCCAGAGATAATTCCCAAAGCATCGTCTATCTTCATATGAATGCCCTG AGAGCTGAGGACAGTGCCACTTATTACTGTACAAGATATGTATCGCTATGGTTACTCGGGTACTTC GATGTCTGGGGCACAGGGACCACGGTCACCGTCTCCTCA SEQ ID NO: 5931E6H8 light chain amino acid sequence DVQITQSPSYLAASPGETITINCRASKSISKYLAWYQEKPGKTNKLLIYSGSTLQSGIPSRFSGSG SGTDFTLTISSLEPEDFAMYYCQQHNEYPLTFGAGTKLELK SEQ ID NO: 6031E6H8 light chain nucleic acid sequence GATGTCCAGATAACCCAGTCTCCATCTTATCTTGCTGCATCTCCTGGAGAAACCATTACTATTAAT TGCAGGGCAAGTAAGAGCATTAGCAAATATTTAGCCTGGTATCAAGAGAAACCTGGGAAAACTAAT AAGCTTCTTATCTACTCTGGATCCACTTTGCAATCTGGAATTCCATCAAGGTTCAGTGGCAGTGGA TCTGGTACAGATTTCACTCTCACCATCAGTAGCCTGGAGCCTGAAGATTTTGCAATGTATTACTGT CAACAGCATAATGAATACCCGCTCACATTCGGTGCTGGGACCAAGCTGGAGCTGAAA SEQ ID NO: 61 35G6G1 heavy chain amino acid sequenceAttorney Docket No.206193-0150-P1US

[0374] EVKLVESGGGLVQPGGSLSLSCAASGFTFADYYMTWVRQPPGKALEWLGFIRNKANGFTTEYSAS VKGRFTISRDNSQSILYLQMNALRAEDSATYYCARYGLRGFAYWGQGTLVTVSA SEQ ID NO: 6235G6G1 heavy chain nucleic acid sequence GAGGTGAAGCTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGAGTCTCTCCTGT GCAGCTTCTGGATTCACCTTCGCTGATTACTACATGACCTGGGTCCGCCAGCCTCCAGGGAAGGCA CTTGAGTGGTTGGGTTTTATTAGAAACAAAGCTAATGGTTTCACAACAGAGTACAGTGCATCTGTG AAGGGTCGGTTCACCATCTCCAGAGATAATTCCCAAAGCATCCTCTATCTTCAAATGAATGCCCTG AGAGCTGAGGACAGTGCCACTTATTACTGTGCAAGATATGGGTTACGGGGGTTTGCTTACTGGGGC CAAGGGACTCTGGTCACTGTCTCTGCA SEQ ID NO: 6335G6G1 light chain amino acid sequence DIVMTQSPSSLAMSVGQKVTLNCKSSQSLLNSSNQKNYLAWYQQKPGQSPKLLVYFASTRESGVPD RFIGSGSGTDFTLTISSVQAEDLADYFCHQHYSTPFTFGSGTKLEMK SEQ ID NO: 6435G6G1 light chain nucleic acid sequence GACATTGTGATGACACAGTCTCCATCCTCCCTGGCTATGTCAGTAGGACAGAAGGTCACTTTGAA CTGCAAGTCCAGTCAGAGCCTTTTAAATAGTAGCAATCAAAAGAACTATTTGGCCTGGTACCAGC AGAAACCAGGACAGTCTCCTAAACTTCTGGTATACTTTGCATCCACTAGGGAATCTGGGGTCCCT GATCGCTTCATAGGCAGTGGATCTGGGACAGATTTCACTCTTACCATCAGCAGTGTGCAGGCTGA AGACCTGGCAGATTACTTCTGTCACCAACATTATAGTACTCCATTCACGTTCGGCTCGGGGACAA AGTTGGAAATGAAA SEQ ID NO: 6538B2G5 heavy chain amino acid sequence QVQLQQSGAEVAKPGASVKLSCKASGYTFTSYWMHWVKQRPGQGLEWIGYINPSNNYTKYNQKFN DKATLTADKSSSTAYMQLSSLTYEDSALYYCARVYYYGNSPAWFAYWGQGTLVTVSA SEQ ID NO: 6638B2G5 heavy chain nucleic acid sequence CAGGTCCAGCTGCAGCAGTCTGGGGCTGAAGTGGCAAAACCTGGGGCCTCAGTGAAGCTGTCCTGC AAGGCTTCTGGCTACACCTTTACTAGCTACTGGATGCACTGGGTAAAACAGAGGCCTGGACAGGGT CTGGAATGGATTGGATACATTAATCCTAGCAATAATTATACTAAGTACAATCAGAAATTCAATGAC AAGGCCACATTGACTGCAGACAAATCCTCCAGCACAGCCTACATGCAGCTGAGCAGCCTGACATAT GAGGACTCTGCACTCTATTACTGTGCAAGAGTTTATTACTACGGTAATAGTCCTGCCTGGTTTGCT TACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCA SEQ ID NO: 6738B2G5 light chain amino acid sequence QIVLSQSPAILSASPGEKVTMTCRASSSVSYMHWYQQKPGSSPKPWIYATSNLASGVPARFSGSGS GTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIK SEQ ID NO: 6838B2G5 light chain nucleic acid sequence CAAATTGTTCTCTCCCAGTCTCCAGCAATCCTGTCTGCATCTCCAGGGGAGAAGGTCACAATGAC TTGCAGGGCCAGCTCAAGTGTAAGTTACATGCACTGGTACCAGCAGAAGCCAGGATCCTCCCCCA AACCCTGGATTTATGCCACATCCAACCTGGCTTCTGGAGTCCCTGCTCGCTTCAGTGGCAGTGGG TCTGGGACCTCTTACTCTCTCACAATCAGCAGAGTGGAGGCTGAAGATGCTGCCACTTATTACTG CCAGCAGTGGACTAGTAACCCACCCACGTTCGGAGGGGGGACCAAGCTGGAAATAAAA

[0375] SEQ ID NO: 6948D6F4 heavy chain amino acid sequence EVRLVESGGGLVQPGGSLRLSCAASGFTFTDYYMSWVRQPPGKALEWLGFIRNKPSGYTTEYSAS VKGRFTFSRDNSQSILYLQMNALRAEDSATYYCARYISLWLLGYLDVWGTGTTVTVSSAttorney Docket No.206193-0150-P1US

[0376] SEQ ID NO: 7048D6F4 heavy chain nucleic acid sequence GAGGTGAGGCTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGCGTCTCTCCTGT GCAGCTTCTGGATTCACCTTCACTGATTACTACATGAGCTGGGTCCGCCAGCCTCCAGGGAAGGCA CTTGAGTGGTTGGGTTTTATTAGAAACAAACCTAGTGGTTACACAACAGAATACAGTGCATCTGTG AAGGGTCGGTTCACCTTCTCCAGAGATAATTCCCAAAGCATCCTCTATCTTCAAATGAATGCCCTG AGAGCTGAGGACAGTGCCACTTACTACTGTGCAAGATATATATCGCTATGGTTACTCGGCTACCTC GATGTCTGGGGCACAGGGACCACGGTCACCGTCTCCTCA SEQ ID NO: 71 48D6F4 light chain amino acid sequence DVQITQSPSYLAASPGETIIINCRTSKSISKYLAWYQEKPGKTNNLLIYSGSTLQSGIPSRFSGSG SGTDFSLTISSLEPEDFAIYYCQQHNEYPLTFGAGTKLELN SEQ ID NO: 7248D6F4 light chain nucleic acid sequence GATGTCCAGATAACCCAGTCTCCATCTTATCTTGCTGCATCTCCTGGAGAAACCATTATTATTAA TTGCAGGACAAGTAAGAGCATTAGCAAATATTTAGCCTGGTATCAAGAGAAACCTGGGAAAACTA ATAACCTTCTTATCTACTCTGGATCCACTTTGCAATCTGGAATTCCATCAAGGTTCAGTGGCAGT GGATCTGGTACAGATTTCTCTCTCACCATCAGTAGCCTGGAGCCTGAAGATTTTGCAATCTATTA CTGTCAACAACATAATGAATACCCGCTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAT SEQ ID NO: 7373D4G2 heavy chain amino acid sequence EVRLVESGGGLVQPGGSLRLSCAASGFTFTDYYMSWVRQPPGKALEWLGFIRNKPSGYTTEYSAS VKGRFTISRDNSQSILYLQMNALRAEDSATYYCARYISLWLLGYLDVWGTGTTVTVSS SEQ ID NO: 7473D4G2 heavy chain nucleic acid sequence GAGGTGAGGCTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGCGTCTCTCCTGT GCAGCTTCTGGATTCACCTTCACTGATTACTACATGAGCTGGGTCCGCCAGCCTCCAGGGAAGGCA CTTGAGTGGTTGGGTTTTATTAGAAACAAACCTAGTGGTTACACAACAGAGTACAGTGCATCTGTG AAGGGTCGGTTCACCATCTCCAGAGATAATTCCCAAAGCATCCTCTATCTTCAAATGAATGCCCTG AGAGCTGAGGACAGTGCCACTTACTACTGTGCAAGATATATATCGTTATGGTTACTCGGCTACCTC GATGTCTGGGGCACAGGGACCACGGTCACCGTCTCCTCA SEQ ID NO: 7573D4G2 light chain amino acid sequence DVQITQSPSYLAASPGETIIINCRTSKSISKYLAWYQEKPGKTNKLLIYSGSTLQSGIPSRFSGSG SGTDFTLTISSLEPEDFAMYYCQQHNEYPLTFGAGTKLELK SEQ ID NO: 7673D4G2 light chain nucleic acid sequence GATGTCCAGATAACCCAGTCTCCATCTTATCTTGCTGCATCTCCTGGAGAAACCATTATTATTAA TTGCAGGACAAGTAAGAGCATTAGCAAATATTTAGCCTGGTATCAAGAGAAACCTGGGAAAACTA ATAAGCTTCTTATCTACTCTGGATCCACTTTGCAATCTGGAATTCCATCAAGGTTCAGTGGCAGT GGATCTGGTACAGATTTCACTCTCACCATCAGTAGCCTGGAGCCTGAAGATTTTGCAATGTATTA CTGTCAACAACATAATGAATACCCGCTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAA

[0377] In the following sequences, CDR sequences are underlined, and signal sequences are bolded.

