Anti-SEZ6L2 antibodies and antibody-drug conjugates

Abstract

To provide anti-SEZ6L2 antibodies and antibody-drug conjugates.SOLUTION: Disclosed herein are anti-seizure related 6 homolog like 2 (SEZ6L2) antibodies and antibody-drug conjugates (ADCs), including compositions and methods based on the antibodies and ADCs. In one aspect, the disclosure provides anti-human seizure related 6 homolog like 2 (anti-hSEZ6L2) antibodies, ADCs, or antigen binding fragments thereof that inhibit tumor growth in an in vivo human small-cell lung carcinoma (SCLC) xenograft assay with a tumor growth inhibition percent (TGI%) of at least about 50% relative to a human IgG antibody which is not specific for SEZ6L2, where the human IgG antibody is administered in the SCLC xenograft assay at the same dose and frequency as the anti-hSEZ6L2 antibodies, ADCs, or antigen binding fragments thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 438,943, filed December 23, 2016, the entire contents of which are expressly incorporated herein by reference in their entirety.

[0002] Sequence Listing This application has been submitted electronically in ASCII format and contains a Sequence Listing, which is hereby incorporated by reference in its entirety. The ASCII copy was created on December 22, 2017, has the file name 127913-00120_SL.txt, and is 133,786 bytes in size. [Background technology]

[0003] The seizure-related gene 6 (SEZ6) family has three members: SEZ6, SEZ6L, and SEZ6L2 (also known as Seizure Related 6 Homolog (Mouse)-Like 2 and Seizure 6-Like Protein 2). SEZ6L2 is a type 1 transmembrane glycoprotein of approximately 155 kDa, containing an N-terminal signal peptide, five SUSHI domains, three CUB domains, and a C-terminal transmembrane domain. SEZ6L2 shares approximately 41% sequence identity with the two other family members. Specifically, the SEZ6L2 gene was identified by screening a cDNA library after treatment with the seizure-inducing drug pentylentetrazole (Shimizu-Nishikawa K et al., 1995 Brain Res Mol Brain Res 28:201-210; Shimizu-Nishikawa K et al., 1995 Biochem Biophys Res Commun 216:382-389). SEZ6L2 exists in six isoforms produced by alternative splicing. The sequence identity between human SEZ6L2 and its mouse / rat and cynomolgus monkey homologs is 96% and 99%, respectively.

[0004] Although the normal physiological role of SEZ6L2 is not fully understood, mutations in genes in the SEZ6 family have been associated with febrile seizures, bipolar disorder, and possibly autism (Yu ZL et al., 2007 J Neurosci Res 85:166-172; Kumar RA et al., 2009 PLoS One 4:e4582; Mulley JC et al., 2011 Neurol Res Int 2011:917565; Konyukh M et al., 2011 PLoS One 6:e17289; Xu C, 2013 J Affect Disord 145:95-99). Mice lacking all three SEZ6 family members suffer from impaired coordination, cognitive deficits, and abnormal neuronal innervation (Miyazaki T et al., 2006 FEBS Lett 580:4057-4064). SEZ6 has also been suggested to modulate neuronal branching in mice (Gunnersen JM et al., 2007 Neuron 56:621-639).

[0005] In mouse neurons, SEZ6L2 has been shown to bind to the aspartic protease cathepsin D and promote its transport from the trans-Golgi network to endosomes (Boonen M et al., 2016 J Cell Sci 129:557-568). Cathepsin D has also been shown to be essential for normal neuronal function, as its mutations or mislocalization are closely associated with neurodegenerative diseases (Siintola E et al., 2006 Brain 129:1438-1445; Steinfeld R et al., 2006 Am J Hum Genet 78:988-998; Tyynela J et al., 2000 EMBO J 19:2786-2792). Furthermore, proteolytic cleavage of SEZ6L2 by cathepsin D has been shown to release a soluble N-terminal fragment that modulates neuronal differentiation (Boonen M et al., 2016 J Cell Sci 129:557-568). SEZ6L2 has also been identified as a substrate of BACE2 and BACE1, proteases known as sheddases, in pancreatic cells and primary neurons, respectively (Stutzer I, S et al., 2013 J Biol Chem 288:10536-10547; Hemming ML et al., 2009 PLoS One 4:e8477).

[0006] Several proteomic and transcriptomic databases suggest that SEZ6L2 is differentially upregulated in certain tumors. In addition, a study of primary lung cancer specimens by Ishikawa et al. (2006 Cancer Sci 97:737-745) found that SEZ6L2 was differentially expressed when comparing tumors with normal tissues. Ishikawa also found that 78% of non-small cell lung cancer (NSCLC) specimens and 65% of small cell lung cancer (SCLC) specimens were positive for SEZ6L2 expression.

[0007] Antibody drug conjugates (ADCs) represent a new class of therapeutic agents comprising antibodies conjugated to cytotoxic drugs via chemical linkers. The therapeutic concept of ADCs is to combine the binding capacity of antibodies with drugs, using antibodies to deliver the drugs to tumor cells by binding to target surface antigens. Therefore, there remains a need in the art for anti-SEZ6L2-specific antibodies and ADCs that can be used for therapeutic purposes in the treatment of cancer. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Shimizu-Nishikawa K et al., 1995, Brain Res Mol Brain Res 28:201-210 [Non-patent document 2] Shimizu-Nishikawa K et al., 1995, Biochem Biophys Res Commun 216:382-389 [Non-patent document 3] Yu ZL et al., 2007, J Neurosci Res 85:166-172 [Non-patent document 4] Kumar RA et al., 2009. PLoS One 4:e4582 [Non-patent document 5] Mulley JC et al. 2011 Neurol Res Int 2011:917565 [Non-patent document 6] Konyukh M et al. 2011 PLoS One 6: e17289 [Non-Patent Document 7] Xu C, 2013 J Affect Disord 145:95-99 [Non-patent document 8] Miyazaki T et al., 2006, FEBS Lett 580:4057-4064 Summary of the Invention [Means for solving the problem]

[0009] In certain aspects, the present disclosure provides anti-SEZ6L2 antibodies and antibody drug conjugates (ADCs).

[0010] In one aspect, the disclosure provides an anti-human stroke-associated 6 homolog-like 2 (anti-hSEZ6L2) antibody, ADC, or antigen-binding fragment thereof that inhibits tumor growth by at least about 50% tumor growth inhibition % (TGI%) compared to a human IgG antibody in an in vivo human small cell lung cancer (SCLC) xenograft assay in which a human IgG antibody that is not specific for SEZ6L2 is administered at the same dose and frequency as an anti-human stroke-associated 6 homolog-like 2 (anti-hSEZ6L2) antibody, ADC, or antigen-binding fragment thereof.

[0011] In yet another aspect of the disclosure, the antibody, ADC, or antigen-binding fragment thereof inhibits tumor growth by at least about 60% in an in vivo human SCLC xenograft assay compared to a human IgG antibody that is not specific for SEZ6L2. In certain embodiments, the disclosure features an antibody, ADC, or antigen-binding fragment thereof that inhibits tumor growth by at least about 70% in an in vivo human SCLC xenograft assay compared to a human IgG antibody that is not specific for SEZ6L2. In certain embodiments, the antibody, ADC, or antigen-binding fragment thereof inhibits tumor growth by at least about 80% in an in vivo human SCLC xenograft assay compared to a human IgG antibody that is not specific for SEZ6L2.

[0012] In certain embodiments of the present disclosure, the antibodies or antigen-binding portions thereof have a K between about 1 pM (0.001 nM) and 50 nM, about 500 pM (0.5 nM) and 20 nM, about 1 nM and 10 nM, or about 1 nM and 5 nM. d binds to huSEZ6L2.

[0013] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO:4 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO:8; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO:12 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO:16; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO:20 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO:24; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO:28 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO:31; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO:35 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO:39; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO:43 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO:46; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO:35 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO:50; a CDR3 having the amino acid sequence of SEQ ID NO:54 a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 3 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 58; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 62 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 66; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 70 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 72; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 76 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 78; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 87 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 89; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 93 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 95; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 99 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 103;A heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 107 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 89; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 112 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 58; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 70 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 119; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 236 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 238; or a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 242 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 245.

[0014] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR3 described herein, and a light chain variable region CDR3 described herein, wherein the heavy chain variable region comprises a CDR2 having the amino acid sequence of SEQ ID NO:3 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO:7; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO:11 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO:15; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO:19 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO:23; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO:27 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO:15; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO:34 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO:38; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO:42 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO:38; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO:34 a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 53 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 57; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 61 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 65; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 69 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 65; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 75 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 49; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 75 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 49; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 86 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 38; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 92 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 38;The heavy chain variable region may further comprise a CDR2 having the amino acid sequence of SEQ ID NO: 98 and a light chain variable region having a CDR2 having the amino acid sequence of SEQ ID NO: 102; a heavy chain variable region having a CDR2 having the amino acid sequence of SEQ ID NO: 106 and a light chain variable region having a CDR2 having the amino acid sequence of SEQ ID NO: 38; a heavy chain variable region having a CDR2 having the amino acid sequence of SEQ ID NO: 111 and a light chain variable region having a CDR2 having the amino acid sequence of SEQ ID NO: 57; a heavy chain variable region having a CDR2 having the amino acid sequence of SEQ ID NO: 69 and a light chain variable region having a CDR2 having the amino acid sequence of SEQ ID NO: 118; a heavy chain variable region having a CDR2 having the amino acid sequence of SEQ ID NO: 235 and a light chain variable region having a CDR2 having the amino acid sequence of SEQ ID NO: 38; or a heavy chain variable region having a CDR2 having the amino acid sequence of SEQ ID NO: 241 and a light chain variable region having a CDR2 having the amino acid sequence of SEQ ID NO: 38.

[0015] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR3 and CDR2 described herein, and a light chain variable region comprising a CDR3 and CDR2 described herein, and includes a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 2 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 10 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 14; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 18 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 22; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 26 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 30; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 33 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 37; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 41 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 45; a CDR1 having the amino acid sequence of SEQ ID NO: 33 a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 48; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 52 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 56; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 60 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 64; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 68 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 74 a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 80 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 48; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 85 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 37; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 91 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 37;A heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO:97 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO:101; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO:105 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO:37; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO:110 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO:114; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO:68 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO:117; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO:234 ​​and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO:37; or a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO:240 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO:244.

[0016] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 3, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 2, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 8, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 7, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 6.

[0017] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 12, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 11, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 10, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 16, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 15, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 14.

[0018] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 20, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 19, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 18, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 24, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 23, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 22.

[0019] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 28, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 27, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 26, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 31, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 15, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 30.

[0020] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 39, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37.

[0021] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 43, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 42, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 41, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 46, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 45.

[0022] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 50, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 49, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 48.

[0023] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 54, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 53, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 52, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 58, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 57, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 56.

[0024] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 62, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 61, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 60, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 66, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 65, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 64.

[0025] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 69, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 68, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 72, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 65, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 64.

[0026] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 76, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 75, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 74, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 78, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 49, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 48.

[0027] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 81, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 75, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 80, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 83, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 49, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 48.

[0028] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 87, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 86, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 85, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 89, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37.

[0029] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 93, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 92, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 91, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 95, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37.

[0030] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 99, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 98, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 97, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 103, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 102, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 101.

[0031] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 107, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 106, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 105, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 89, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37.

[0032] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 112, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 111, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 110, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 58, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 57, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 114.

[0033] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 69, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 68, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 119, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 118, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 117.

[0034] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 236, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 235, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 234, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 238, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37.

[0035] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 242, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 241, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 240, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 245, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 244.

[0036] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:1, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:5.

[0037] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:13.

[0038] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:17, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:21.

[0039] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:25, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:29.

[0040] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:32, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:36.

[0041] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:40, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:44.

[0042] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:32, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:47.

[0043] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:51, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:55.

[0044] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:59, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:63.

[0045] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:67, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:71.

[0046] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:73, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:77.

[0047] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:79 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:82.

[0048] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:84 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:88.

[0049] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:90, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:94.

[0050] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:96 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:100.

[0051] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:104 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:108.

[0052] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:109 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:113.

[0053] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:115, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:116.

[0054] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:233 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:237.

[0055] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:239 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:243.

[0056] In some embodiments, the present disclosure provides antibodies, or antigen-binding portions thereof, that bind to the same epitope as antibodies, or antigen-binding portions thereof, such as those described herein.

[0057] In other embodiments, the antibody or antigen-binding portion thereof does not bind to SEZ6 or SEZ6L.

[0058] In one embodiment, the antibody or antigen-binding portion thereof is a bispecific or multispecific antibody.

[0059] The present disclosure also provides, in certain embodiments, isolated nucleic acids encoding the antibodies or antigen-binding portions thereof of the present disclosure.

[0060] In some embodiments of the present disclosure, the antibody or antigen-binding portion thereof comprises a heavy chain immunoglobulin constant domain selected from the group consisting of a human IgG constant domain, a human IgM constant domain, a human IgE constant domain, and a human IgA constant domain. In some embodiments, the IgG constant domain is selected from the group consisting of an IgG1 constant domain, an IgG2 constant domain, an IgG3 constant domain, and an IgG4 constant domain. In other embodiments, the antibody is a multispecific antibody.

[0061] In other embodiments of the disclosure, the antibodies or antigen-binding portions thereof include Fab, Fab', F(ab')2, Fv, disulfide-linked Fv, scFv, single domain antibodies, and diabodies.

[0062] In other embodiments, the present disclosure provides a pharmaceutical composition comprising an antibody or antigen-binding portion thereof as described herein and a pharmaceutically acceptable carrier.

[0063] In other embodiments, the present disclosure provides an antibody, or antigen-binding portion thereof, as described herein, conjugated to at least one drug.

[0064] In some embodiments, the at least one drug is selected from the group consisting of anti-apoptotic agents, antimitotic agents, antitumor antibiotics, immunomodulatory agents, nucleic acids for gene therapy, antiangiogenic agents, antimetabolites, boron-containing agents, chemoprotective agents, hormones, antihormones, corticosteroids, photoactive therapeutic agents, oligonucleotides, radionuclides, radiosensitizers, topoisomerase inhibitors, and tyrosine kinase inhibitors. In one embodiment, the antitumor antibiotic is a pyrrolobenzodiazepine (PBD).

[0065] In other embodiments, the at least one drug is selected from the group consisting of an auristatin, a maytansinoid, and a DNA alkylating agent. In one embodiment, the auristatin is monomethylauristatin E (MMAE). In another embodiment, the maytansinoid is 4-methyl-4-mercapto-1-oxopentyl)-maytansine (DM4). In another embodiment, the DNA alkylating agent is an indolino-benzodiazepine (IGN). In one embodiment, the at least one drug is a pyrrolobenzodiazepine (PBD).

[0066] In some embodiments, the at least one drug is conjugated to the antibody or antigen-binding portion thereof via a linker, such as a cleavable linker or a non-cleavable linker.

[0067] In some embodiments, the auristatin is monomethylauristatin E (MMAE) and the linker is maleimido-caproyl-valine-citrulline (MC-VC). In some embodiments, the maytansinoid is 4-methyl-4-mercapto-1-oxopentyl)-maytansine (DM4) and the linker is D-Ala-L-dpa or sSPDB. In some embodiments, the DNA alkylating agent is indolino-benzodiazepine (IGN) and the linker is D-Ala-L-dpa.

[0068] In other aspects, the present disclosure provides antibody drug conjugates (ADCs) comprising an antibody, or antigen-binding portion thereof, conjugated to at least one drug, e.g., a pyrrolobenzodiazepine (PBD), an auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO:4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:3, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:2, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO:8, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:7, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:6.

[0069] In other aspects, the present disclosure provides antibody drug conjugates (ADCs) comprising an antibody, or antigen-binding portion thereof, conjugated to at least one drug, e.g., a pyrrolobenzodiazepine (PBD), an auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 12, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 11, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 10, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 16, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 15, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 14.

[0070] In other aspects, the present disclosure provides antibody drug conjugates (ADCs) comprising an antibody, or antigen-binding portion thereof, conjugated to at least one drug, e.g., a pyrrolobenzodiazepine (PBD), an auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 20, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 19, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 18, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 24, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 23, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 22.

[0071] In other aspects, the present disclosure provides antibody drug conjugates (ADCs) comprising an antibody, or antigen-binding portion thereof, conjugated to at least one drug, e.g., a pyrrolobenzodiazepine (PBD), an auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO:28, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:27, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:26, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO:31, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:15, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:30.

[0072] In other aspects, the present disclosure provides antibody drug conjugates (ADCs) comprising an antibody, or antigen-binding portion thereof, conjugated to at least one drug, e.g., a pyrrolobenzodiazepine (PBD), an auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 39, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37.

[0073] In other aspects, the present disclosure provides antibody drug conjugates (ADCs) comprising an antibody, or antigen-binding portion thereof, conjugated to at least one drug, e.g., a pyrrolobenzodiazepine (PBD), an auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 43, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 42, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 41, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 46, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 45.

[0074] In other aspects, the present disclosure provides antibody drug conjugates (ADCs) comprising an antibody, or antigen-binding portion thereof, conjugated to at least one drug, e.g., a pyrrolobenzodiazepine (PBD), an auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 50, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 49, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 48.

[0075] In other aspects, the present disclosure provides antibody drug conjugates (ADCs) comprising an antibody, or antigen-binding portion thereof, conjugated to at least one drug, e.g., a pyrrolobenzodiazepine (PBD), an auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 54, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 53, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 52, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 58, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 57, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 56.

[0076] In other aspects, the present disclosure provides antibody drug conjugates (ADCs) comprising an antibody, or antigen-binding portion thereof, conjugated to at least one drug, e.g., a pyrrolobenzodiazepine (PBD), an auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 62, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 61, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 60, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 66, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 65, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 64.

[0077] In other aspects, the present disclosure provides antibody drug conjugates (ADCs) comprising an antibody, or antigen-binding portion thereof, conjugated to at least one drug, e.g., a pyrrolobenzodiazepine (PBD), an auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 69, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 68, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 72, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 65, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 64.

[0078] In other aspects, the present disclosure provides antibody drug conjugates (ADCs) comprising an antibody, or antigen-binding portion thereof, conjugated to at least one drug, e.g., a pyrrolobenzodiazepine (PBD), an auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 76, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 75, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 74, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 78, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 49, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 48.

[0079] In other aspects, the present disclosure provides antibody drug conjugates (ADCs) comprising an antibody, or antigen-binding portion thereof, conjugated to at least one drug, e.g., a pyrrolobenzodiazepine (PBD), an auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 81, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 75, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 80, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 83, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 49, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 48.

[0080] In other aspects, the present disclosure provides antibody drug conjugates (ADCs) comprising an antibody, or antigen-binding portion thereof, conjugated to at least one drug, e.g., a pyrrolobenzodiazepine (PBD), an auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 87, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 86, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 85, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 89, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37.

[0081] In other aspects, the present disclosure provides antibody drug conjugates (ADCs) comprising an antibody, or antigen-binding portion thereof, conjugated to at least one drug, e.g., a pyrrolobenzodiazepine (PBD), an auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 93, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 92, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 91, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 95, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37.

[0082] In other aspects, the present disclosure provides antibody drug conjugates (ADCs) comprising an antibody, or antigen-binding portion thereof, conjugated to at least one drug, e.g., a pyrrolobenzodiazepine (PBD), an auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 99, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 98, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 97, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 103, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 102, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 101.

[0083] In other aspects, the present disclosure provides antibody drug conjugates (ADCs) comprising an antibody, or antigen-binding portion thereof, conjugated to at least one drug, e.g., a pyrrolobenzodiazepine (PBD), an auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 107, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 106, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 105, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 89, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37.

[0084] In other aspects, the present disclosure provides antibody drug conjugates (ADCs) comprising an antibody, or antigen-binding portion thereof, conjugated to at least one drug, e.g., a pyrrolobenzodiazepine (PBD), an auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 112, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 111, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 110, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 58, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 57, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 114.

[0085] In other aspects, the present disclosure provides antibody drug conjugates (ADCs) comprising an antibody, or antigen-binding portion thereof, conjugated to at least one drug, e.g., a pyrrolobenzodiazepine (PBD), an auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 69, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 68, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 119, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 118, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 117.

[0086] In other aspects, the present disclosure provides antibody drug conjugates (ADCs) comprising an antibody, or antigen-binding portion thereof, conjugated to at least one drug, e.g., a pyrrolobenzodiazepine (PBD), an auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 236, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 235, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 234, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 238, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37.

[0087] In other aspects, the disclosure provides antibody drug conjugates (ADCs) comprising an antibody, or antigen-binding portion thereof, conjugated to at least one drug, e.g., a pyrrolobenzodiazepine (PBD), an auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 242, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 241, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 240, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 245, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 244.

[0088] In other embodiments, the antibody or antigen-binding portion thereof of the ADC comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:1, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:5.

[0089] In other embodiments, the antibody or antigen-binding portion thereof of the ADC comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:13.

[0090] In other embodiments, the antibody or antigen-binding portion thereof of the ADC comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:17, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:21.