[0378] SEQ ID NO: 30629F2C7 heavy chain amino acid sequence (FR1-CDR1-FR2-CDR2- FR3-CDR3-FR4)

[0379] MKLWLNWIFLVTLLNGIQCEVKLVESGGGLVQPGGSLSLSCAASGFT FTDYYMSWVRQSPGKALE WLG FIRNRPSGYTTEYSASVKGR FTFSRDNSQNIL Y LQMN L RSEDSATYY CARYISLWLLGYFD VWGTGTTVTVSSAttorney Docket No.206193-0150-P1US

[0380] SEQ ID NO: 30729F2C7 heavy chain nucleic acid sequence (FR1-CDR1-FR2- CDR2-FR3-CDR3-FR4) ATGAAGTTGTGGCTGAACTGGATTTTCCTTGTAACACTTTTAAATGGTATCCAGTGTGAGGTGAAG CTGGTGGAGTCTGGAGGAGGCTTGGTCCAGCCTGGGGGTTCTCTGAGTCTCTCCTGTGCAGCTTCT GGATTCACCTTCACTGATTACTACATGAGCTGGGTCCGCCAGTCTCCAGGGAAGGCACTTGAGTGG TTGGGTTTTATTAGAAACAGACCTAGTGGTTACACAACAGAGTACAGTGCATCTGTGAAGGGTCGG TTCACCTTCTCCAGAGATAATTCCCAAAACATCCTCTATCTTCAAATGAATGCCCTGAGATCTGAG GAC AGT GCC ACTT AT T AC T GT GCAAGATATATATCGCTATGGTTACTCGGGTACTTCGATGTCT GG GGCACAGGGACCACGGTCACCGTCTCCTCA SEQ ID NO: 30829F2C7 light chain amino acid sequence (FR1-CDR1-FR2-CDR2- FR3-CDR3-FR4)

[0381] MRFQVQVLGLLLLWI SGAQCD VQ I T Q S P S Y L AAS PGE T I T I NCRTSKSISKYLAWY Q E KPGRT I NL L I Y SGSTLQS GL P S R FS GT GS GT D F LT I S S L E P E D FAMY Y CQQHNEFPLT FGAGT KL E L K SEQ ID NO: 30929F2C7 light chain nucleic acid sequence (FR1-CDR1-FR2-CDR2- FR3-CDR3-FR4) ATGAGGTTCCAGGTTCAGGTTCTGGGGCTCCTTCTGCTCTGGATATCAGGTGCCCAGTGTGATGT CCAGATAACCCAGTCTCCATCTTATCTTGCTGCATCTCCTGGAGAAACCATTACTATTAATTGCA GGACAAGTAAGAGCATTAGCAAATATTTAGCCTGGTATCAAGAGAAACCTGGGAGAACTATTAAC CTTCTGATCTACTCTGGATCCACTTTGCAATCTGGACTTCCATCAAGGTTCAGTGGCACTGGATC TGGTACAGATTTCACTCTCACCATCAGTAGCCTGGAGCCTGAAGATTTTGCAATGTATTACTGTC AACAGCATAATGAATTCCCGCTCACATTCGGTGCTGGGACCAAGCTGGAGCTGAAA SEQ ID NO: 31034F4A2 heavy chain amino acid sequence (FR1-CDR1-FR2-CDR2- FR3-CDR3-FR4)

[0382] MKLWLNWIFLVTLLNGIQCEVKLVESGGGLVQPGGSLSLSCAASGFT FTDYYMTWVRQPPGKALE WLGFVRNKANGYTTEYSASVKGRFT I SRDNSQS ILYLQMNALRAEDSATYYCARYGLRGFAYWGQ GTLVTVSA SEQ ID NO: 311 34F4A2 heavy chain nucleic acid sequence (FR1-CDR1-FR2- CDR2-FR3-CDR3-FR4) ATGAAGTTGTGGCTGAACTGGATTTTCCTTGTAACACTTTTAAATGGTATCCAGTGTGAGGTGAAG CTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGAGTCTCTCCTGTGCAGCTTCT GGATTCACCTTCACTGATTACTACATGACCTGGGTCCGCCAGCCTCCAGGGAAGGCACTTGAGTGG TTGGGTTTTGTTAGAAACAAAGCTAATGGTTACACAACAGAGTACAGTGCATCTGTGAAGGGTCGG TTCACCATCTCCAGAGATAATTCCCAAAGCATCCTCTATCTTCAAATGAATGCCCTGAGAGCTGAG GACAGTGCCACTTATTACTGTGCAAGATATGGATTACGCGGATTTGCTTACTGGGGCCAAGGGACT CTGGTCACTGTCTCTGCA SEQ ID NO: 31234F4A2 light chain amino acid sequence (FR1-CDR1-FR2-CDR2- FR3-CDR3-FR4)

[0383] ME SQTQVLMFLLLWVSGACAD I VMT QSPSSLAMSVGQ KVTMS C ESSQSLLNSSNLKNYLAW Y QQ KP GQSPKLLVYFASTRDSGVPDRFIGSGSGTDFTLTISVVQAEDLADYFCHQHYSAPYTFGGGTKLEI K SEQ ID NO: 31334F4A2 light chain nucleic acid sequence (FR1-CDR1-FR2-CDR2- FR3-CDR3-FR4) ATGGAATCACAGACCCAGGTCCTCATGTTTCTTCTGCTCTGGGTATCTGGTGCCTGTGCAGACATT GTGATGACACAGTCTCCATCCTCCCTGGCTATGTCAGTAGGACAGAAGGTCACTATGAGCTGCGAG TCCAGTCAGAGCCTTTTAAATAGTAGCAATCTAAAGAACTATTTGGCCTGGTACCAACAGAAACCAAttorney Docket No.206193-0150-P1US

[0384] GGACAGTCTCCTAAACTTCTGGTATACTTTGCATCCACTAGGGACTCTGGGGTCCCTGATCGCTTC ATAGGCAGTGGATCTGGGACAGATTTCACTCTTACCATCAGCGTTGTGCAGGCTGAAGACCTGGCA GAT T CT TC T GTCACCAACATTATAGCGCTCCGTACACGT T CGGAGGGGGGACC AAGC T GGAAAT A AAA SEQ ID NO: 31435A3G11 heavy chain amino acid sequence (FR1-CDR1-FR2- CDR2-FR3-CDR3-FR4) MKLWLNWIFLVTLLNGLQCEVKLVESGGGLVQPGGSLSLSCAASGFTFTDYYMSWVRQPPGKALE WLGFIRNKVSGYTTDYSSSVKGRFTFSRDNSQSIVYLHMNALRAEDSATYYCTRYVSLWLLGYFD VWGTGTTVTVSS SEQ ID NO: 31535A3G11 heavy chain nucleic acid sequence (FR1-CDR1-FR2- CDR2-FR3-CDR3-FR4) ATGAAGTTGTGGCTGAACTGGATTTTCCTTGTAACACTTTTAAATGGTCTCCAGTGTGAGGTGAAA CTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGAGTCTCTCCTGTGCAGCTTCT GGATTCACCTTCACTGATTACTACATGAGTTGGGTCCGCCAGCCTCCAGGGAAGGCACTTGAGTGG TTGGGTTTTATTAGAAATAAAGTTAGTGGTTACACAACAGACTACAGTTCATCTGTGAAGGGTCGG TTCACCTTCTCCAGAGATAATTCCCAAAGCATCGTCTATCTTCATATGAATGCCCTGAGAGCTGAG GAC AGT GCC ACTT AT TACTGTACAAGATATGTATCGCTATGGTTACTCGGGTACTTCGATGTCT GG GGCACAGGGACCACGGTCACCGTCTCCTCA SEQ ID NO: 31635A3G11 light chain amino acid sequence (FR1-CDR1-FR2-CDR2- FR3-CDR3-FR4) MRFQVQVLGLLLLWISVPGAQCDVQITQSPSYLAASPGETITINCRASKSISKYLAWYQEKPGKTN KLLIYSGSTLQSGIPSRFSGSGSGTDFTLTISSLEPEDFAMYYCQQHNEYPLTFGAGTKLELK SEQ ID NO: 31735A3G11 light chain nucleic acid sequence (FR1-CDR1-FR2- CDR2-FR3-CDR3-FR4) ATGAGGTTCCAGGTTCAGGTTCTGGGGCTCCTTCTGCTCTGGATATCAGTTCCAGGTGCCCAGTGT GATGTCCAGATAACCCAGTCTCCATCTTATCTTGCTGCATCTCCTGGAGAAACCATTACTATTAAT TGCAGGGCAAGTAAGAGCATTAGCAAATATTTAGCCTGGTATCAAGAGAAACCTGGGAAAACTAAT AAGCTTCTTATCTACTCTGGATCCACTTTGCAATCTGGAATTCCATCAAGGTTCAGTGGCAGTGGA TCTGGTACAGATTTCACTCTCACCATCAGTAGCCTGGAGCCTGAAGATTTTGCAATGTATTACTGT CAACAGCATAATGAATACCCGCTCACATTCGGTGCTGGGACCAAGCTGGAGCTGAAA SEQ ID NO: 31835B3F9 heavy chain amino acid sequence (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) MKLWLNWIFLVTLLNGIQCEVKLVESGGGLVQPGGSLRLSCAASGFTFTDYYMSWVRQPPGECALE WLGFIRNKVSGYTTDNSASVKGRFT I SRDDSQS I VYLQMNDLRAEDSATY YC RY VSLWLLGY FD VWGTGTTVTVSS SEQ ID NO: 31935B3F9 heavy chain nucleic acid sequence (FR1-CDR1-FR2- CDR2- FR3-CDR3- F R4) ATGAAGTTGTGGCTGAACTGGATTTTCCTTGTAACACTTTTAAATGGTATCCAGTGTGAGGTGAAG CTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGAGGCTCTCCTGTGCAGCTTCT GGATTCACCTTCACTGATTACTACATGAGCTGGGTCCGCCAGCCCCCAGGGAAGGCACTTGAGTGG TTGGGTTTTATTAGAAATAAAGTTAGTGGTTACACAACAGACAACAGTGCATCTGTGAAGGGTCGG TTCACCATCTCCAGAGATGATTCCCAAAGCATCGTCTATCTTCAAATGAATGACCTGAGAGCTGAG GACAGTGCCACCTATTACTGTGCAAGATATGTTTCGCTTTGGTTACTCGGGTACTTCGATGTCTGG GGCACAGGGACCACGGTCACCGTCTCCTCAAttorney Docket No.206193-0150-P1US

[0385] SEQ ID NO: 32035B3F9 light chain amino acid sequence (FR1-CDR1-FR2-CDR2- FR3-CDR3-FR4)

[0386]

[0387] MRFQVQVLGLLLLWISGAQCDVQITQSPSYLAASPGETITINCRASKSISKYLAWYQEKPGKTNKL LIYSGSTLQSGIPSRFSGSGSGTDFTLTISSLEPEDFAMYYCQQHNEYPLTFGTGTKLELK SEQ ID NO: 321 35B3F9 light chain nucleic acid sequence (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) ATGAGGTTCCAGGTTCAGGTTCTGGGGCTCCTTCTGCTCTGGATATCAGGTGCCCAGTGTGATGT CCAGATAACCCAGTCTCCATCTTATCTTGCTGCATCTCCTGGAGAAACCATTACTATTAATTGCA GGGCAAGTAAGAGCATTAGCAAATATTTAGCCTGGTATCAAGAGAAACCTGGGAAAACTAATAAG CTTCTTATCTACTCTGGATCCACTTTGCAATCTGGAATTCCATCAAGGTTCAGTGGCAGTGGATC TGGCACAGATTTCACTCTCACCATCAGTAGCCTGGAGCCTGAAGATTTTGCAATGTATTACTGTC AACAGCATAATGAATACCCACTCACATTCGGTACTGGGACCAAGCTGGAGCTGAAA SEQ ID NO: 32236F7B3 heavy chain amino acid sequence (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) MKLWLNWIFLVTLLNGIQCEVKLVESGGGLVQPGGSLSLSCAASGFTFTDYYMTWVRQPPGKALEWLCFIRNKANGYTTEYSASVKGRFTISRDNSQSILYLQVNALRAEDSATYYCATYVLRGLAYWGQ GTLVTVSA SEQ ID NO: 32336F7B3 heavy chain nucleic acid sequence (FR1-CDR1-FR2- CDR2- FR3-CDR3- F R4) ATGAAGTTGTGGCTGAACTGGATTTTCCTTGTAACACTTTTAAATGGTATCCAGTGTGAGGTGAAG CTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGAGTCTCTCCTGTGCAGCTTCT GGATTCACCTTCACTGATTACTACATGACCTGGGTCCGCCAGCCTCCAGGGAAGGCACTTGAGTGG T T GT GTTTTATTAGAAACAAAGCTAATGGTTACACAACAGAGTACAGTGCATCTGTGAAGGGTCGG TTCACCATCTCCAGAGATAATTCTCAAAGCATCCTCTATCTTCAAGTGAATGCCCTGAGAGCTGAG GACAGTGCCACTTATTACTGTGCAACATATGTCCTACGTGGGCTTGCTTACTGGGGCCAAGGGACT CTGGTCACTGTCTCTGCA SEQ ID NO: 32436F7B3 light chain amino acid sequence (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)

[0388] MESQTQVLMFLLLWVSGACADIVMTQSPSSLAMSVGQKVTMSCKSSQSLLNSSNQKNYLAWYQQKPGQSPKLLVYFASTRESGVPDRFIGSGSGTNFTLTISSVQAEDLADYFCHQHYSTPLTFGAGTKLELK SEQ ID NO: 32536F7B3 light chain nucleic acid sequence (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) ATGGAATCACAGACCCAGGTCCTCATGTTTCTTCTGCTCTGGGTATCTGGTGCCTGTGCAGACAT TGTGATGACACAGTCTCCATCCTCCCTGGCTATGTCAGTAGGACAGAAGGTCACTATGAGCTGCA AGTCCAGTCAGAGCCTTTTAAATAGTAGCAATCAAAAGAACTATTTGGCCTGGTACCAGCAGAAA CCAGGACAGTCTCCTAAACTTCTGGTATACTTTGCATCCACTAGGGAATCTGGGGTCCCTGATCG CTTCATAGGCAGTGGATCTGGGACAAATTTCACTCTTACCATCAGCAGTGTGCAGGCTGAAGACC TGGCAGATTACTTCTGTCACCAACATTATAGCACTCCGCTCACGTTCGGTGCTGGGACCAAGCTG GAGCTGAAA SEQ ID NO: 32636D6A8 heavy chain amino acid sequence (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)

[0389] MKLWLNWIFLVTLLNGIQCEVKLVESGGGLVQPGGSLSLSCAASGFT FTDYYMSWVRQPPGKALE WLG FIRNKASGYTTEYSASVKGR FTISRDNSQNIL Y LQMNAL RAE DG AT Y Y CVRYISLWLLGYFD VWGTGTTVTVSSAttorney Docket No.206193-0150-P1US

[0390] SEQ ID NO: 32736D6A8 heavy chain nucleic acid sequence (FR1-CDR1-FR2- CDR2- FR3-CDR3- F R4) ATGAAGTTGTGGCTGAACTGGATTTTCCTTGTAACACTTTTAAATGGTATCCAGTGTGAGGTGAAG CTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGAGTCTCTCCTGTGCAGCTTCT GGATTCACCTTCACTGATTACTACATGAGCTGGGTCCGCCAGCCTCCAGGGAAGGCACTTGAGTGG TTGGGTTTTATTAGAAACAAAGCTAGTGGTTACACAACAGAGTACAGTGCATCTGTGAAGGGTCGG TTCACCATCTCCAGAGATAATTCCCAAAACATCCTCTATCTTCAAATGAATGCCCTGAGAGCTGAG GACGGTGCCACTTATTACTGTGTAAGATATATATCGCTATGGTTACTCGGGTACTTCGATGTCTGG GGCACAGGGACCACGGTCACCGTCTCCTCA SEQ ID NO: 32836D6A8 light chain amino acid sequence (FR1-CDR1-FR2-CDR2- FR3-CDR3-FR4) MRFQVQVLGLLLLWISGAQCDVQITQSPSYLAASPGETITINCRASKSISKYLAWYQEKPGKTNKL LIYSGSTLQSGIPSRFSGSGSGTDFTLTISSLEPEDFAMYYCQQHNDYPLTFGAGTKLELK SEQ ID NO: 32936D6A8 light chain nucleic acid sequence (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) ATGAGGTTCCAGGTTCAGGTTCTGGGGCTCCTTCTGCTCTGGATATCAGGTGCCCAGTGTGATGT CCAGATAACCCAGTCTCCATCTTATCTTGCTGCATCTCCTGGAGAAACCATTACTATTAATTGCA GGGCAAGTAAGAGCATTAGCAAATATTTAGCCTGGTATCAAGAGAAACCTGGGAAAACTAATAAG CTTCTTATCTATTCTGGATCCACTTTGCAATCTGGAATTCCATCAAGGTTCAGTGGCAGTGGATC TGGTACAGATTTCACTCTCACCATCAGTAGCCTGGAGCCTGAAGATTTTGCAATGTATTACTGTC AACAGCATAATGATTATCCGCTCACATTCGGTGCTGGGACCAAGCTGGAGCTGAAA SEQ ID NO: 33054C3B11 heavy chain amino acid sequence (FR1-CDR1-FR2- CDR2- FR3-CDR3- F R4)

[0391]

[0392] MKLWLNWIFLVTLLNGIQCEVKLVESGGGLVQPGGSLSLSCAASGFTFTDYYMTWVRQPPGKALEWLCFIRNKANGYTTEYSASVKGRFTISRDNSQSILYLQVNALRAEDSATYYCATYVLRGLAYWGQ GTLVTVSA SEQ ID NO: 331 54C3B11 heavy chain nucleic acid sequence (FR1-CDR1-FR2- CDR2- FR3-CDR3- F R4) ATGAAGTTGTGGCTGAACTGGATTTTCCTTGTAACACTTTTAAATGGTATCCAGTGTGAGGTGAAG CTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGAGTCTCTCCTGTGCAGCTTCT GGATTCACCTTCACTGATTACTACATGACCTGGGTCCGCCAGCCTCCAGGGAAGGCACTTGAGTGG TTGTGTTTTATTAGAAACAAAGCTAATGGTTACACAACAGAGTACAGTGCATCTGTGAAGGGTCGG TTCACCATCTCCAGAGATAATTCTCAAAGCATCCTCTATCTTCAAGTGAATGCCCTGAGAGCTGAG GACAGTGCCACTTATTACTGTGCAACATATGTCCTACGTGGGCTTGCTTACTGGGGCCAAGGGACT CTGGTCACTGTCTCTGCA SEQ ID NO: 33254C3B11 light chain amino acid sequence (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)

[0393] MESQTQVLMFLLLWVSGACADIVMTQSPSSLAMSVGQKVTMSCKSSQSLLNSSNQKNYLAWYQQKPGQSPKLLVYFASTRESGVPDRFIGSGSGTNFTLTISSVQAEDLADYFCHQHYSTPLTFGAGTKLELK SEQ ID NO: 33354C3B11 light chain nucleic acid sequence (FR1-CDR1-FR2- CDR2- FR3-CDR3- F R4) ATGGAATCACAGACCCAGGTCCTCATGTTTCTTCTGCTCTGGGTATCTGGTGCCTGTGCAGACAT TGTGATGACACAGTCTCCATCCTCCCTGGCTATGTCAGTAGGACAGAAGGTCACTATGAGCTGCAAttorney Docket No.206193-0150-P1US

[0394] AGTCCAGTCAGAGCCTTTTAAATAGTAGCAATCAAAAGAACTATTTGGCCTGGTACCAGCAGAAA CCAGGACAGTCTCCTAAACTTCTGGTATACTTTGCATCCACTAGGGAATCTGGGGTCCCTGATCG CTTCATAGGCAGTGGATCTGGGACAAATTTCACTCTTACCATCAGCAGTGTGCAGGCTGAAGACC TGGCAGATTACTTCTGTCACCAACATTATAGCACTCCGCTCACGTTCGGTGCTGGGACCAAGCTG GAGCTGAAA SEQ ID NO: 33466E8F8 heavy chain amino acid sequence (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)

[0395] MKLWLNWIFLVTLLNGIQCEVKLVESGGGLVQPGGSLSLSCAASGFT FTDYYMSWVRQPPGKALE WLCFIRNKANGYTTEYSASVKGRFTISRDNSQSILYLQVNALRAEDSATYYCATYVLRGLAYWGQ GTLVTVSA SEQ ID NO: 33566E8F8 heavy chain nucleic acid sequence (FR1-CDR1-FR2- CDR2- FR3-CDR3- F R4) ATGAAGTTGTGGCTGAACTGGATTTTCCTTGTAACACTTTTAAATGGTATCCAGTGTGAGGTGAAG CTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGAGTCTCTCCTGTGCAGCTTCT GGATTCACCTTCACTGATTACTACATGAGCTGGGTCCGCCAGCCTCCAGGGAAGGCACTTGAGTGG T T GT GTTTTATTAGAAACAAAGCTAATGGTTACACAACAGAGTACAGTGCATCTGTGAAGGGTCGG TTCACCATCTCCAGAGATAACTCCCAAAGCATCCTCTATCTTCAAGTGAATGCCCTGAGAGCTGAG GACAGTGCCACTTATTACTGTGCAACATATGTCCTACGTGGGCTTGCTTACTGGGGCCAAGGGACT CTGGTCACTGTCTCTGCA SEQ ID NO: 33666E8F8 light chain amino acid sequence (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) MESQTQVLMFLLLWVSGACADIVMTQSPSSLAMSVGQKVTMSCKSSQSLLNSSNQKNYLAWYQQKP GQSPKLLVYFASTRESGVPDRFIGSGSGTDFTLTISSVQAEDLADYFCHQHYSTPLTFGAGTKLEL K SEQ ID NO: 33766E8F8 light chain nucleic acid sequence (FR1-CDR1-FR2-CDR2- FR3-CDR3-FR4) ATGGAATCACAGACCCAGGTCCTCATGTTTCTTCTGCTCTGGGTATCTGGTGCCTGTGCAGACAT TGTGATGACACAGTCTCCATCCTCCCTGGCTATGTCAGTAGGACAGAAGGTCACTATGAGCTGCA AATCCAGTCAGAGCCTTTTAAATAGTAGCAATCAAAAGAACTATTTGGCCTGGTACCAGCAGAAA CCAGGACAGTCTCCTAAACTTCTGGTATACTTTGCATCCACTAGGGAATCTGGGGTCCCTGATCG CTTCATAGGCAGTGGATCTGGGACAGATTTCACTCTTACCATCAGCAGTGTGCAGGCTGAGGACC TGGCAGATTACTTCTGTCACCAACATTATAGCACTCCGCTCACGTTCGGTGCTGGGACCAAGCTG GAGCTGAAA SEQ ID NO: 33868A11A1 heavy chain amino acid sequence (FR1-CDR1-FR2- CDR2- FR3-CDR3- F R4) MKLWLNWIFLVTLLNGFQCEVKLVESGGGLVQPGGSLSLSCAASGFTFTDYYMSWVRQPPGKALEWLGFIRNKVSGYTTDYSSVKGRFTFSRDNSQSIVYLHMNALRAEDSATYYCTRYVSLWLLGYFDVWGTGTTVTVSS SEQ ID NO: 33968A11A1 heavy chain nucleic acid sequence (FR1-CDR1-FR2- CDR2- FR3-CDR3- F R4) ATGAAGTTGTGGCTGAACTGGATTTTCCTTGTAACACTTTTAAATGGTTTCCAGTGTGAGGTGAAA CTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGAGTCTCTCCTGTGCAGCTTCT GGATTCACCTTCACTGATTACTACATGAGTTGGGTCCGCCAGCCTCCAGGGAAGGCACTTGAGTGG TTGGGTTTTATTAGAAACAAAGTTAGTGGTTACACAACAGACTACAGTTCATCTGTGAAGGGTCGG TTCACCTTCTCCAGAGATAATTCCCAAAGCATCGTCTATCTTCATATGAATGCCCTGAGAGCTGAGAttorney Docket No.206193-0150-P1US