[0091] In other embodiments, the antibody or antigen-binding portion thereof of the ADC comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:25, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:29.

[0092] In other embodiments, the antibody or antigen-binding portion thereof of the ADC comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:32, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:36.

[0093] In other embodiments, the antibody or antigen-binding portion thereof of the ADC comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:40, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:44.

[0094] In other embodiments, the antibody or antigen-binding portion thereof of the ADC comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:32 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:47.

[0095] In other embodiments, the antibody or antigen-binding portion thereof of the ADC comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:51, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:55.

[0096] In other embodiments, the antibody or antigen-binding portion thereof of the ADC comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:59 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:63.

[0097] In other embodiments, the antibody or antigen-binding portion thereof of the ADC comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:67 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:71.

[0098] In other embodiments, the antibody or antigen-binding portion thereof of the ADC comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:73, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:77.

[0099] In other embodiments, the antibody or antigen-binding portion thereof of the ADC comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:79 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:82.

[0100] In other embodiments, the antibody or antigen-binding portion thereof of the ADC comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:84 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:88.

[0101] In other embodiments, the antibody or antigen-binding portion thereof of the ADC comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:90 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:94.

[0102] In other embodiments, the antibody or antigen-binding portion thereof of the ADC comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:96 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:100.

[0103] In other embodiments, the antibody or antigen-binding portion thereof of the ADC comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:104 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:108.

[0104] In other embodiments, the antibody or antigen-binding portion thereof of the ADC comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:109 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:113.

[0105] In other embodiments, the antibody or antigen-binding portion thereof of the ADC comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:115, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:116.

[0106] In other embodiments, the antibody or antigen-binding portion thereof of the ADC comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:233 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:237.

[0107] In other embodiments, the antibody or antigen-binding portion thereof of the ADC comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:239 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:243.

[0108] In one embodiment, the ADC comprises an auristatin, wherein the auristatin is monomethylauristatin E (MMAE). In another embodiment, the ADC comprises a maytansinoid, wherein the maytansinoid is 4-methyl-4-mercapto-1-oxopentyl)-maytansine (DM4). In another embodiment, the ADC comprises a DNA alkylating agent, wherein the DNA alkylating agent is an indolino-benzodiazepine (IGN). In one embodiment, the ADC comprises a pyrrolobenzodiazepine (PBD).

[0109] In some embodiments, the at least one drug is conjugated to the antibody or antigen-binding portion thereof via a linker, such as a cleavable linker or a non-cleavable linker.

[0110] In some embodiments, the auristatin is monomethylauristatin E (MMAE) and the linker is maleimido-caproyl-valine-citrulline (MC-VC). In some embodiments, the maytansinoid is 4-methyl-4-mercapto-1-oxopentyl)-maytansine (DM4) and the linker is D-Ala-L-dpa or sSPDB. In some embodiments, the DNA alkylating agent is indolino-benzodiazepine (IGN) and the linker is D-Ala-L-dpa.

[0111] In one embodiment, the disclosure provides a pharmaceutical composition comprising an ADC mixture comprising a plurality of ADCs of the disclosure and a pharmaceutically acceptable carrier.

[0112] In some embodiments, the ADC mixture has an average drug-to-antibody ratio (DAR) of 1-8.

[0113] In another aspect, the present disclosure provides a method for treating a subject having a SEZ6L2-associated disorder, comprising administering an effective amount of an ADC comprising an anti-SEZ6L2 antibody or antigen-binding portion thereof conjugated to at least one drug, e.g., a pyrrolobenzodiazepine (PBD), a maytansinoid, or at least one DNA alkylating agent, wherein the anti-SEZ6L2 antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 3, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 2, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 8, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 7, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 6; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 12, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 11, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 10, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 16, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 15, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 14; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 20, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 19, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 18, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 24, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 23, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 22; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 28, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 27, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 26, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 31, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 15, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 30; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 39, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 43, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 42, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 41, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 46, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 45; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 50, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 49, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 48; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 54, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 53, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 52, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 58, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 57, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 56; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 62, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 61, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 60, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 66, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 65, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 64; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 69, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 68, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 72, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 65, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 64; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 76, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 75, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 74, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 78, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 49, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 48; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 81, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 75, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 80, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 83, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 49, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 48; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 87, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 86, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 85, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 89, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 93, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 92, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 91, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 95, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 99, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 98, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 97, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 103, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 102, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 101; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 107, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 106, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 105, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 89, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 112, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 111, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 110, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 58, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 57, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 114; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 69, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 68, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 119, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 118, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 117; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 236, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 235, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 234, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 238, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37; or a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 242, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 241, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 240; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 245, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 244. Includes:

[0114] In one embodiment, the SEZ6L2-related disease is cancer, such as small cell lung cancer, prostate cancer, such as castration-resistant prostate cancer, and neuroendocrine tumors. In another embodiment, the cancer is characterized as exhibiting SEZ6L2 overexpression.

[0115] In another aspect, the disclosure provides a method for treating a subject having a SEZ6L2-associated disorder, the method comprising administering a therapeutically effective amount of an ADC of the disclosure to a subject in need thereof.

[0116] In another aspect, the disclosure provides a method for inhibiting or reducing solid tumor growth in a subject having a solid tumor, the method comprising administering an effective amount of an ADC of the disclosure to the subject having the solid tumor, such that the solid tumor growth is inhibited or reduced.

[0117] In one embodiment, the solid tumor is small cell lung cancer. In another embodiment, the solid tumor is a prostate tumor. In another embodiment, the solid tumor is a neuroendocrine tumor. In one embodiment, the solid tumor is characterized as exhibiting SEZ6L2 overexpression.

[0118] In one embodiment, the ADC is administered in combination with an additional agent or therapy, e.g., radiation or a chemotherapeutic agent. In one embodiment, the additional therapy is a PARP inhibitor, e.g., olaparib, rucaparib, niraparib, or iniparib. In an embodiment of the present invention, for example, the following items are provided: (Item 1) An anti-human stroke-associated 6 homolog-like 2 (anti-hSEZ6L2) antibody or an antigen-binding portion thereof, a) inhibits tumor growth in an in vivo human small cell lung cancer (SCLC) xenograft assay by at least about 50% tumor growth inhibition % (TGI%) compared to a human IgG antibody that is not specific for SEZ6L2, wherein the human IgG antibody is administered at the same dose and frequency as the anti-hSEZ6L2 antibody or antigen-binding portion thereof in the SCLC xenograft assay; and b) does not bind to SEZ6 or SEZ6L An antibody or antigen-binding portion thereof. (Item 2) a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 4 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 8; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 12 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 16; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 20 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 24; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 28 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 31; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 35 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 39; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 43 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 46; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 35 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 50; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 54 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 58; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 62 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 66; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 70 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 72; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 76 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 78; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 81 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 83; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 87 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 89; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 93 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 95; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 99 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 103; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 107 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 89; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 112 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 58; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 70 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 119; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 236 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 238; or A heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 242 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 245 An isolated anti-SEZ6L2 antibody or an antigen-binding portion thereof, comprising: (Item 3) a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 4 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 8; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 12 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 16; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 20 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 24; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 28 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 31; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 35 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 39; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 43 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 46; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 35 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 50; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 54 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 58; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 62 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 66; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 70 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 72; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 76 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 78; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 81 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 83; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 87 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 89; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 93 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 95; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 99 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 103; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 107 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 89; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 112 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 58; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 70 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 119; a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 236 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 238; or A heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 242 and a light chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 245 2. The isolated antibody or antigen-binding portion thereof of item 1, comprising: (Item 4) a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 3 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 7; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 11 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 15; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 19 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 23; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 27 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 15; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 34 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 38; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 42 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 38; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 34 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 49; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 53 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 57; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 61 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 65; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 69 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 65; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 75 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 49; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 75 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 49; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 86 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 38; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 92 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 38; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 98 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 102; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 106 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 38; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 111 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 57; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 69 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 118; a heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 235 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 38; or A heavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 241 and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 38 4. The antibody or antigen-binding portion thereof according to item 2 or 3, comprising: (Item 5) a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 2 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 10 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 14; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 18 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 22; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 26 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 30; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 33 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 37; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 41 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 45; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 33 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 48; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 52 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 56; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 60 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 64; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 68 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 64; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 74 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 48; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 80 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 48; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 85 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 37; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 91 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 37; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 97 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 101; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 105 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 37; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 110 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 114; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 68 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 117; a heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 234 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 37; or A heavy chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 240 and a light chain variable region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 244 5. The antibody or antigen-binding portion thereof according to any one of items 2 to 4, comprising: (Item 6) a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 3, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 2, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 8, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 7, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 6; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 12, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 11, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 10, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 16, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 15, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 14; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 20, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 19, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 18, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 24, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 23, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 22; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 28, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 27, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 26, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 31, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 15, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 30; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 39, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 43, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 42, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 41, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 46, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 45; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 50, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 49, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 48; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 54, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 53, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 52, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 58, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 57, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 56; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 62, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 61, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 60, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 66, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 65, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 64; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 69, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 68, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 72, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 65, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 64; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 76, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 75, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 74, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 78, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 49, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 48; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 81, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 75, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 80, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 83, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 49, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 48; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 87, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 86, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 85, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 89, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 93, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 92, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 91, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 95, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 99, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 98, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 97, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 103, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 102, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 101; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 107, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 106, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 105, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 89, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 112, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 111, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 110, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 58, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 57, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 114; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 69, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 68, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 119, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 118, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 117; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 236, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 235, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 234, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 238, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37; or a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 242, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 241, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 240; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 245, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 244. 6. The antibody or antigen-binding portion thereof according to any one of items 1 to 5, comprising: (Item 7) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 5; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 13; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 17, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 21; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 25, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 29; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 32, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 40, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 44; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 32, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 47; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 51, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 55; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 59, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 63; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 67, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 71; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 73, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 79, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 82; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 84, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 88; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 90, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 94; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 96, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 100; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 104, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 108; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 109, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 113; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 115, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 116; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 233, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 237; or A heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 239, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 243. 7. The antibody or antigen-binding portion thereof according to any one of items 1 to 6, comprising: (Item 8) An antibody or antigen-binding portion thereof that binds to the same epitope as the antibody or antigen-binding portion thereof according to any one of items 1 to 7. (Item 9) 9. The antibody or antigen-binding portion thereof according to any one of items 1 to 8, which does not bind to SEZ6 or SEZ6L. (Item 10) 10. An isolated nucleic acid encoding the antibody or antigen-binding portion thereof according to any one of items 1 to 9. (Item 11) 10. A pharmaceutical composition comprising the antibody or antigen-binding portion thereof according to any one of items 1 to 9 and a pharmaceutically acceptable carrier. (Item 12) 10. The antibody or antigen-binding portion thereof according to any one of items 1 to 9, conjugated to at least one drug. (Item 13) 13. The antibody or antigen-binding portion thereof of item 12, wherein the at least one drug is selected from the group consisting of anti-apoptotic agents, antimitotic agents, antitumor antibiotics, immunomodulatory agents, nucleic acids for gene therapy, anti-angiogenic agents, antimetabolites, boron-containing agents, chemoprotective agents, hormonal agents, antihormonal agents, corticosteroids, photoactive therapeutic agents, oligonucleotides, radionuclide agents, radiosensitizers, topoisomerase inhibitors, and tyrosine kinase inhibitors. (Item 14) 13. The antibody or antigen-binding portion thereof of item 12, wherein the at least one drug is selected from the group consisting of an auristatin, a maytansinoid, a DNA alkylating agent, and a pyrrolobenzodiazepine (PBD). (Item 15) 15. The antibody or antigen-binding portion thereof of item 14, wherein the auristatin is monomethyl auristatin E (MMAE). (Item 16) 15. The antibody or antigen-binding portion thereof of item 14, wherein the maytansinoid is 4-methyl-4-mercapto-1-oxopentyl)-maytansine (DM4). (Item 17) 15. The antibody or antigen-binding portion thereof of item 14, wherein the DNA alkylating agent is an indolino-benzodiazepine (IGN). (Item 18) 13. The antibody or antigen-binding portion thereof of claim 12, wherein the at least one drug is conjugated to the antibody or antigen-binding portion thereof via a linker. (Item 19) 19. The antibody or antigen-binding portion thereof of item 18, wherein the linker is a cleavable linker. (Item 20) 19. The antibody or antigen-binding portion thereof of item 18, wherein the linker is a non-cleavable linker. (Item 21) 19. The antibody or antigen-binding portion thereof of item 18, wherein the auristatin is monomethylauristatin E (MMAE) and the linker is maleimido-caproyl-valine-citrulline (MC-VC). (Item 22) 19. The antibody or antigen-binding portion thereof of item 18, wherein the drug is 4-methyl-4-mercapto-1-oxopentyl)-maytansine (DM4) and the linker is D-Ala-L-dpa or sSPDB. (Item 23) 19. The antibody or antigen-binding portion thereof of item 18, wherein the drug is an indolino-benzodiazepine (IGN) and the linker is D-Ala-L-dpa. (Item 24) An antibody drug conjugate (ADC) comprising an antibody or antigen-binding portion thereof conjugated to at least one drug, wherein the antibody or antigen-binding portion thereof is: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 3, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 2, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 8, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 7, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 6; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 12, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 11, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 10, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 16, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 15, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 14; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 20, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 19, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 18, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 24, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 23, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 22; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 28, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 27, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 26, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 31, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 15, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 30; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 39, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 43, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 42, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 41, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 46, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 45; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 50, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 49, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 48; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 54, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 53, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 52, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 58, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 57, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 56; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 62, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 61, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 60, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 66, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 65, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 64; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 69, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 68, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 72, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 65, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 64; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 76, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 75, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 74, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 78, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 49, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 48; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 81, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 75, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 80, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 83, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 49, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 48; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 87, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 86, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 85, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 89, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 93, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 92, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 91, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 95, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 99, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 98, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 97, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 103, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 102, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 101; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 107, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 106, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 105, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 89, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 112, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 111, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 110, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 58, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 57, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 114; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 69, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 68, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 119, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 118, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 117; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 236, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 235, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 234, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 238, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37; or a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 242, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 241, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 240; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 245, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 244. An antibody drug conjugate (ADC) comprising: (Item 25) the antibody or antigen-binding portion thereof, a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 5; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 13; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 17, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 21; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 25, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 29; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 32, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 40, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 44; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 32, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 47; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 51, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 55; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 59, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 63; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 67, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 71; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 73, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 79, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 82; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 84, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 88; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 90, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 94; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 96, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 100; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 104, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 108; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 109, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 113; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 115, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 116; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 233, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 237; or A heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 239, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 243. 25. The ADC according to item 24, comprising: (Item 26) 26. The ADC of item 24 or 25, wherein the drug is an auristatin, at least one maytansinoid, or at least one DNA alkylating agent. (Item 27) 27. The ADC of item 26, wherein the maytansinoid is 4-methyl-4-mercapto-1-oxopentyl-maytansine (DM4) and the auristatin is monomethylauristatin E (MMAE). (Item 28) 27. The ADC of item 26, wherein the DNA alkylating agent is an indolino-benzodiazepine (IGN). (Item 29) 29. The ADC of any one of items 24 to 28, wherein the at least one drug is conjugated via a linker. (Item 30) 30. The ADC of item 29, wherein the linker is a cleavable linker. (Item 31) 30. The ADC of item 29, wherein the linker is a non-cleavable linker. (Item 32) 30. The ADC of item 29, wherein the drug is monomethyl auristatin E (MMAE) and the linker is maleimido-caproyl-valine-citrulline (MC-VC). (Item 33) 30. The ADC of item 29, wherein the drug is 4-methyl-4-mercapto-1-oxopentyl)-maytansine (DM4) and the linker is D-Ala-L-dpa or sSPDB. (Item 34) 30. The ADC of item 29, wherein the drug is an indolino-benzodiazepine (IGN) and the linker is D-Ala-L-dpa. (Item 35) 35. The ADC of any one of Items 24 to 34, wherein the antibody or antigen-binding portion thereof is of the IgG1 isotype. (Item 36) A pharmaceutical composition comprising an ADC mixture comprising a plurality of ADCs according to any one of items 24 to 35 and a pharmaceutically acceptable carrier. (Item 37) 37. The pharmaceutical composition of item 36, wherein the ADC mixture has an average drug-to-antibody ratio (DAR) of 0 to 8. (Item 38) A method for treating a subject having a SEZ6L2-associated disorder, comprising administering an effective amount of an ADC comprising an anti-SEZ6L2 antibody or an antigen-binding portion thereof conjugated to at least one drug, wherein the anti-SEZ6L2 antibody or antigen-binding portion thereof: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 3, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 2, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 8, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 7, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 6; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 12, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 11, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 10, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 16, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 15, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 14; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 20, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 19, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 18, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 24, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 23, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 22; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 28, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 27, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 26, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 31, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 15, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 30; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 39, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 43, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 42, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 41, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 46, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 45; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 50, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 49, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 48; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 54, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 53, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 52, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 58, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 57, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 56; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 62, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 61, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 60, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 66, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 65, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 64; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 69, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 68, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 72, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 65, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 64; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 76, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 75, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 74, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 78, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 49, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 48; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 81, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 75, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 80, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 83, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 49, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 48; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 87, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 86, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 85, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 89, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 93, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 92, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 91, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 95, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 99, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 98, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 97, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 103, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 102, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 101; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 107, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 106, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 105, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 89, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 112, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 111, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 110, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 58, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 57, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 114; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 69, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 68, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 119, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 118, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 117; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 236, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 235, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 234, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 238, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37; or a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 242, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 241, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 240; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 245, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 244. A method comprising: (Item 39) 39. The method of claim 38, wherein the SEZ6L2-associated disease is cancer. (Item 40) 40. The method of claim 39, wherein the cancer is selected from the group consisting of small cell lung cancer, prostate cancer, and neuroendocrine tumors. (Item 41) Item 42. The method of item 40, wherein the cancer is characterized as exhibiting SEZ6L2 overexpression. 42. The method of any one of items 38 to 41, wherein the drug is an auristatin, a maytansinoid, a DNA alkylating agent, or a pyrrolobenzodiazepine (PBD). (Item 43) 43. The method of claim 42, wherein the maytansinoid is 4-methyl-4-mercapto-1-oxopentyl)-maytansine (DM4) or the auristatin is monomethylauristatin E (MMAE). (Item 44) 43. The method of claim 42, wherein the DNA alkylating agent is an indolino-benzodiazepine (IGN). (Item 45) A method for treating a subject having a SEZ6L2-associated disorder, the method comprising administering a therapeutically effective amount of the ADC described in any one of items 24 to 35 to a subject in need thereof. (Item 46) Item 46. The method of item 45, wherein the SEZ6L2-associated disease is cancer. (Item 47) Item 47. The method of item 46, wherein the cancer is small cell lung cancer. (Item 48) Item 47. The method of item 46, wherein the cancer is prostate cancer. (Item 49) 47. The method of claim 46, wherein the cancer is a neuroendocrine tumor. (Item 50) A method for inhibiting or reducing solid tumor growth in a subject having a solid tumor, the method comprising administering an effective amount of the ADC described in any one of Items 24 to 35 to the subject having the solid tumor, such that the solid tumor growth is inhibited or reduced. (Item 51) 51. The method of claim 50, wherein the solid tumor is small cell lung cancer. (Item 52) 51. The method of claim 50, wherein the solid tumor is a prostate tumor. (Item 53) 51. The method of claim 50, wherein the solid tumor is a neuroendocrine tumor. (Item 54) 54. The method of any one of items 38 to 53, wherein the ADC is administered in combination with an additional agent or therapy. (Item 55) 55. The method of claim 54, wherein the additional therapy is radiation. (Item 56) 55. The method of claim 54, wherein the additional agent is a chemotherapeutic agent. (Item 57) 55. The method of claim 54, wherein the additional agent is a PARP inhibitor. (Item 58) 54. The method of any one of items 50 to 53, wherein the solid tumor is characterized as exhibiting SEZ6L2 overexpression. (Item 59) A method for treating castration-resistant prostate cancer (CRPC) in a subject, comprising administering a therapeutically effective amount of an anti-SEZ6L2 antibody or an antigen-binding portion thereof to a subject in need thereof. (Item 60) Item 61. The method of Item 59, wherein the antibody or antigen-binding portion thereof is an IgG1 antibody. 61. The method of claim 59 or 60, wherein the antibody or antigen-binding portion thereof does not bind to SEZ6 or SEZ6L. (Item 62) the isolated antibody or antigen-binding portion thereof, a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 3, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 2, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 8, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 7, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 6; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 12, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 11, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 10, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 16, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 15, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 14; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 20, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 19, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 18, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 24, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 23, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 22; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 28, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 27, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 26, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 31, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 15, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 30; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 39, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 43, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 42, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 41, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 46, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 45; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 50, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 49, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 48; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 54, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 53, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 52, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 58, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 57, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 56; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 62, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 61, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 60, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 66, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 65, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 64; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 69, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 68, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 72, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 65, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 64; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 76, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 75, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 74, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 78, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 49, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 48; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 81, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 75, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 80, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 83, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 49, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 48; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 87, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 86, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 85, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 89, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 93, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 92, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 91, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 95, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 99, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 98, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 97, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 103, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 102, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 101; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 107, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 106, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 105, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 89, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 112, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 111, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 110, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 58, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 57, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 114; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 69, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 68, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 119, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 118, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 117; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 236, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 235, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 234, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 238, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37; or a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 242, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 241, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 240; and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 245, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 244. 62. The method according to any one of Items 59 to 61, comprising: (Item 63) 63. The method of any one of items 59 to 62, wherein the anti-SEZ6L2 antibody or antigen-binding portion thereof is conjugated to at least one drug. (Item 64) 63. The method of any one of items 59 to 62, wherein the anti-SEZ6L2 antibody or antigen-binding portion thereof is administered in combination with an additional agent or therapy. [Brief explanation of the drawings]