[0396] GACAGTGCCACTTATTACTGTACAAGATATGTATCGCTTTGGTTACTCGGGTACTTCGATGTCTGG GGCACAGGGACCACGGTCACCGTCTCCTCA SEQ ID NO: 34068A11A1 light chain amino acid sequence (FR1-CDR1-FR2-CDR2- FR3-CDR3-FR4) MRFQVQVLGLLLLWISVPGAQCDVQLTQSPSYLAASPGETITINCRTSKSISKYLAWYQEKPGKTN KLLIYSGSTLQSGIPSRFSGSGSGTDFTLTISSLEPEDFAMYYCQQHNEYPLTFGAGTKLELK SEQ ID NO: 341 68A11A1 light chain nucleic acid sequence (FR1-CDR1-FR2- CDR2- FR3-CDR3- F R4) ATGAGGTTCCAGGTTCAGGTTCTGGGGCTCCTTCTGCTCTGGATATCAGTTCCAGGTGCCCAGTGT GATGTCCAGCTAACCCAGTCTCCATCTTATCTTGCTGCATCTCCTGGAGAAACCATTACTATTAAT TGCAGGACAAGTAAGAGCATTAGCAAATATTTAGCCTGGTATCAAGAGAAACCTGGGAAAACTAAT AAGCTTCTTATCTACTCTGGATCCACTTTGCAATCTGGAATTCCATCAAGGTTCAGTGGCAGTGGA TCTGGTACAGATTTCACTCTCACCATCAGTAGCCTGGAGCCTGAAGATTTTGCAATGTATTACTGT CAACAGCATAATGAATACCCGCTCACATTCGGTGCTGGGACCAAGCTGGAGCTGAAA SEQ ID NO: 34268B1E2 heavy chain amino acid sequence (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)

[0397] MKLWLNWIFLVTLLNGIQCEVKLVESGGGLVQPGGSLSLSCAASGFT FTDYYMSWVRQPPGKALE WLG FIRNKASGYTTEYNASVKGR FTISRDNSQNIL Y LQMNAL RAE DG AT Y Y CVRYISLWLLGYFD VWGTGTTVTVSS SEQ ID NO: 34368B1E2 heavy chain nucleic acid sequence (FR1-CDR1-FR2- CDR2- FR3-CDR3- F R4) ATGAAGTTGTGGCTGAACTGGATTTTCCTTGTAACACTTTTAAATGGTATCCAGTGTGAGGTGAAG CTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGAGTCTCTCCTGCGCAGCTTCT GGATTCACCTTCACTGATTACTACATGAGCTGGGTCCGCCAGCCTCCAGGGAAGGCACTTGAGTGG TTGGGTTTTATTAGAAACAAAGCTAGTGGTTACACAACAGAGTACAATGCATCTGTGAAGGGTCGG TTCACCATCTCCAGAGATAATTCCCAAAACATCCTCTATCTTCAAATGAATGCCCTGAGAGCTGAG GACGGTGCCACTTATTACTGTGTAAGATATATATCGCTATGGTTACTCGGGTACTTCGATGTCTGG GGCACAGGGACCACGGTCACCGTCTCCTCA SEQ ID NO: 34468B1E2 light chain amino acid sequence (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) MRFQVQVLGLLLLWISGAQCDVQITQSPSYLAASPGETITINCRASKSISKYLAWYQEKPGKTNKL LIYSGSTLQSGIPSRFSGSGSGTDFTLTISSLEPEDFAMYYCQQHNDYPLTFGAGTKLELK SEQ ID NO: 34568B1E2 light chain nucleic acid sequence (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) ATGAGGTTCCAGGTTCAGGTTCTGGGGCTCCTTCTGCTCTGGATATCAGGTGCCCAGTGTGATGT CCAGATAACCCAGTCTCCATCTTATCTTGCTGCATCTCCTGGAGAAACCATTACTATTAATTGCA GGGCAAGTAAGAGCATTAGCAAATATTTAGCCTGGTATCAAGAGAAACCTGGGAAAACTAATAAG CTTCTTATCTATTCTGGATCCACTTTGCAATCTGGAATTCCATCAAGGTTCAGTGGCAGTGGATC TGGTACAGATTTCACTCTCACCATCAGTAGCCTGGAGCCTGAAGATTTTGCAATGTATTACTGTC AACAGCATAATGATTATCCACTCACATTCGGTGCTGGGACCAAGCTGGAGCTGAAA SEQ ID NO: 34656C3E6 heavy chain amino acid sequence (FR1-CDR1-FR2-CDR2- FR3-CDR3-FR4)Attorney Docket No.206193-0150-P1US

[0398] MKLWLNWIFLVTLLNGIQCEVNLVESGGGLVQPGDSLSLSCATSGFTFTDYYMSWVRQPPGKALE WLGFIRNKANGYTTEYSASVKGRFTISRDNSQSILYLQMNALRPEDSATYYCASPVLRGFAYWGR GTLVTVSA SEQ ID NO: 34756C3E6 heavy chain nucleic acid sequence (FR1-CDR1-FR2- CDR2- FR3-CDR3- F R4) ATGAAGTTGTGGCTGAACTGGATTTTCCTTGTAACACTTTTAAATGGTATCCAGTGTGAGGTGAAC CTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGATTCTCTGAGTCTCTCCTGTGCAACTTCT GGATTCACCTTCACTGATTACTACATGAGCTGGGTCCGCCAGCCTCCCGGGAAGGCACTTGAGTGG TTGGGTTTTATTAGAAACAAAGCTAATGGTTACACAACAGAGTACAGTGCATCTGTGAAGGGTCGG TTTACCATCTCCAGAGATAATTCCCAAAGCATCCTCTATCTTCAAATGAATGCCCTGAGACCTGAG GACAGTGCCACTTATTACTGTGCAAGCCCTGTACTACGGGGGTTTGCTTACTGGGGCCGAGGGACT CTGGTCACTGTCTCTGCA SEQ ID NO: 34856C3E6 light chain amino acid sequence (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) MSVLTQVLALLLLWLTGARCDIQMTQSPASLSASVGETVTITCRASGNIHNYLAWYQQKQGKSPQL LVYNAKTLADGVPSRFSGSGSGTQYSLKINSLQPEDFGSYYCQHFWSTPFTFGSGTKLEIK SEQ ID NO: 34956C3E6 light chain nucleic acid sequence (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) ATGAGTGTGCTCACTCAGGTCCTGGCGTTGCTGCTGCTGTGGCTTACAGGTGCCAGATGTGACATC CAGATGACTCAGTCTCCAGCCTCCCTATCTGCATCTGTGGGAGAAACTGTCACCATCACATGTCGA GCAAGTGGGAATATTCACAATTATTTAGCATGGTATCAGCAGAAACAGGGAAAATCTCCTCAGCTC CTGGTCTATAATGCAAAAACCTTAGCAGATGGTGTGCCATCAAGGTTCAGTGGCAGTGGATCAGGA ACACAATATTCTCTCAAGATCAACAGCCTGCAGCCTGAAGATTTTGGGAGTTATTACTGTCAACAT TTTTGGAGTACTCCATTCACGTTCGGCTCGGGGACAAAGTTGGAAATAAAA SEQ ID NO: 35054C2F11 heavy chain amino acid sequence (FR1-CDR1-FR2- CDR2- FR3-CDR3- F R4) MKLWLNWIFLVTLLNGIQCEVRLVESGGGLVQPGGSLRLSCAASGFTFTDYYMSWVRQPPGKALE WLGFIRNKPSGYTTEYSASVKGRFTISRDNSQSILYLQMNALRAEDSTYYCARYISLWLLGYLD VWGTGTTVTVSS SEQ ID NO: 351 54C2F11 heavy chain nucleic acid sequence (FR1-CDR1-FR2- CDR2- FR3-CDR3- F R4) ATGAAGTTGTGGCTGAACTGGATTTTCCTTGTAACACTTTTAAATGGTATCCAGTGTGAGGTGAGG CTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGCGTCTCTCCTGTGCAGCTTCT GGATTCACCTTCACTGATTACTACATGAGCTGGGTCCGCCAGCCTCCAGGGAAGGCACTTGAGTGG TTGGGTTTTATTAGAAACAAACCTAGTGGTTACACAACAGAGTACAGTGCATCTGTGAAGGGTCGG TTCACCATCTCCAGAGATAATTCCCAAAGCATCCTCTATCTTCAAATGAATGCCCTGAGAGCTGAG GACAGTGCCACTTACTACTGTGCAAGATATATATCGCTATGGTTACTCGGCTACCTCGATGTCTGG GGCACAGGGACCACGGTCACCGTCTCCTCA SEQ ID NO: 35254C2F11 light chain amino acid sequence (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) MRFQVQVLGLLLLWISGAQCDVQITQSPSYLAASPGETIIINCRTSKSISKYLAWYQEKPGKTNKL LIYSGSTLQSGIPSRFSGSGSGTDFTLTISSLEPEDFAMYYCQQHNEYPLTFGAGTKLELN SEQ ID NO: 35354C2F11 light chain nucleic acid sequence (FR1-CDR1-FR2-CDR2- FR3-CDR3-FR4)Attorney Docket No.206193-0150-P1US