[0119] [Figure 1] Figures 1A-1B show that anti-SEZ6L2 antibodies demonstrate in vitro ADC efficacy in SCLC cell lines. NCI-H524 cells were treated with 10 ng / ml of anti-SEZ6L2 monoclonal antibody alone (black bars) or in combination with a mouse Fab-ZAP secondary antibody (gray bars; 0.4 μg / ml). After 3 days, the percentage of viable cells was quantified and compared with a positive control (anti-transferrin receptor antibody (TR) (Figure 1A) or human antibody 1A1 (Figure 1B)) and a negative control (mouse IgG (mIgG) (Figure 1A) or non-binding antibody 3B5 (Figure 1B)). FIG. 1A shows the results for murine antibodies 2E4, 3E2, 16H8, and 20C4, and FIG. 1B shows the results for human antibodies 1A1, 3A1, 3A2, 3A3, 3A4, 3B1, 3B2, 3B3, 3B6, and humanized antibodies 2E4, 3E2, 16H8, and 20C4.

[0120] [Figure 2]Figures 2A-2B show that the anti-SEZ6L2 antibody demonstrates in vivo ADC efficacy in an SCLC cell tumor model. NCI-H524 cell-derived tumors were grown subcutaneously in the flanks of nude mice. When tumor volumes reached 250 mm3, mice were randomly assigned to treatment groups and intraperitoneally injected with either the murine parental clone mu16H8 conjugated to MMAE (mu16H8-MMAE), the humanized progeny of mu16H8 (16H8) conjugated to MMAE (16H8-MMAE), naked 16H8, a murine IgG control conjugated to MMAE (mIgG-MMAE), or PBS alone. Mice received four 5 mg / kg injections over a 10-day period and were sacrificed when tumors reached 1200 mm3 or became pathological. FIG. 2A shows the ability of conjugated SEZ6L2 antibodies to delay the in vivo growth of SCLC tumors, and FIG. 2B shows the increased survival of mice treated with conjugated anti-SEZ6L2 antibodies.

[0121] [Figure 3] Figures 3A-3F show that SEZ6L2 ADC modulators mediate cytotoxic drug delivery in SCLC and prostate cancer cell lines. Antibodies 3E2 and 1A1 conjugated to pyrrolobenzodiazepines (PBDs) were tested for their effects on small cell lung cancer and prostate cancer cell lines. Results are shown for the small cell lung cancer cell lines H524 (Figure 3A), DMS79 (Figure 3B), H209 (Figure 3C), and H1048 (Figure 3D), and the prostate adenocarcinoma cell lines LNCaP (Figure 3E), and 22Rv1 (Figure 3F). As shown in Figures 3A-3F, treatment of cells with anti-SEZ6L2 ADCs resulted in an increased reduction in the percent viable cells in some cell lines compared to control hIgG. Although hIgG IgG-PBD can be cytotoxic to cells at high concentrations, the anti-SEZ6L2 ADC tested was more potent, indicating an immunospecific response to SEZ6L2 rather than a general response to the PBD cytotoxin.

[0122] [Figure 4] Figures 4A-4B show that SEZ6L2 ADC modulators suppress tumor growth in vivo. Figure 4A is a graph showing that MMAE-conjugated anti-SEZ6L2 antibodies 3E2 and 3A1 suppress NCI-H524 tumor growth in mice compared to vehicle or isotype control. Figure 4B is a Kaplan-Meier survival curve showing increased antigen-specific survival.

[0123] [Figure 5ABCD] Figures 5A-5M show detection of SEZ6L2 surface expression in engineered HEK-293 cells. Figures 5A-5L show flow cytometry results to assess whether SEZ6L2 antibody modulators immunospecifically associate with human SEZ6L2 and whether the same modulators cross-react with SEZ6 and SEZ6L. More specifically, antibodies disclosed herein were tested for cross-reactivity against cell lines overexpressing the human homologs of SEZ6 (293-SEZ6), SEZ6L (293-SEZ6L), and SEZ6L2 (293-SEZ6L2). The right-hand graphs in Figures 5A-5L represent 293-SEZ6L2. The left-hand graphs in Figures 5A-5L represent 293-SEZ6L and 293-SEZ6. Results for the following antibodies are shown in Figures 5A-5L: 1A1 (Figure 5A), 1C6 (Figure 5B), 3A1 (Figure 5C), 3A2 (Figure 5D), 3A3 (Figure 5E), 3B1 (Figure 5F), 3B3 (Figure 5G), 3B6 (Figure 5H), 2E4:4D2 (Figure 5I), 3E2:7D4 (Figure 5J), 16H8:A3F5 (Figure 5K), and 20C4:red (Figure 5L). Figure 5M represents a control containing secondary antibody alone. As demonstrated by the datasets shown in Figures 5A-M, the SEZ6L2 antibody recognizes cell lines overexpressing SEZ6L2 but shows no detectable binding to the two other family members, SEZ6L and SEZ6. [Figure 5EFGH] Same as above [Figure 5IJKL] Same as above [Figure 5M] Same as above

[0124] [Figure 6] Figure 6 shows that SEZ6L2 ADCs combined with PARP inhibitors exhibit enhanced in vitro efficacy. The humanized SEZ6L2 antibody 3E2 conjugated to a PBD (3E2-PBD) was tested to determine whether additional reductions in cell viability would occur when combined with PARP inhibitors. As shown in Figure 6, small cell lung cancer cell line NCI-209 cells treated with the PARP inhibitor olaparib alone responded in a dose-dependent manner, with an increasing reduction in the percent viable cells observed with increasing inhibitor concentration. Cells incubated with both the PARP inhibitor and 3E2-PBD (10 pM) showed an increased reduction in viable cells, indicating an additive effect. In contrast, when IgG-PBD (10 pM) was combined with the inhibitor, there was no measurable difference in cell death, indicating an immunospecific response to SEZ6L2 rather than a general response to the PBD cytotoxin. DETAILED DESCRIPTION OF THE INVENTION

[0125] Various aspects of the present disclosure relate to SEZ6L2 antibodies and antibody fragments, anti-SEZ6L2 ADCs, and pharmaceutical compositions thereof, as well as nucleic acids, recombinant expression vectors, and host cells for producing such antibodies and fragments. Methods of using the antibodies and ADCs described herein to detect human SEZ6L2, inhibit human SEZ6L2 activity (in vitro or in vivo), and treat SEZ6L2-associated disorders, such as, but not limited to, small cell lung cancer (SCLC), neuroendocrine tumors (NETs), and prostate cancer, including castration-resistant prostate cancer.

[0126] I. Definition In order to make the present invention more readily understandable, certain terms are first defined. In addition, it should be noted that whenever a value or range of values ​​for a parameter is given, it is intended that values ​​intermediate to the given values ​​and intermediate ranges are also part of the present invention.

[0127] The terms "stroke-associated 6 homolog-like 2 antibody" or "anti-SEZ6L2 antibody" are used interchangeably herein and refer to an antibody that specifically binds to SEZ6L2. An antibody that "binds" an antigen of interest, i.e., SEZ6L2, is one that is capable of binding to that antigen with sufficient affinity so that the antibody is useful for targeting cells expressing the antigen. In a preferred embodiment, the antibody specifically binds to human SEZ6L2 (hSEZ6L2). In another preferred embodiment, the antibody does not bind to SEZ6. In another preferred embodiment, the antibody does not bind to SEZ6L. Examples of anti-SEZ6L2 antibodies are disclosed in Examples 3 and 4 below. Unless otherwise specified, the term "anti-SEZ6L2 antibody" is intended to refer to an antibody that binds to wild-type SEZ6L2 or a variant or isoform of SEZ6L2.

[0128] SEZL2 exists in six isoforms produced by alternative splicing. An exemplary amino acid sequence of wild-type human SEZ6L2, containing 910 amino acids, is provided below as SEQ ID NO: 167 (Uniprot accession number Q6UXD5), ​​with the signal peptide (amino acid residues 1-27) underlined. The mature form of wild-type SEZ6L2 corresponds to the protein without the signal peptide, i.e., amino acid residues 28-910 of SEQ ID NO: 167. [ka]

[0129] SEZ6L2 is a member of the seizure-related gene (SEZ) protein family, which includes seizure protein 6 homolog (SEZ6) and seizure 6-like protein (SEZ6L). SEZ6L2 shares approximately 41% sequence identity with SEZ6 and SEZ6L. SEZ6L2 is a type 1 transmembrane glycoprotein with an N-terminal signal peptide, five SUSHI domains (SCR repeats), three CUB domains (an acronym for the first three proteins identified to contain such domains: complement factor C1r / C1s, embryonic sea urchin protein uEGF, and bone morphogenetic protein 1), and a C-terminal transmembrane domain (Ishikawa et al., Cancer Sci 2006;97:737-745). The three CUB domains comprise amino acid residues 173-286 (CUB1), 349-459 (CUB2), and 527-638 (CUB3). The five SUSHI domains contain amino acid residues 288–347, 462–525, 642–701, 703–766, and 769–830, respectively.

[0130] The terms "specific binding" or "specifically binds," as used herein with reference to the interaction of a SEZ6L2 antibody or ADC with a second chemical species, mean that the interaction is dependent on the presence of a particular structure (e.g., an antigenic determinant or epitope) on that chemical species; for example, an antibody recognizes and binds to a particular protein structure, rather than proteins in general. If an antibody or ADC is specific for epitope "A," then in a reaction involving labeled "A," the presence of a molecule containing epitope A (or free, unlabeled A) and an antibody will reduce the amount of labeled A bound to the antibody or ADC.