[0399] ATGAGGTTCCAGGTTCAGGTTCTGGGGCTCCTTCTGCTCTGGATATCAGGTGCCCAGTGTGATGTC CAGATAACCCAGTCTCCATCTTATCTTGCTGCATCTCCTGGAGAAACCATTATTATTAATTGCAGG ACAAGTAAGAGCATTAGCAAATATTTAGCCTGGTATCAAGAGAAACCTGGGAAAACTAATAAGCTT CTTATCTACTCTGGATCCACTTTGCAATCTGGAATTCCATCAAGGTTCAGTGGCAGTGGATCTGGT ACAGATTTCACTCTCACCATCAGTAGCCTGGAGCCTGAAGATTTTGCAATGTATTACTGTCAACAA CATAATGAATACCCGCTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAT SEQ ID NO: 35422F1A9 heavy chain amino acid sequence (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) MNFGLSLIFLVLVLKGVQCEVQLVESGGGLVKPGGSLKLSCAASGFTFSSYAMSWVRQTPEKRLE WVATISDGGSYTYYPDNVKGR FT I S RDNT KNNL Y L QMS H L KS E DT AM F Y CARDLSPLYYRGPMDY WGQGTSVTVSS SEQ ID NO: 35522F1A9 heavy chain nucleic acid sequence (FR1-CDR1-FR2- CDR2-FR3-CDR3-FR4) ATGAACTTCGGGCTCAGCTTGATTTTCCTTGTCCTTGTTTTAAAAGGTGTCCAGTGTGAAGTGCAG CTGGTGGAGTCTGGGGGAGGCTTAGTGAAGCCTGGAGGGTCCCTGAAACTCTCCTGTGCAGCCTCT GGATTCACTTTCAGTAGCTATGCCATGTCTTGGGTTCGCCAGACTCCGGAAAAGAGGCTGGAGTGG GTCGCAACCATTAGTGATGGTGGTAGTTACACCTACTATCCAGACAATGTAAAGGGCCGATTCACC ATCTCCAGAGACAATACCAAGAACAACCTGTACCTGCAAATGAGCCATCTGAAGTCTGAGGACACA GCCATGTTTTACTGTGCAAGAGATCTGTCCCCTCTCTACTATCGTGGGCCTATGGACTACTGGGGT CAAGGAACCTCAGTCACCGTCTCCTCA SEQ ID NO: 35622F1A9 light chain amino acid sequence (FR1-CDR1-FR2-CDR2- FR3-CDR3-FR4) MRAPAQIFGFLLLLFPGTRCDIQMTQSPASLSASLGERVSLTCRASQDIGSSLNWLQQEPDGTIKR LIYATSSLDSGVPKRFSGSRSGSDYSLTISSLESEDFVDYYCLQYASSPFTFGSGTKLEIK SEQ ID NO: 35722F1A9 light chain nucleic acid sequence (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) ATGAGGGCTCCTGCACAGATTTTTGGCTTCTTGTTGCTCTTGTTTCCAGGTACCAGATGTGACAT CCAGATGACCCAGTCTCCAGCTTCCTTATCTGCCTCTCTGGGAGAAAGAGTCAGTCTCACTTGTC GGGCAAGTCAGGACATTGGTAGTAGCTTAAACTGGCTTCAGCAGGAACCAGATGGAACTATTAAA CGCCTGATCTACGCCACATCCAGTTTAGATTCTGGTGTCCCCAAAAGGTTCAGTGGCAGTAGGTC TGGGTCAGATTATTCTCTCACCATCAGCAGCCTTGAGTCTGAAGATTTTGTAGACTATTACTGTC TACAATATGCTAGTTCTCCATTCACGTTCGGCTCGGGGACAAAGTTGGAAATAAAA SEQ ID NO: 35831E6H8 heavy chain amino acid sequence (FR1-CDR1-FR2-CDR2- FR3-CDR3-FR4) MKLWLNWIFLVTLLNGIQCEVKLVESGGGLVQPGGSLSLSCAASGFTFTDYYMTWVRQPPGKALE WLGFIRNKANGYTTEYSASVKGRFTISRDNSQSILSLQMNALSAEDSATYYCASLVLRGFAYWGQ GTLVTVSA SEQ ID NO: 35931E6H8 heavy chain nucleic acid sequence (FR1-CDR1-FR2- CDR2- FR3-CDR3- F R4) ATGAAGTTGTGGCTGAACTGGATTTTCCTTGTAACACTTTTAAATGGTATCCAGTGTGAGGTGAAG CTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGAGTCTCTCCTGTGCAGCTTCT GGATTCACCTTCACTGATTACTACATGACCTGGGTCCGCCAGCCTCCAGGGAAGGCACTTGAGTGG TTGGGTTTTATTAGAAACAAAGCTAATGGTTACACAACAGAGTACAGTGCATCTGTGAAGGGTCGG TTCACCATCTCCAGAGATAATTCCCAAAGCATCCTCTCTCTTCAAATGAATGCCCTGAGCGCTGAGAttorney Docket No.206193-0150-P1US

[0400] GACAGTGCCACTTATTACTGTGCAAGCCTTGTACTACGGGGGTTTGCTTACTGGGGCCAAGGGACT CTGGTCACTGTCTCTGCA SEQ ID NO: 36031E6H8 light chain amino acid sequence (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)

[0401] MESQTQVLMFLLLWVSGACADIVMTQSPSSLAMSVGQKVTMNCKSSQSLLNNSNQKNYLAWYQQKP GQSPKLLVYFASTRESGVPDRFIGSGSGTDFTLTLSSVQAEDLADYFCQQHYITPYTFGGGTKLEI K SEQ ID NO: 361 31E6H8 light chain nucleic acid sequence (FR1-CDR1-FR2-CDR2- FR3-CDR3-FR4) ATGGAATCACAGACCCAGGTCCTCATGTTTCTTCTGCTCTGGGTATCTGGTGCCTGTGCAGACAT TGTGATGACACAGTCTCCATCCTCCCTGGCTATGTCAGTAGGACAGAAGGTCACTATGAACTGCA AGTCCAGTCAGAGCCTTTTAAATAATAGCAATCAAAAGAACTATTTGGCCTGGTACCAGCAGAAA CCAGGACAGTCTCCTAAACTTCTGGTATACTTTGCATCCACTAGGGAATCTGGGGTCCCTGATCG CTTCATAGGCAGTGGATCTGGGACAGATTTCACTCTTACCCTCAGCAGTGTGCAGGCTGAAGACC TGGCAGATTACTTCTGTCAACAACATTATATCACTCCGTACACGTTCGGAGGGGGGACCAAGCTG GAGATAAAA SEQ ID NO: 36235A3C10 heavy chain amino acid sequence (FR1-CDR1-FR2- CDR2- FR3-CDR3- F R4) MKLWLNWIFLVTLLNGLQCEVKLVESGGGLVQPGGSLSLSCAASGFTFTDYYMSWVRQPPGKALE WLGFIRNKVSGYTTDYSSSVKGRFTFSRDNSQSIVYLHMNALRAEDSTYYCTRYVSLWLLGYFD VWGTGTTVTVSS SEQ ID NO: 36335A3C10 heavy chain nucleic acid sequence (FR1-CDR1-FR2- CDR2- FR3-CDR3- F R4) ATGAAGTTGTGGCTGAACTGGATTTTCCTTGTAACACTTTTAAATGGTCTCCAGTGTGAGGTGAAA CTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGAGTCTCTCCTGTGCAGCTTCT GGATTCACCTTCACTGATTACTACATGAGTTGGGTCCGCCAGCCTCCAGGGAAGGCACTTGAGTGG TTGGGTTTTATTAGAAATAAAGTTAGTGGTTACACAACAGACTACAGTTCATCTGTGAAGGGTCGG TTCACCTTCTCCAGAGATAATTCCCAAAGCATCGTCTATCTTCATATGAATGCCCTGAGAGCTGAG GACAGTGCCACTTATTACTGTACAAGATATGTATCGCTATGGTTACTCGGGTACTTCGATGTCTGG GGCACAGGGACCACGGTCACCGTCTCCTCA SEQ ID NO: 36431A3C10 light chain amino acid sequence (FR1-CDR1-FR2-CDR2- FR3-CDR3-FR4) MRFQVQVLGLLLLWISVPGAQCDVQITQSPSYLAASPGETITINCRASKSISKYLAWYQEKPGKTN KLLIYSGSTLQSGIPSRFSGSGSGTDFTLTISSLEPEDFAMYYCQQHNEYPLTFGAGTKLELK SEQ ID NO: 36531A3C10 light chain nucleic acid sequence (FR1-CDR1-FR2- CDR2- FR3-CDR3- F R4) ATGAGGTTCCAGGTTCAGGTTCTGGGGCTCCTTCTGCTCTGGATATCAGTTCCAGGTGCCCAGTGT GATGTCCAGATAACCCAGTCTCCATCTTATCTTGCTGCATCTCCTGGAGAAACCATTACTATTAAT TGCAGGGCAAGTAAGAGCATTAGCAAATATTTAGCCTGGTATCAAGAGAAACCTGGGAAAACTAAT AAGCTTCTTATCTACTCTGGATCCACTTTGCAATCTGGAATTCCATCAAGGTTCAGTGGCAGTGGA TCTGGTACAGATTTCACTCTCACCATCAGTAGCCTGGAGCCTGAAGATTTTGCAATGTATTACTGT CAACAGCATAATGAATACCCGCTCACATTCGGTGCTGGGACCAAGCTGGAGCTGAAA SEQ ID NO: 36635G6G1 heavy chain amino acid sequence (FR1-CDR1-FR2-CDR2- FR3-CDR3-FR4)Attorney Docket No.206193-0150-P1US

[0402] MKLWLNWIFLVTLLNGIQCEVKLVESGGGLVQPGGSLSLSCAASGFTFADYYMTWVRQPPGKALE WLGFIRNKANGFTTEYSASVKGRFTISRDNSQSILYLQMNALRAEDSTYYCARYGLRGFAYWGQ GTLVTVSA SEQ ID NO: 36735G6G1 heavy chain nucleic acid sequence (FR1-CDR1-FR2- CDR2- FR3-CDR3- F R4) ATGAAGTTGTGGCTGAACTGGATTTTCCTTGTAACACTTTTAAATGGTATCCAGTGTGAGGTGAAG CTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGAGTCTCTCCTGTGCAGCTTCT GGATTCACCTTCGCTGATTACTACATGACCTGGGTCCGCCAGCCTCCAGGGAAGGCACTTGAGTGG TTGGGTTTTAT T AGAAAC AAAGCT AAT GGT T T C AC AAC AGAGT AC AGT GC AT CT GT GAAGGGT CGG TTCACCATCTCCAGAGATAATTCCCAAAGCATCCTCTATCTTCAAATGAATGCCCTGAGAGCTGAG GACAGTGCCACTTATTACTGTGCAAGATATGGGTTACGGGGGTTTGCTTACTGGGGCCAAGGGACT CTGGTCACTGTCTCTGCA SEQ ID NO: 36835G6G1 light chain amino acid sequence (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)

[0403] MESQTQVLMFLLLWVSGACADIVMTQSPSSLAMSVGQKVTLNCKSSQSLLNSSNQKNYLAWYQQKP GQSPKLLVYFASTRESGVPDRFIGSGSGTDFTLTISSVQAEDLADYFCHQHYSTPFTFGSGTKLEM K SEQ ID NO: 36935G6G1 light chain nucleic acid sequence (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) ATGGAATCACAGACCCAGGTCCTCATGTTTCTTCTGCTCTGGGTATCTGGTGCCTGTGCAGACAT TGTGATGACACAGTCTCCATCCTCCCTGGCTATGTCAGTAGGACAGAAGGTCACTTTGAACTGCA AGTCCAGTCAGAGCCTTTTAAATAGTAGCAATCAAAAGAACTATTTGGCCTGGTACCAGCAGAAA CCAGGACAGTCTCCTAAACTTCTGGTATACTTTGCATCCACTAGGGAATCTGGGGTCCCTGATCG CTTCATAGGCAGTGGATCTGGGACAGATTTCACTCTTACCATCAGCAGTGTGCAGGCTGAAGACC TGGCAGATTACTTCTGTCACCAACATTATAGTACTCCATTCACGTTCGGCTCGGGGACAAAGTTG GAAATGAAA SEQ ID NO: 37038B2G5 heavy chain amino acid sequence (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) MERHWIFLSLLSVIAGVHSQVQLQQSGAEVAKPGASVKLSCKASGYTFTSYWMHWVKQRPGQGLE I G YINPSNNYTKYNQKFNDKAT LT AD KSSSTAYMQLSSLTYEDSALYY C ARV Y Y Y GN S PAW FAY WGQGTLVTVSA SEQ ID NO: 371 38B2G5 heavy chain nucleic acid sequence (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4~) ATGGAAAGGCACTGGATCTTTCTCTCCCTGTTGTCAGTAATAGCAGGTGTCCACTCCCAGGTCCAG CTGCAGCAGTCTGGGGCTGAAGTGGCAAAACCTGGGGCCTCAGTGAAGCTGTCCTGCAAGGCTTCT GGCTACACCTTTACTAGCTACTGGATGCACTGGGTAAAACAGAGGCCTGGACAGGGTCTGGAATGG ATTGGATACATTAATCCTAGCAATAATTATACTAAGTACAATCAGAAATTCAATGACAAGGCCACA TTGACTGCAGACAAATCCTCCAGCACAGCCTACATGCAGCTGAGCAGCCTGACATATGAGGACTCT GCACTCTATTACTGTGCAAGAGTTTATTACTACGGTAATAGTCCTGCCTGGTTTGCTTACTGGGGC CAAGGGACTCTGGTCACTGTCTCTGCA SEQ ID NO: 37238B2G5 light chain amino acid sequence (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) MDFQVQIFSFLLISASVIMSRGQIVLSQSPAILSASPGEKVTMTCRASSSVSYMHWYQQKPGSSPK PWIYATSNLASGVPARFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIKAttorney Docket No.206193-0150-P1US