[0131] In one embodiment, an antibody or antigen-binding portion thereof that is "specific" for SEZ6L2 does not bind to SEZ6. In one embodiment, an antibody or antigen-binding portion thereof that is "specific" for SEZ6L2 does not bind to SEZ6L. In one embodiment, an antibody or antigen-binding portion thereof that is "specific" for SEZ6L2 does not bind to either SEZ6 or SEZ6L.

[0132] In one embodiment, the phrase "specifically binds to hSEZ6L2" or "specific binding to hSEZ6L2," as used herein, means that an anti-SEZ6L2 antibody or ADC has a dissociation constant (K) of 200 nM or less, 100 nM or less, 75 nM or less, 26 nM or less, 24 nM or less, 12 nM or less, 7 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.5 nM or less, 0.3 nM or less, 0.1 nM or less, or 0.01 nM or less. D In another embodiment, the phrase "specifically binds to hSEZ6L2" or "specific binding to hSEZ6L2," as used herein, refers to the ability of an anti-SEZ6L2 antibody or ADC to interact with hSEZ6L2 with a dissociation constant (K) of between about 1 pM (0.001 nM) and 50 nM, about 500 pM (0.5 nM) and 20 nM, about 1 nM and 10 nM, or between about 1 nM and 5 nM. D ) refers to the ability to interact with hSEZ6L2. D is determined by surface plasmon resonance. D is determined as described in Example 4 herein.

[0133] The term "antibody" generally refers to an immunoglobulin (Ig) molecule, which is generally composed of four polypeptide chains, two heavy (H) chains and two light (L) chains, or any functional fragment, mutant, variant, or derivative thereof that retains the essential target-binding characteristics of an Ig molecule. Such mutant, variant, or derivative antibody formats are known in the art. Non-limiting embodiments thereof are discussed below.

[0134] In full-length antibodies, each heavy chain is composed of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region is composed of three domains, CH1, CH2, and CH3. Each light chain is composed of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region is composed of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed framework regions (FR), interspersed with more conserved regions, termed complementarity-determining regions (CDRs). Each VH and VL is composed of three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Immunoglobulin molecules may be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY) and class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) or subclass.

[0135] The term "antigen-binding portion" of an antibody (or simply "antibody portion"), as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., hIL-13). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Such antibody embodiments may also be bispecific, dual specific, or multispecific in format, i.e., specifically binding to two or more different antigens. Examples of binding fragments encompassed within the term "antigen-binding portion" of an antibody include: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge in the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (v) a dAb fragment comprising a single variable domain (Ward et al., (1989) Nature 341:544-546; Winter et al., PCT Publication WO 90 / 05144 A1, which are incorporated herein by reference); and (vi) isolated complementarity-determining regions (CDRs). Furthermore, although the two domains of an Fv fragment, VL and VH, are encoded by separate genes, they can be joined using recombinant methods by a synthetic linker that allows them to form a single protein chain in which the VL and VH regions pair to form a monovalent molecule (known as a single-chain Fv (scFv); see, e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single-chain antibodies are also intended to be encompassed within the term "antigen-binding portion" of an antibody. In certain embodiments, scFv molecules may be incorporated into fusion proteins. Other forms of single-chain antibodies, such as diabodies, are also encompassed.Diabodies are bivalent, bispecific antibodies in which the VH and VL domains are expressed on a single polypeptide chain, but with a linker that is too short to allow pairing between the two domains on the same chain, thereby forcing them to pair with complementary domains on another chain and creating two antigen-binding sites (see, e.g., Holliger, P. et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, RJ et al. (1994) Structure 2:1121-1123). Such antibody-binding moieties are known in the art (Kontermann and Dubel, eds., Antibody). Engineering (2001) Springer-Verlag, New York, 790 pages (ISBN3-540-41354-5).

[0136] The term "antibody construct," as used herein, refers to a polypeptide comprising one or more of the antigen-binding moieties disclosed herein linked to a linker polypeptide or immunoglobulin constant domain. A linker polypeptide comprises two or more amino acid residues joined by peptide bonds and is used to link one or more antigen-binding moieties. Such linker polypeptides are well known in the art (see, e.g., Holliger, P. et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, RJ et al. (1994) Structure 2:1121-1123). An immunoglobulin constant domain refers to a heavy or light chain constant domain. Exemplary human IgG heavy and light chain constant domain amino acid sequences are known in the art and are shown below. Human IgG heavy and light chain constant domain sequences [Table A]

[0137] Antibody portions, such as Fab and F(ab')2 fragments, can be prepared from whole antibodies using conventional techniques, such as papain or pepsin digestion, respectively, of whole antibodies. Moreover, antibodies, antibody portions, and immunoadhesion molecules can be obtained using standard recombinant DNA techniques, as described herein.

[0138] As used herein, an "isolated antibody" is intended to refer to an antibody that is substantially free of other antibodies with different antigen specificities (e.g., an isolated antibody that specifically binds to SEZ6L2 is substantially free of antibodies that specifically bind to antigens other than SEZ6L2). However, an isolated antibody that specifically binds to SEZ6L2 may have cross-reactivity with other antigens, such as SEZ6L2 molecules from other species. Furthermore, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0139] The term "humanized antibody" refers to an antibody comprising heavy and light chain variable region sequences derived from a non-human species (e.g., mouse), but in which at least a portion of the VH and / or VL sequences have been altered to be more "human-like," i.e., more similar to human germline variable sequences. In particular, the term "humanized antibody" refers to an antibody, or a variant, derivative, analog, or fragment thereof, that immunospecifically binds to an antigen of interest and comprises framework (FR) regions having substantially the amino acid sequence of a human antibody and complementarity-determining regions (CDRs) having substantially the amino acid sequence of a non-human antibody. As used herein, the term "substantially," in the context of a CDR, refers to a CDR having an amino acid sequence that is at least 80%, preferably at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of the non-human antibody CDR. A humanized antibody comprises substantially all of at least one, and typically two, variable domains (Fab, Fab', F(ab')2, FabC, Fv), in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin (i.e., donor antibody) and all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence. Preferably, the humanized antibody also comprises at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. In some embodiments, the humanized antibody comprises both a light chain and at least a heavy chain variable domain. The antibody may also comprise the CH1, hinge, CH2, CH3, and CH4 regions of the heavy chain. In some embodiments, the humanized antibody comprises only a humanized light chain. In other embodiments, the humanized antibody comprises only a humanized heavy chain. In certain embodiments, the humanized antibody comprises only a humanized variable domain of the light chain and / or a humanized heavy chain.

[0140] The humanized antibody can be selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA, and IgE, and any isotype, including but not limited to IgG1, IgG2, IgG3, and IgG4. The humanized antibody may comprise sequences from more than one class or isotype, and particular constant domains can be selected to optimize desired effector functions using techniques well known in the art.

[0141] The terms "Kabat numbering," "Kabat definition," and "Kabat notation" are used interchangeably herein. These terms are art-recognized and refer to a system for numbering amino acid residues that are more variable (i.e., hypervariable) than other amino acid residues in the heavy and light chain variable regions of an antibody, or antigen-binding portion thereof (Kabat et al. (1971) Ann. NY Acad. Sci. 190:382-391, and Kabat, EA et al. (1991) Sequences of Proteins of Immunological Interest, 5th ed., US Department of Health and Human Services, NIH Publication No. 91-3242). For the heavy chain variable region, the hypervariable region ranges from amino acid positions 31 to 35 for CDR1, from amino acid positions 50 to 65 for CDR2, and from amino acid positions 95 to 102 for CDR3. In the light chain variable region, the hypervariable region ranges from amino acid positions 24 to 34 in CDR1, from amino acid positions 50 to 56 in CDR2, and from amino acid positions 89 to 97 in CDR3.

[0142] As used herein, the term "CDR" refers to a complementarity-determining region within an antibody variable sequence. In each of the heavy chain (HC) and light chain (LC) variable regions, there are three CDRs, designated CDR1, CDR2, and CDR3 for each variable region (or specifically, HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3). The term "CDR set," as used herein, refers to a group of three CDRs occurring in a single variable region capable of binding to an antigen. The exact boundaries of these CDRs are defined differently by different systems. The system described by Kabat (Kabat et al., Sequences of Proteins of the Immunological Interest (National Institute of The Kabat CDRs (Kabat CDRs) are sometimes referred to as Kabat CDRs. Chothia and colleagues (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987) and Chothia et al., Nature 342:877-883 (1989)) found that certain subportions within the Kabat CDRs adopt nearly identical peptide backbone conformations despite great diversity at the amino acid sequence level. These subportions are designated L1, L2, and L3, or H1, H2, and H3, with "L" and "H" referring to the light and heavy chain regions, respectively. These regions are sometimes referred to as Chothia CDRs and have boundaries that overlap with Kabat CDRs. Other boundaries defining CDRs that overlap with Kabat CDRs have been described by Padlan (FASEB J. 9:133-139 (1995)) and MacCallum (J Mol Biol 262(5):732-45 (1996)). Still other CDR boundary definitions may not strictly follow one of the above systems, but may be shortened or extended in light of predictions or experimental findings that certain residues or groups of residues, or even entire CDRs, do not significantly affect antigen binding, yet still overlap with Kabat CDRs. The methods used herein can use CDRs defined according to any of these systems, although preferred embodiments use Kabat-defined or Chothia-defined CDRs.

[0143] As used herein, the term "framework" or "framework sequence" refers to the remaining sequence of a variable region excluding CDRs. The precise definition of a CDR sequence can be determined by various systems, and the meaning of a framework sequence is subject to correspondingly various interpretations. The six CDRs (CDR-L1, CDR-L2, and CDR-L3 in the light chain and CDR-H1, CDR-H2, and CDR-H3 in the heavy chain) divide the framework regions of the light and heavy chains into four subregions (FR1, FR2, FR3, and FR4) of each chain, with CDR1 located between FR1 and FR2, CDR2 between FR2 and FR3, and CDR3 between FR3 and FR4. As referred to elsewhere, the framework region represents the combination of FRs in the variable region of a single naturally occurring immunoglobulin chain, without specifying the specific subregions as FR1, FR2, FR3, or FR4. As used herein, FR refers to one of the four subregions, and FR refers to two or more of the four subregions that make up a framework region.

[0144] The framework and CDR regions of a humanized antibody need not correspond exactly to the parent sequences. For example, the donor antibody CDR or consensus framework may be mutagenized by substitution, insertion, and / or deletion of at least one amino acid residue so that the CDR or framework residue at that site does not correspond to either the donor antibody or the consensus framework. However, in preferred embodiments, such mutations are not extensive. Typically, at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% of the humanized antibody residues correspond to those of the parent FR and CDR sequences. As used herein, the term "consensus framework" refers to the framework region of a consensus immunoglobulin sequence. As used herein, the term "consensus immunoglobulin sequence" refers to a sequence formed from the most frequently occurring amino acids (or nucleotides) in a family of related immunoglobulin sequences (see, e.g., Winnaker, From Genes to Clones (Verlagsgesellschaft, Weinheim, Germany, 1987)). In a family of immunoglobulins, each position in the consensus sequence is occupied by the amino acid that occurs most frequently at that position in the family. If two amino acids occur equally frequently, either can be included in the consensus sequence.