[0404] SEQ ID NO: 37338B2G5 light chain nucleic acid sequence (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) ATGGATTTTCAAGTGCAGATTTTCAGCTTCCTGCTAATCAGTGCTTCAGTCATAATGTCCAGAGG ACAAATTGTTCTCTCCCAGTCTCCAGCAATCCTGTCTGCATCTCCAGGGGAGAAGGTCACAATGA CTTGCAGGGCCAGCTCAAGTGTAAGTTACATGCACTGGTACCAGCAGAAGCCAGGATCCTCCCCC AAACCCTGGATTTATGCCACATCCAACCTGGCTTCTGGAGTCCCTGCTCGCTTCAGTGGCAGTGG GTCTGGGACCTCTTACTCTCTCACAATCAGCAGAGTGGAGGCTGAAGATGCTGCCACTTATTACT GCCAGCAGTGGACTAGTAACCCACCCACGTTCGGAGGGGGGACCAAGCTGGAAATAAAA

[0405] SEQ ID NO: 37448D6F4 heavy chain amino acid sequence (Signal sequence-FR1- CDR1- F R2-CDR2- FR3-CDR3- F R4) MKLWLNWIFLVTLLNGIQCEVRLVESGGGLVQPGGSLRLSCAASGFT FTDYYMSWVRQPPGKALE WLGFIRNKPSGYTTEYSASVKGRFTFSRDNSQSILYLQMNALRAEDSATYYCARYISLWLLGYLDVWGTGTTVTVSS SEQ ID NO: 37548D6F4 heavy chain nucleic acid sequence (Signal sequence- F R 1 -CDR1- F R2-CDR2- FR3-CDR3- F R4) ATGAAGTTGTGGCTGAACTGGATTTTCCTTGTAACACTTTTAAATGGTATCCAGTGTGAGGTGAGG CTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGCGTCTCTCCTGTGCAGCTTCT GGATTCACCTTCACTGATTACTACATGAGCTGGGTCCGCCAGCCTCCAGGGAAGGCACTTGAGTGG TTGGGTTTTATTAGAAACAAACCTAGTGGTTACACAACAGAATACAGTGCATCTGTGAAGGGTCGG TTCACCTTCTCCAGAGATAATTCCCAAAGCATCCTCTATCTTCAAATGAATGCCCTGAGAGCTGAG GACAGTGCCACTTACTACTGTGCAAGATATATATCGCTATGGTTACTCGGCTACCTCGATGTCTGG GGCACAGGGACCACGGTCACCGTCTCCTCA SEQ ID NO: 37648D6F4 light chain amino acid sequence (Signal sequence-FR1- CDR1- F R2-CDR2- FR3-CDR3- F R4) MRFQVQVLGLLLLWISGAQCDVQITQSPSYLAASPGETIIINCRTSKSISKYLAWYQEKPGKTNNL LIYSGSTLQSGIPSRFSGSGSGTDFSLTISSLEPEDFAIYYCQQHNEYPLTFGAGTKLELN SEQ ID NO: 37748D6F4 light chain nucleic acid sequence (Signal sequence-FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) ATGAGGTTCCAGGTTCAGGTTCTGGGGCTCCTTCTGCTCTGGATATCAGGTGCCCAGTGTGATGT CCAGATAACCCAGTCTCCATCTTATCTTGCTGCATCTCCTGGAGAAACCATTATTATTAATTGCA GGACAAGTAAGAGCATTAGCAAATATTTAGCCTGGTATCAAGAGAAACCTGGGAAAACTAATAAC CTTCTTATCTACTCTGGATCCACTTTGCAATCTGGAATTCCATCAAGGTTCAGTGGCAGTGGATC TGGTACAGATTTCTCTCTCACCATCAGTAGCCTGGAGCCTGAAGATTTTGCAATCTATTACTGTC AACAACATAATGAATACCCGCTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAT SEQ ID NO: 37873D4G2 heavy chain amino acid sequence (Signal sequence-FR1- CDR1- F R2-CDR2- FR3-CDR3- F R4) MKLWLNWIFLVTLLNGIQCEVRLVESGGGLVQPGGSLRLSCAASGFT FTDYYMSWVRQPPGKALE WLGFIRNKPSGYTTEYSASVKGRFTISRDNSQSILYLQMNALRAEDSATYYCARYISLWLLGYLD VWGTGTTVTVSS SEQ ID NO: 37973D4G2 heavy chain nucleic acid sequence (Signal sequence- F R 1 -CDR1- F R2-CDR2- FR3-CDR3- F R4) ATGAAGTTGTGGCTGAACTGGATTTTCCTTGTAACACTTTTAAATGGTATCCAGTGTGAGGTGAGG CTGGTGGAGTCTGGAGGAGGCTTGGTACAGCCTGGGGGTTCTCTGCGTCTCTCCTGTGCAGCTTCT GGATTCACCTTCACTGATTACTACATGAGCTGGGTCCGCCAGCCTCCAGGGAAGGCACTTGAGTGGAttorney Docket No.206193-0150-P1US

[0406] TTGGGTTTTATTAGAAACAAACCTAGTGGTTACACAACAGAGTACAGTGCATCTGTGAAGGGTCGG TTCACCATCTCCAGAGATAATTCCCAAAGCATCCTCTATCTTCAAATGAATGCCCTGAGAGCTGAG GACAGTGCCACTTACTACTGTGCAAGATATATATCGTTATGGTTACTCGGCTACCTCGATGTCTGG GGCACAGGGACCACGGTCACCGTCTCCTCA SEQ ID NO: 38073D4G2 light chain amino acid sequence (Signal sequence-FR1- CDR1- F R2-CDR2- F R3-CDR3- F R4) MRFQVQVLGLLLLWISGAQCDVQITQSPSYLAASPGETIIINCRTSKSISKYLAWYQEKPGKTNKL LIYSGSTLQSGIPSRFSGSGSGTDFTLTISSLEPEDFAMYYCQQHNEYPLTFGAGTKLELK SEQ ID NO: 381 73D4G2 light chain nucleic acid sequence (Signal sequence-FR1- CDR1- F R2-CDR2- FR3-CDR3- F R4) ATGAGGTTCCAGGTTCAGGTTCTGGGGCTCCTTCTGCTCTGGATATCAGGTGCCCAGTGTGATGT CCAGATAACCCAGTCTCCATCTTATCTTGCTGCATCTCCTGGAGAAACCATTATTATTAATTGCA GGACAAGTAAGAGCATTAGCAAATATTTAGCCTGGTATCAAGAGAAACCTGGGAAAACTAATAAG CTTCTTATCTACTCTGGATCCACTTTGCAATCTGGAATTCCATCAAGGTTCAGTGGCAGTGGATC TGGTACAGATTTCACTCTCACCATCAGTAGCCTGGAGCCTGAAGATTTTGCAATGTATTACTGTC AACAACATAATGAATACCCGCTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAA

[0407] Table 1: SEQUENCES

[0408] Sequence Type Full-length

[0409] Variable Region

[0410] (without signal

[0411] sequence)

[0412] SEQ ID NO:

[0413] 29F2C7 heavy Amino acid 1

[0414] chain Nucleotide 2

[0415] 29F2C7 light Amino acid 3

[0416] chain Nucleotide 4

[0417] 34F4A2 heavy Amino acid 5

[0418] chain Nucleotide 6

[0419] 34F4A2 light Amino acid 7

[0420] chain Nucleotide 8

[0421] 35A3G11 heavy Amino acid 9

[0422] chain Nucleotide 10

[0423] 35A3G11 light Amino acid 11

[0424] chain Nucleotide 12

[0425] 35B3F9 heavy Amino acid 13

[0426] chain Nucleotide 14

[0427] 35B3F9 light Amino acid 15

[0428] chain Nucleotide 16

[0429] 36F7B3 heavy Amino acid 17

[0430] chain Nucleotide 18

[0431] 36F7B3 light Amino acid 19

[0432] chain Nucleotide 20

[0433]

[0434] Amino acid 21Attorney Docket No.206193-0150-P1US

[0435] 36D6A8 heavy Nucleotide 22 chain

[0436] 36D6A8 light Amino acid 23 chain Nucleotide 24 54C3B11 heavy Amino acid 25 chain Nucleotide 26 54C3B11 light Amino acid 27 chain Nucleotide 28 66E8F8 heavy Amino acid 29 chain Nucleotide 30 66E8F8 light Amino acid 31 chain Nucleotide 32 68A11A1 heavy Amino acid 33 chain Nucleotide 34 68A11A1 light Amino acid 35 chain Nucleotide 36 68B1E2 heavy Amino acid 37 chain Nucleotide 38 68B1E2 light Amino acid 39 chain Nucleotide 40 56C3E6 heavy Amino acid 41 chain Nucleotide 42 56C3E6 light Amino acid 43 chain Nucleotide 44 54C2F11 heavy Amino acid 45 chain Nucleotide 46 54C2F11 light Amino acid 47 chain Nucleotide 48 22F1A9 heavy Amino acid 49 chain Nucleotide 50 22F1A9 light Amino acid 51 chain Nucleotide 52 31E6H8 heavy Amino acid 53 chain Nucleotide 54 31E6H8 light Amino acid 55 chain Nucleotide 56 35 A3C 10 heavy Amino acid 57 chain Nucleotide 58 35 A3C 10 light Amino acid 59 chain Nucleotide 60 35G6G1 heavy Amino acid 61 chain Nucleotide 62 35G6G1 light Amino acid 63 chain Nucleotide 64

[0437]

[0438] Amino acid 65Attorney Docket No.206193-0150-P1US

[0439] 38B2G5 heavy Nucleotide 66

[0440] chain

[0441] 38B2G5 light Amino acid 67

[0442] chain Nucleotide 68

[0443] 48D6F4 heavy Amino acid 69

[0444] chain Nucleotide 70

[0445] 48D6F4 light Amino acid 71

[0446] chain Nucleotide 72

[0447] 73D4G2 heavy Amino acid 73

[0448] chain Nucleotide 74

[0449] 73D4G2 light Amino acid 75

[0450]

[0451] chain Nucleotide 76

[0452] Table 2: SEQUENCES

[0453] Sequence CDR1 CDR2 CDR3 Full-length Signal Type SEQ ID SEQ ID NO: SEQ ID Variable Sequence NO: NO: Region (with