[0145] "Percent (%) amino acid sequence identity" with respect to a peptide or polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to those in a specific peptide or polypeptide sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and without considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in a variety of ways that are within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms required to achieve maximum alignment over the entire length of the sequences being compared. In one embodiment, the present disclosure includes an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to the amino acid sequence set forth in any one of SEQ ID NOS: 1-119 and 156-166.

[0146] The term "multivalent antibody" is used herein to refer to an antibody that comprises two or more antigen-binding sites. In certain embodiments, multivalent antibodies may be engineered to have three or more antigen-binding sites and are generally not naturally occurring antibodies.

[0147] The term "multispecific antibody" refers to an antibody capable of binding to two or more unrelated antigens.

[0148] The terms "dual variable domain" or "DVD" are used interchangeably herein to refer to an antigen-binding protein that contains two or more antigen-binding sites and is a tetravalent or multivalent binding protein. Such DVDs may be monospecific, i.e., capable of binding to one antigen, or multispecific, i.e., capable of binding to two or more antigens. A DVD-binding protein containing two heavy chain DVD polypeptides and two light chain DVD polypeptides is called a DVD Ig. Each half of a DVD Ig contains a heavy chain DVD polypeptide and a light chain DVD polypeptide and two antigen-binding sites. Each binding site contains a heavy chain variable domain and a light chain variable domain, with a total of six CDRs per antigen-binding site involved in antigen binding. In one embodiment, the CDRs described herein are used in an anti-SEZ6L2 DVD.

[0149] The term "activity" includes activities such as the binding specificity / affinity of an antibody against an antigen, e.g., an hSEZ6L2 antigen, e.g., binding to wild-type SEZ6L2 in vitro, binding to wild-type SEZ6L2 on cancer cells expressing SEZ6L2 (e.g., neuroendocrine tumor cells, lung cancer cells, or prostate cancer cells), and reducing or inhibiting tumor cell proliferation or tumor growth, of an anti-hSEZ6L2 antibody or ADC.

[0150] The terms "neuroendocrine tumor" or "NET" or "neuroendocrine cancer," as used herein, include tumors containing neuroendocrine features (genotype or phenotype). True or "standard neuroendocrine tumors" arise from cells of the endocrine system and are typically highly invasive. Neuroendocrine tumors can arise in the kidney, genitourinary tract (bladder, prostate, ovaries, cervix, and endometrium), gastrointestinal tract (stomach, colon), thyroid (medullary thyroid carcinoma), and lung (small cell lung carcinoma and large cell neuroendocrine carcinoma). Neoplasms that exhibit neuroendocrine features are also considered NETs, ​​including neuroblastoma, medullary thyroid carcinoma, and carcinoid tumors. The antibodies disclosed herein also have the advantage of being able to treat, prevent, or diagnose pseudoneuroendocrine tumors (pNETs), which genotypically or phenotypically mimic, contain, resemble, or exhibit common traits of standard neuroendocrine tumors. "Pseudoneuroendocrine tumors" are tumors arising from cells of the diffuse neuroendocrine system or from cells in which the neuroendocrine differentiation cascade is aberrantly reactivated during the carcinogenic process. Such pNETs generally share certain genotypic, phenotypic, or biochemical characteristics with conventionally defined neuroendocrine tumors, including the ability to produce a subset of biologically active amines, neurotransmitters, and peptide hormones. Thus, the phrases "neuroendocrine tumor," "NET," "neuroendocrine carcinoma," "tumor containing neuroendocrine features," or "tumor exhibiting neuroendocrine features" are intended to include both neuroendocrine tumors and pseudoneuroendocrine tumors.

[0151] The term "epitope" refers to the region of an antigen to which an antibody, antibody fragment, or ADC binds. In certain embodiments, epitopic determinants include chemically active surface groups of molecules, such as amino acids, sugar side chains, phosphoryl, or sulfonyl, and in certain embodiments, may have specific three-dimensional structural and / or specific charge characteristics. In certain embodiments, an antibody is said to specifically bind an antigen when it preferentially recognizes its target antigen in a complex mixture of proteins and / or macromolecules.

[0152] The term "surface plasmon resonance," as used herein, refers to an optical phenomenon that allows for the analysis of real-time biospecific interactions by detecting changes in protein concentration within a biosensor matrix, for example, using a BIAcore system (Pharmacia Biosensor AB, Uppsala, Sweden, and Piscataway, NJ). For further explanation, see Joensson, U. et al. (1993) Ann. Biol. Clin. 51:19-26; Joensson, U. et al. (1991) Biotechniques 11:620-627; Johnson, B. et al. (1995) J. Mol. Recognit. 8:125-131; and Johnson, B. et al. (1991 Anal. Biochem. 198:268-277).

[0153] The term "k" on " or "k a " as used herein is intended to refer to the binding rate constant for an antibody to associate with an antigen to form an antibody / antigen complex.

[0154] The term "k" off " or "k d ", as used herein, is intended to refer to the dissociation rate constant for dissociation of an antibody from the antibody / antigen complex.

[0155] The term “K D ", as used herein, is intended to refer to the equilibrium dissociation constant of a particular antibody-antigen interaction. D is k a / k d In one embodiment, the antibody of the present disclosure has a cytotoxicity of about 10 -8 M or less, 10 -9 M or less, or 10 -10 M, or 10 -11 M or less K D It has.

[0156] The term "competitive binding," as used herein, refers to a situation in which a first antibody competes with a second antibody for the binding site of a third molecule, such as an antigen. In one embodiment, competitive binding between two antibodies is determined using FACS analysis.

[0157] The term "competitive binding assay" refers to an assay used to determine whether two or more antibodies bind to the same epitope. In one embodiment, a competitive binding assay is a competitive fluorescence-activated cell sorting (FACS) assay used to determine whether two or more antibodies bind to the same epitope by determining whether the fluorescent signal of a labeled antibody is reduced by the introduction of an unlabeled antibody, where competition for the same epitope reduces the level of fluorescence.

[0158] The term "labeled antibody," as used herein, refers to an antibody or antigen-binding portion thereof having an incorporated label that provides identification of the binding protein, e.g., antibody. Preferably, the label is a detectable marker, such as the incorporation of a radioisotope-labeled amino acid or the attachment of a biotinyl moiety to the polypeptide that can be detected by labeled avidin (e.g., streptavidin containing a fluorescent marker or enzymatic activity that can be detected by optical or colorimetric methods). Examples of labels for polypeptides include, but are not limited to, the following: radioisotopes or radionuclides (e.g., 3 H, 14 C. 35 S, 90 Y, 99 Tc, 111 In, 125 I, 131 I, 177 Lu, 166 Ho, or 153Sm); fluorescent labels (e.g., FITC, rhodamine, lanthanide fluorophores), enzymatic labels (e.g., horseradish peroxidase, luciferase, alkaline phosphatase); chemiluminescent markers; biotinyl groups; predetermined polypeptide epitopes recognized by secondary reporters (e.g., leucine zipper pair sequences, binding sites for secondary antibodies, metal binding domains, epitope tags); and magnetic agents such as gadolinium chelates.

[0159] The term "antibody-drug conjugate" or "ADC" refers to a binding protein, such as an antibody or antigen-binding fragment thereof, chemically linked to one or more chemical drugs (also referred to herein as agents), which may optionally be therapeutic or cytotoxic agents. In preferred embodiments, an ADC comprises an antibody, a cytotoxic or therapeutic agent, and a linker that allows for attachment or conjugation of the drug to the antibody. ADCs typically have one to eight drugs conjugated to the antibody, including two, four, six, or eight drug-loaded species. Non-limiting examples of drugs that may be included in an ADC include antimitotic agents, antitumor antibiotics, immunomodulators, vectors for gene therapy, alkylating agents, antiangiogenic agents, antimetabolites, boron-containing agents, chemoprotectants, hormones, antihormonal agents, corticosteroids, photoactive therapeutic agents, oligonucleotides, radionuclide agents, topoisomerase inhibitors, tyrosine kinase inhibitors, and radiosensitizers.

[0160] The terms "anti-seizure-associated 6 homolog-like 2 antibody-drug conjugate," "anti-SEZ6L2 antibody-drug conjugate," or "anti-SEZ6L2 ADC" are used interchangeably herein and refer to an ADC comprising an antibody that specifically binds to SEZ6L2 and is conjugated to one or more chemical agents or payloads. In one embodiment, the chemical agent is linked to the antibody via a linker.

[0161] In one embodiment, the anti-SEZ6L2 ADC is conjugated to a DNA alkylating agent, such as an indolinobenzodiazepine (IGN). In one embodiment, the DNA alkylating agent, such as an IGN, is conjugated to the antibody via a linker, such as a cleavable peptide linker (D-Ala-L-dpa). In one embodiment, the anti-SEZ6L2 ADC is conjugated to a pyrrolobenzodiazepine (PBD).

[0162] In another embodiment, the anti-SEZ6L2 ADC is conjugated to a microtubule inhibitor such as an auristatin, e.g., monomethyl auristatin E (MMAE). In another embodiment, the anti-SEZ6L2 ADC is conjugated to a microtubule inhibitor such as a maytansinoid, e.g., DM4. In one embodiment, the auristatin (e.g., MMAE) is conjugated to the antibody via a linker, e.g., maleimido-caproyl-valine-citrulline (MC-VC). In another embodiment, the maytansinoid (e.g., DM4) is conjugated to the antibody via a linker, e.g., a cleavable peptide linker (D-Ala-L-dpa) or a charged hindered disulfide N-succinimidyl-4-(2-pyridyldithio)butanoate (sSPDB) linker.

[0163] The term "DNA alkylating agent," as used herein, refers to a family of DNA alkylating agents, including indolino-benzodiazepines (IGNs), which are cytotoxic small molecules that can be used in ADCs. Examples of IGN DNA alkylating agents that can be used as cytotoxic payloads in ADCs are described in Miller et al. (2016) Molecular Cancer Therapeutics, Vol. 15(8)). In one embodiment, an anti-SEZ6L2 antibody described herein is conjugated to an IGN to form an anti-SEZ6L2 ADC.