[0454] signal sequence)

[0455] SEQ ID NO:

[0456] 29F2C7 heavy Amino acid 77 78 79 306 382 chain Nucleotide 80 81 82 307 383 29F2C7 light Amino acid 83 84 85 308 384 chain Nucleotide 86 87 88 309 385 34F4A2 heavy Amino acid 89 90 91 310 382 chain Nucleotide 92 93 94 311 383 34F4A2 light Amino acid 95 96 97 312 386 chain Nucleotide 98 99 100 313 387 35A3G11 heavy Amino acid 101 102 103 314 388 chain Nucleotide 104 105 106 315 389 35A3G11 light Amino acid 107 108 109 316 390 chain Nucleotide 110 111 112 317 391 35B3F9 heavy Amino acid 113 114 115 318 382 chain Nucleotide 116 117 118 319 383 35B3F9 light Amino acid 119 120 121 320 384 chain Nucleotide 122 123 124 321 385 36F7B3 heavy Amino acid 125 126 127 322 382 chain Nucleotide 128 129 130 323 383 36F7B3 light Amino acid 131 132 133 324 386 chain Nucleotide 134 135 136 325 387 36D6A8 heavy Amino acid 137 138 139 326 382 chain Nucleotide 140 141 142 327 383 36D6A8 light Amino acid 143 144 145 328 384 chain Nucleotide 146 147 148 329 385

[0457]

[0458] Amino acid 149 150 151 330 382Attorney Docket No.206193-0150-P1US

[0459] 54C3B11 heavy Nucleotide 152 153 154 331 383 chain

[0460] 54C3B11 light Amino acid 155 156 157 332 386 chain Nucleotide 158 159 160 333 387 66E8F8 heavy Amino acid 161 162 163 334 382 chain Nucleotide 164 165 166 335 383 66E8F8 light Amino acid 167 168 170 336 386 chain Nucleotide 171 172 173 337 387 68A11A1 heavy Amino acid 174 175 176 338 392 chain Nucleotide 177 178 179 339 393 68A11A1 light Amino acid 180 181 182 340 390 chain Nucleotide 183 184 185 341 391 68B1E2 heavy Amino acid 186 187 188 342 382 chain Nucleotide 189 190 191 343 383 68B1E2 light Amino acid 192 193 194 344 384 chain Nucleotide 195 196 197 345 385 56C3E6 heavy Amino acid 198 199 200 346 382 chain Nucleotide 201 202 203 347 383 56C3E6 light Amino acid 204 205 206 348 394 chain Nucleotide 207 208 209 349 395 54C2F11 heavy Amino acid 210 211 212 350 382 chain Nucleotide 213 214 215 351 383 54C2F11 light Amino acid 216 217 218 352 384 chain Nucleotide 219 220 221 353 385 22F1A9 heavy Amino acid 222 223 224 354 396 chain Nucleotide 225 226 227 355 397 22F1A9 light Amino acid 228 229 230 356 398 chain Nucleotide 231 232 233 357 399 31E6H8 heavy Amino acid 234 235 236 358 382 chain Nucleotide 237 238 239 359 383 31E6H8 light Amino acid 240 241 242 360 386 chain Nucleotide 243 244 245 361 387 35A3C10 heavy Amino acid 246 247 248 362 388 chain Nucleotide 249 250 251 363 389 35 A3C 10 light Amino acid 252 253 254 364 390 chain Nucleotide 255 256 257 365 391 35G6G1 heavy Amino acid 258 259 260 366 382 chain Nucleotide 261 262 263 367 383 35G6G1 light Amino acid 264 265 266 368 386 chain Nucleotide 267 268 269 369 387 38B2G5 heavy Amino acid 270 271 272 370 400 chain Nucleotide 273 274 275 371 401 38B2G5 light Amino acid 276 277 278 372 402 chain Nucleotide 279 280 281 373 403

[0461]

[0462] Amino acid 282 283 284 374 382Attorney Docket No.206193-0150-P1US

[0463] 48D6F4 heavy Nucleotide 285 286 287 375 383 chain

[0464] 48D6F4 light Amino acid 288 289 290 376 384 chain Nucleotide 291 292 293 377 385 73D4G2 heavy Amino acid 294 295 296 378 382 chain Nucleotide 297 298 299 379 383 73D4G2 light Amino acid 300 301 302 380 384

[0465]

[0466] chain Nucleotide 303 304 305 381 385

[0467] The disclosures of each and every patent, patent application, and

[0468] publication cited herein are hereby incorporated herein by reference in their entirety.

[0469] While this invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by

[0470] others skilled in the art without departing from the true spirit and scope of the invention.

[0471] The appended claims are intended to be construed to include all such embodiments and equivalent variations.

Claims

1. Attorney Docket No.206193-0150-00WOCLAIMSWhat is claimed is:

1. A Siglec-10 binding molecule, comprising a Siglec-10 antibody, a Siglec-10 binding antibody fragment or a variant of a Siglec-10 antibody.

2. The Siglec-10 binding molecule of claim 1, wherein the antibody comprises an amino acid sequence selected from the group consisting of:g) a variable heavy chain sequence comprising the CDR sequences selected from the group consisting of SEQ ID NO:77-79; SEQ ID NO:89-91; SEQ ID NO:101-103; SEQ ID NO: 113-115; SEQ ID NO: 125-127; SEQ ID NO: 137-139; SEQ ID NO: 149-151; SEQ ID NO: 161-163; SEQ ID NO: 174-176; SEQ ID NO: 186-188; SEQ ID NO: 198-200; SEQ ID NO:210-212; SEQ ID NO:222-224; SEQ ID NO:234-236; SEQ ID NO:246-248; SEQ ID NO:258-260; SEQ ID NO:270-272; SEQ ID NO:282-284; and SEQ ID NO:294-296;h) a variable light chain sequence comprising the CDR sequences selected from the group consisting of SEQ ID NO:83-85; SEQ ID NO:95-97; SEQ ID NO: 107-109; SEQ ID NO: 119-121; SEQ ID NO: 131-133; SEQ ID NO: 143-145; SEQ ID NO:155-157; SEQ ID NO: 167-170; SEQ ID NO: 180-182; SEQ ID NO: 192-194; SEQ ID NO:204-206; SEQ ID NO:216-218; SEQ ID NO:228-230; SEQ ID NO:240-242; SEQ ID NO:252-254; SEQ ID NO:264-266; SEQ ID NO:276-278; SEQ ID NO:288-290; and SEQ ID NO: 300-302;i) a sequence having at least 95% identity to a variable heavy chain sequence of one or more of SEQ ID NO: 1, SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 13, SEQ ID NO: 17, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 37, SEQ ID NO: 41, SEQ ID NO: 45, SEQ ID NO: 49, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 61, SEQ ID NO: 65, SEQ ID NO: 69, or SEQ ID NO: 73;j) a sequence having at least 95% identity to a variable light chain sequence of one or more of SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 15, SEQ ID NO: 19, SEQ ID NO: 23, SEQ ID NO: 27, SEQ ID NO: 31, SEQ ID NO: 35, SEQ ID NO: 39, SEQ ID NO: 43, SEQ ID NO: 47, SEQ ID NO: 51, SEQ IDAttorney Docket No.206193-0150-P1USNO: 55, SEQ ID NO: 59, SEQ ID NO: 63, SEQ ID NO: 67, SEQ ID NO: 71, or SEQ ID NO: 75;k) a fragment comprising at least 80% of the full- length sequence of a variable heavy chain sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 13, SEQ ID NO: 17, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 37, SEQ ID NO: 41, SEQ ID NO: 45, SEQ ID NO: 49, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 61, SEQ ID NO: 65, SEQ ID NO: 69, or SEQ ID NO: 73; andl) a fragment comprising at least 80% of the full-length sequence of a variable light chain sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 15, SEQ ID NO: 19, SEQ ID NO: 23, SEQ ID NO: 27, SEQ ID NO: 31, SEQ ID NO: 35, SEQ ID NO: 39, SEQ ID NO: 43, SEQ ID NO: 47, SEQ ID NO: 51, SEQ ID NO: 55, SEQ ID NO: 59, SEQ ID NO: 63, SEQ ID NO: 67, SEQ ID NO: 71, or SEQ ID NO: 75.

3. The Siglec-10 binding molecule or fragment thereof of claim 1, wherein the Siglec-10 binding molecule comprises an amino acid sequence selected from the group consisting of:a) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO:77-79 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO:83-85;b) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 89-91and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 95-97;c) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 101-103 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 107-109;d) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 113-115 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 119-121;Attorney Docket No.206193-0150-P1USe) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 125-127 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 131-133;f) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 137-139 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 143-145;g) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO:97-99 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 105-107;h) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 149-151 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 155-157;i) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 161-163 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 167-170;j) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 174-176 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 180-182;k) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 186-188 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 192-194;l) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 198-200 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 204-206;m) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 210-212 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 216-218;n) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 222-224 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 228-230;Attorney Docket No.206193-0150-P1USo) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 234-236 and a variable light chain sequence comprising the CDR sequences of SEQ IDNO: 240-242;p) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 246-248 and a variable light chain sequence comprising the CDR sequences of SEQ IDNO: 252-254;q) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 258-260 and a variable light chain sequence comprising the CDR sequences of SEQ ID NO: 264-266;r) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 270-272 and a variable light chain sequence comprising the CDR sequences of SEQ IDNO: 276-278;s) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 282-284 and a variable light chain sequence comprising the CDR sequences of SEQ IDNO: 288-290; andt) a variable heavy chain sequence comprising the CDR sequences of SEQ ID NO: 294-296 and a variable light chain sequence comprising the CDR sequences of SEQ IDNO: 300-302.

4. The Siglec-10 binding molecule or fragment thereof of claim 1, wherein the Siglec-10 binding molecule comprises an amino acid sequence selected from the group consisting of:a) a variable heavy chain sequence of SEQ ID NO: 1 and a variable light chain sequence of SEQ ID NO:3;b) a variable heavy chain sequence of SEQ ID NO: 5 and a variable light chain sequence of SEQ ID NO: 7;c) a variable heavy chain sequence of SEQ ID NO:9 and a variable light chain sequence of SEQ ID NO: 11;d) a variable heavy chain sequence of SEQ ID NO: 13 and a variable light chain sequence of SEQ ID NO: 15;Attorney Docket No.206193-0150-P1USe) a variable heavy chain sequence of SEQ ID NO: 17 and a variable light chain sequence of SEQ ID NO: 19;f) a variable heavy chain sequence of SEQ ID NO:21 and a variable light chain sequence of SEQ ID NO:23;g) a variable heavy chain sequence of SEQ ID NO:25 and a variable light chain sequence of SEQ ID NO:27;h) a variable heavy chain sequence of SEQ ID NO:29 and a variable light chain sequence of SEQ ID NO: 31;i) a variable heavy chain sequence of SEQ ID NO:33 and a variable light chain sequence of SEQ ID NO:35;j) a variable heavy chain sequence of SEQ ID NO:37 and a variable light chain sequence of SEQ ID NO: 39;k) a variable heavy chain sequence of SEQ ID NO:41 and a variable light chain sequence of SEQ ID NO:43;l) a variable heavy chain sequence of SEQ ID NO:45 and a variable light chain sequence of SEQ ID NO:47;m) a variable heavy chain sequence of SEQ ID NO:49 and a variable light chain sequence of SEQ ID NO:51;n) a variable heavy chain sequence of SEQ ID NO:53 and a variable light chain sequence of SEQ ID NO: 55;o) a variable heavy chain sequence of SEQ ID NO:57 and a variable light chain sequence of SEQ ID NO:59;p) a variable heavy chain sequence of SEQ ID NO:61 and a variable light chain sequence of SEQ ID NO: 63;q) a variable heavy chain sequence of SEQ ID NO:65 and a variable light chain sequence of SEQ ID NO: 67;r) a variable heavy chain sequence of SEQ ID NO: 69 and a variable light chain sequence of SEQ ID NO:71; ands) a variable heavy chain sequence of SEQ ID NO:73 and a variable light chain sequence of SEQ ID NO: 75.Attorney Docket No.206193-0150-P1US5. The Siglec-10 binding molecule or fragment thereof of any one of claims 1-4, wherein the Siglec-10 binding molecule comprises a fusion protein comprising a Siglec-10 antibody, a Siglec-10 binding antibody fragment or a variant of a Siglec-10 antibody.

6. The Siglec-10 binding molecule or fragment thereof of any one of claims 1-4, wherein the Siglec-10 binding molecule comprises a humanized antibody or fragment thereof.

7. A nucleic acid molecule, or combination of nucleic acid molecules, comprising one or more nucleotide sequence encoding a Siglec-10 binding molecule of any one of claims 1-6.

8. The nucleic acid molecule of claim 7, wherein the nucleic acid molecule comprises one or more nucleotide sequence selected from the group consisting of:g) a nucleotide sequence encoding a variable heavy chain sequence wherein the nucleotide sequence comprises CDR encoding sequences selected from the group consisting of SEQ ID NO:80-82; SEQ ID NO:92-94; SEQ ID NO: 104-106; SEQ ID NO: 116-118; SEQ ID NO: 128-130; SEQ ID NO: 140-142; SEQ ID NO: 152-154; SEQ ID NO: 164-166; SEQ ID NO: 177-179; SEQ ID NO: 189-191; SEQ ID NO: 201-203; SEQ ID NO:213-215; SEQ ID NO:225-227; SEQ ID NO:237-239; SEQ ID NO:249-251; SEQ ID NO:261-263; SEQ ID NO:273-275; SEQ ID NO:285-287; and SEQ ID NO:297-299;h) a nucleotide sequence encoding a variable light chain sequence wherein the nucleotide sequence comprises CDR encoding sequences selected from the group consisting of SEQ ID NO:86-88; SEQ ID NO:98-101; SEQ ID NO: 110-112; SEQ ID NO:122-124; SEQ ID NO: 134-136; SEQ ID NO: 146-148; SEQ ID NO: 158-160; SEQ ID NO: 171-173; SEQ ID NO: 183-185; SEQ ID NO: 195-197; SEQ ID NO:207-209; SEQ ID NO:219-221; SEQ ID NO:231-233; SEQ ID NO:243-245; SEQ ID NO:255-257; SEQ ID NO:267-269; SEQ ID NO:279-281; SEQ ID NO:291-293; and SEQ ID NO:303-305;i) a nucleotide sequence having at least 95% identity to a variable heavy chain encoding sequence selected from the group consisting of SEQ ID NO:2;Attorney Docket No.206193-0150-P1USSEQ ID NO:6; SEQ ID NO:10; SEQ ID NO: 14; SEQ ID NO: 18; SEQ ID NO:22; SEQ ID NO:26; SEQ ID NO:30; SEQ ID NO:34; SEQ ID NO:38; SEQ ID NO:42; SEQ ID NO:46; SEQ ID NO:50; SEQ ID NO:54; SEQ ID NO:58; SEQ ID NO:62; SEQ ID NO:66; SEQ ID NO:70; and SEQ ID NO:74;j) a nucleotide sequence having at least 95% identity to a variable light chain encoding sequence selected from the group consisting of SEQ ID NO:4; SEQ IDN0:8; SEQ ID NO: 12; SEQ ID NO: 16; SEQ ID NO:20; SEQ ID NO:24; SEQ ID NO 28; SEQ ID NO:32; SEQ ID NO:36; SEQ ID NO:40; SEQ ID NO:44; SEQ ID NO:48; SEQ ID NO:52; SEQ ID NO:56; SEQ ID NO:60; SEQ ID NO:64; SEQ ID NO:68; SEQ ID NO:72; and SEQ ID NO:76;k) a fragment comprising at least 80% of the full- length sequence of a variable heavy chain encoding sequence selected from the group consisting of SEQ ID NO:2; SEQ ID NO:6; SEQ ID NO:10; SEQ ID NO: 14; SEQ ID NO: 18; SEQ ID NO:22; SEQ ID NO:26; SEQ ID NO:30; SEQ ID NO:34; SEQ ID NO:38; SEQ ID NO:42; SEQ ID NO:46; SEQ ID NO:50; SEQ ID NO:54; SEQ ID NO:58; SEQ ID NO:62; SEQ ID NO:66; SEQ ID NO:70; and SEQ ID NO:74; andl) a fragment comprising at least 80% of the full-length sequence of a variable light chain encoding sequence selected from the group consisting of SEQ ID NO:4; SEQ ID NO:8; SEQ ID NO: 12; SEQ ID NO: 16; SEQ ID NO:20; SEQ IDNO:24; SEQ ID NO:28; SEQ ID NO:32; SEQ ID NO:36; SEQ ID NO:40; SEQ ID NO:44; SEQ ID NO:48; SEQ ID NO:52; SEQ ID NO:56; SEQ ID NO:60; SEQ ID NO:64; SEQ ID NO:68; SEQ ID NO:72; and SEQ ID NO:76.

9. The nucleic acid molecule(s) of claim 8, wherein the nucleic acid molecule(s) comprises nucleotide sequences selected from the group consisting of:a) a first nucleotide sequence comprising SEQ ID NO: 80-82, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 86-88 encoding a variable light chain sequence;b) a first nucleotide sequence comprising SEQ ID NO: 92-94, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 98-101 encoding a variable light chain sequence;Attorney Docket No.206193-0150-P1USc) a first nucleotide sequence comprising SEQ ID NO: 104-106, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 110-112 encoding a variable light chain sequence;d) a first nucleotide sequence comprising SEQ ID NO: 116-118, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 122-124 encoding a variable light chain sequence;e) a first nucleotide sequence comprising SEQ ID NO: 128-130, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 134-136 encoding a variable light chain sequence;f) a first nucleotide sequence comprising SEQ ID NO: 140-142, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 146-148 encoding a variable light chain sequence;g) a first nucleotide sequence comprising SEQ ID NO: 152-154, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 158-160 encoding a variable light chain sequence;h) a first nucleotide sequence comprising SEQ ID NO: 164-166, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 171-173 encoding a variable light chain sequence;i) a first nucleotide sequence comprising SEQ ID NO: 177-179, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 183-185 encoding a variable light chain sequence;j) a first nucleotide sequence comprising SEQ ID NO: 189-191, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 195-197 encoding a variable light chain sequence;k) a first nucleotide sequence comprising SEQ ID NO: 201-203, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 207-209 encoding a variable light chain sequence;l) a first nucleotide sequence comprising SEQ ID NO: 213-215, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 219-221 encoding a variable light chain sequence;Attorney Docket No.206193-0150-P1USm) a first nucleotide sequence comprising SEQ ID NO: 225-227, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 231-233 encoding a variable light chain sequence;n) a first nucleotide sequence comprising SEQ ID NO: 237-239, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 243-245 encoding a variable light chain sequence;o) a first nucleotide sequence comprising SEQ ID NO: 249-251, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 255-257 encoding a variable light chain sequence;p) a first nucleotide sequence comprising SEQ ID NO: 261-263, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 267-269 encoding a variable light chain sequence;q) a first nucleotide sequence comprising SEQ ID NO: 273-275, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 279-281 encoding a variable light chain sequence;r) a first nucleotide sequence comprising SEQ ID NO: 285-287, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 291-293 encoding a variable light chain sequence; ands) a first nucleotide sequence comprising SEQ ID NO: 297-299, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 303-305 encoding a variable light chain sequence.

10. The nucleic acid molecule(s) of claim 8, wherein the nucleic acid molecule(s) comprises nucleotide sequences selected from the group consisting of: a) a first nucleotide sequence comprising SEQ ID NO:2, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO:4 encoding a variable light chain sequence;b) a first nucleotide sequence comprising SEQ ID NO: 6, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO:8 encoding a variable light chain sequence;Attorney Docket No.206193-0150-P1USc) a first nucleotide sequence comprising SEQ ID NO: 10, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 12 encoding a variable light chain sequence;d) a first nucleotide sequence comprising SEQ ID NO: 14, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 16 encoding a variable light chain sequence;e) a first nucleotide sequence comprising SEQ ID NO: 18, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 20 encoding a variable light chain sequence;f) a first nucleotide sequence comprising SEQ ID NO:22, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 24 encoding a variable light chain sequence;g) a first nucleotide sequence comprising SEQ ID NO:26, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 28 encoding a variable light chain sequence;h) a first nucleotide sequence comprising SEQ ID NO:30, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO:32 encoding a variable light chain sequence;i) a first nucleotide sequence comprising SEQ ID NO:34, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO:36 encoding a variable light chain sequence;j) a first nucleotide sequence comprising SEQ ID NO:38, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO:40 encoding a variable light chain sequence;k) a first nucleotide sequence comprising SEQ ID NO:42, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO:44 encoding a variable light chain sequence;l) a first nucleotide sequence comprising SEQ ID NO:46, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO:48 encoding a variable light chain sequence;Attorney Docket No.206193-0150-P1USm) a first nucleotide sequence comprising SEQ ID NO:50, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 52 encoding a variable light chain sequence;n) a first nucleotide sequence comprising SEQ ID NO: 54, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO:56 encoding a variable light chain sequence;o) a first nucleotide sequence comprising SEQ ID NO: 58, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 60 encoding a variable light chain sequence;p) a first nucleotide sequence comprising SEQ ID NO:62, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 64 encoding a variable light chain sequence;q) a first nucleotide sequence comprising SEQ ID NO:66, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 68 encoding a variable light chain sequence;r) a first nucleotide sequence comprising SEQ ID NO:70, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO: 72 encoding a variable light chain sequence; ands) a first nucleotide sequence comprising SEQ ID NO:74, encoding a variable heavy chain sequence, and a second nucleotide sequence comprising SEQ ID NO:76 encoding a variable light chain sequence.

11. A composition comprising a Siglec-10 binding molecule of any one of claims 1-6.

12. The composition of claim 11, further comprising at least one selected form the group consisting of a pharmaceutically acceptable excipient and an adjuvant.

13. A composition comprising one or more nucleic acid molecule(s) encoding a Siglec-10 binding molecule of any one of claims 7-10.Attorney Docket No.206193-0150-P1US14. A method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering a Siglec-10 binding molecule of any one of claims 1-6, one or more nucleic acid molecules encoding a Siglec-10 binding molecule of any one of claims 7-10, or a composition of any one of claims 11-13 to the subject.

15. The method of claim 14, wherein the disease or disorder is a cancer, or a disease or disorder associated with cancer.

16. The method of claim 15, wherein the cancer is selected from pancreatic cancer and pancreatic ductal adenocarcinoma.

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