[0164] The term "maytansinoid," as used herein, refers to maytansine and its analogs, which are potent microtubule-targeting compounds that inhibit cell proliferation during mitosis. Maytansinoids include DM1, DM2, DM3, and DM4, which exert their antimitotic effects through a common mechanism involving the suppression of microtubule dynamic instability. (See, e.g., Emin Oroudjev et al. (2010) Molecular Cancer Therapeutics, Vol. 9 (No. 10)). In one embodiment, an anti-SEZ6L2 antibody described herein is conjugated to DM4 to form an anti-SEZ6L2 ADC.

[0165] The term "auristatin," as used herein, refers to a family of antimitotic agents that function as microtubule inhibitors. Auristatin derivatives are also included within the definition of the term "auristatin." Examples of auristatins include, but are not limited to, auristatin E (AE), monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), and synthetic analogs of dolastatins. In one embodiment, an anti-SEZ6L2 antibody described herein is conjugated to an auristatin, such as MMAE, to form an anti-SEZ6L2 ADC.

[0166] The term "drug-antibody ratio" or "DAR" refers to the number of drugs, e.g., IGNs, auristatins, or maytansinoids, that are conjugated to the antibodies of an ADC. The DAR of an ADC can range from 1 to 8, although higher loadings, e.g., 10, are possible depending on the number of attachment sites on the antibody. The term DAR can be used in reference to the number of drugs loaded on an individual antibody, or alternatively, in reference to the average or mean DAR of a group of ADCs.

[0167] The term "SEZ6L2-associated disorder," as used herein, includes any disorder or disease (including proliferative disorders, e.g., cancer) that is indicated, diagnosed, detected, or identified by phenotypic or genotypic abnormalities in SEZ6L2 gene components or expression during the course or pathogenesis of the disease or disorder. In this regard, SEZ6L2 phenotypic abnormalities or determinants can include, for example, increased or decreased levels of SEZ6L2 protein expression, or abnormal SEZ6L2 protein expression in a specific, identifiable cell population, or abnormal SEZ6L2 protein expression at an inappropriate phase or stage of the cell life cycle. It is also understood that similar expression patterns of SEZ6L2 genotypic determinants (e.g., mRNA transcription levels) can be used to classify or detect SEZ6L2-associated disorders. In one embodiment, the SEZ6L2-associated disorder is SCLC. In one embodiment, the SEZ6L2-associated disorder is prostate cancer, e.g., castration-resistant prostate cancer (CRPC). In another embodiment, the SEZ6L2-associated disorder is a neuroendocrine tumor.

[0168] The term "cancer" is intended to refer to or describe a physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia, or lymphoid malignancies. More specific examples of such cancers include: neuroendocrine tumors, small cell lung cancer (SCLC), prostate cancer, such as castration-resistant prostate cancer (CRPC), colon cancer, colorectal cancer, head and neck cancer, breast cancer, such as triple-negative breast cancer (TNBC), Her2-positive breast cancer, pancreatic cancer, squamous cell tumors, squamous cell carcinoma (e.g., lung squamous cell carcinoma or head and neck squamous cell carcinoma), renal cell carcinoma, medullary thyroid cancer, non-small cell lung cancer (NSCLC), such as squamous cell NSCLC, large cell NSCLC, lung carcinoid NSCLC, anal cancer, skin cancer, serous ovarian cancer, and vulvar cancer.

[0169] In one embodiment, the antibody or ADC is administered to a patient with a solid tumor that may overexpress SEZ6L2. In one embodiment, the antibody or ADC is administered to a patient with small cell lung cancer (SCLC). In another embodiment, the antibody or ADC is administered to a patient with prostate cancer, such as castration-resistant prostate cancer (CRPC). In yet another embodiment, the antibody or ADC is administered to a patient with a neuroendocrine tumor. In one embodiment, the antibody or ADC is administered to a patient with a solid tumor, including an advanced solid tumor. In another embodiment, the antibody or ADC is administered to a patient with a SEZ6L2-expressing tumor.

[0170] The term "SEZ6L2-expressing tumor" as used herein refers to a tumor that expresses the SEZ6L2 protein. In one embodiment, SEZ6L2 expression in a tumor is determined using immunohistochemical staining of tumor cell membranes, and any immunohistochemical staining higher than background levels in tumor samples indicates that the tumor is a SEZ6L2-expressing tumor. Methods for detecting SEZ6L2 expression in tumors are known in the art. For example, in situ hybridization (ISH) analysis has shown that SEZ6L2 is highly expressed in 66% of SCLC tumor samples and 53% of prostate cancer samples, and at low or undetectable levels in normal samples (see Example 1). In contrast, a "SEZ6L2-negative tumor" is defined as a tumor in which there is no SEZ6L2 membrane staining higher than background in tumor samples, as determined by immunohistochemical techniques.

[0171] The terms "overexpress," "overexpression," or "overexpressed" refer synonymously to a gene that is typically transcribed or translated at a detectably higher level in cancer cells compared to normal cells. Thus, overexpression refers to both protein and RNA overexpression (due to increased transcription, post-transcriptional processing, translation, post-translational processing, altered stability, and altered proteolysis) as well as local overexpression due to altered protein trafficking patterns (increased nuclear localization) and enhanced functional activity, such as increased enzymatic hydrolysis of a substrate. Thus, overexpression refers to either the protein or RNA level. Overexpression may also be 50%, 60%, 70%, 80%, 90%, or higher compared to normal or control cells. In certain embodiments, anti-SEZ6L2 antibodies or ADCs are used to treat solid tumors that may overexpress SEZ6L2.

[0172] The term "administering," as used herein, is intended to refer to the delivery of a substance (e.g., an anti-SEZ6L2 antibody or ADC) to achieve a therapeutic objective (e.g., treatment of a SEZ6L2-associated disorder or inhibition or reduction of a tumor). Modes of administration may be parenteral, enteral, and topical. Parenteral administration is usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0173] The term "combination therapy," as used herein, refers to the administration of two or more therapeutic agents, such as an anti-SEZ6L2 antibody or ADC and an additional therapeutic agent. The additional therapeutic agent may be administered simultaneously with, before, or after administration of the anti-SEZ6L2 antibody or ADC.

[0174] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a drug, e.g., an antibody or ADC, sufficient to reduce or ameliorate the severity and / or duration of a disorder, e.g., cancer, or one or more symptoms thereof, prevent progression of the disorder, cause regression of the disorder, prevent the recurrence, onset, onset, or worsening of one or more symptoms associated with the disorder, detect the disorder, or enhance or improve the prophylactic or therapeutic effect(s) of another treatment (e.g., a prophylactic or therapeutic agent). An effective amount of an antibody or ADC can, for example, inhibit tumor growth (e.g., inhibit an increase in tumor volume), reduce tumor growth (e.g., reduce tumor volume), reduce the number of cancer cells, and / or alleviate to some extent one or more symptoms associated with cancer. An effective amount may, for example, improve disease-free survival (DFS), improve overall survival (OS), or reduce the likelihood of recurrence.

[0175] The term "xenograft assay," as used herein, refers to a human tumor xenograft assay in which human tumor cells, such as human small cell lung carcinoma tumor cells, are implanted either under the skin or within the organ type from which the tumor originated into immunocompromised mice that do not reject the human cells.

[0176] Various aspects of the invention are described in further detail in the following subsections.

[0177] II. Anti-SEZ6L2 antibody One aspect disclosed herein provides a humanized anti-SEZ6L2 antibody, or an antigen-binding portion thereof. Another aspect disclosed herein provides a human anti-SEZ6L2 antibody, or an antigen-binding portion thereof. In one embodiment, the antibody disclosed herein binds to human SEZ6L. In another embodiment, the antibody disclosed herein binds to cynomolgus monkey SEZ6L. In another embodiment, the antibody disclosed herein does not bind to SEZ6 or SEZ6L. In another embodiment, the antibody disclosed herein binds to human SEZ6L expressed on tumor cells.

[0178] Another embodiment disclosed herein features an antibody-drug conjugate (ADC) comprising an anti-SEZ6L2 antibody described herein and at least one drug, such as, but not limited to, a DNA alkylating agent, e.g., IGN, a microtubule inhibitor such as an auristatin (e.g., MMAE), or a maytansinoid (e.g., DM4), or a pyrrolobenzodiazepine (PBD). The antibody or ADC disclosed herein has characteristics including, but not limited to, binding to human or cynomolgus monkey wild-type SEZ6L2 in vitro, binding to wild-type SEZ6L2 on tumor cells expressing SEZ6L2 (e.g., lung cancer tumor cells, or prostate cancer tumor cells, e.g., castration-resistant prostate cancer (CRPC)), and reducing or inhibiting tumor cell proliferation or tumor growth, e.g., lung tumor growth or prostate tumor growth.

[0179] In one embodiment, as described in the Examples below, anti-SEZ6L2 humanized and human antibodies are disclosed that have the ability to inhibit SCLC tumor cell growth in vivo. These novel antibodies are collectively referred to herein as "SEZ6L2 antibodies." As described in Example 6, anti-SEZ6L2 antibodies, ADCs, or antigen-binding fragments thereof can inhibit or reduce tumor growth in vivo, for example, in an NCI-H524 human small cell lung cancer (SCLC) xenograft assay in nude mice. In various embodiments, anti-SEZ6L2 antibodies, ADCs, or antigen-binding fragments thereof are capable of modulating the biological function of SEZ6L2. In other embodiments of the above aspects, the anti-SEZ6L2 antibodies, ADCs, or antigen-binding fragments thereof bind to SEZ6L2 on cells overexpressing SEZ6L2. In further embodiments, the anti-SEZ6L2 antibodies, ADCs, or antigen-binding fragments thereof do not bind to SEZ6 or SEZ6L.

[0180] Thus, the present disclosure includes anti-SEZ6L2 antibodies, ADCs, or antigen-binding fragments thereof that are effective in inhibiting or reducing tumor growth. In one embodiment, the anti-SEZ6L2 antibodies, ADCs, or antigen-binding fragments thereof do not bind to SEZ6 or SEZ6L.

[0181] In one embodiment, the anti-SEZ6L2 antibody, ADC, or antigen-binding fragment thereof can inhibit or reduce tumor growth in an in vivo xenograft mouse model, e.g., an NCI-H524 human small cell lung cancer (SCLC) xenograft assay in nude mice. For example, the antibody, or antigen-binding portion thereof, can inhibit tumor growth by at least about 50% in an in vivo human small cell lung cancer (SCLC) xenograft assay compared to a human IgG antibody that is not specific for SEZ6L2. In certain embodiments, the anti-SEZ6L2 antibody, ADC, or antigen-binding fragment thereof can inhibit or reduce tumor growth by at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80% in an in vivo human small cell lung cancer (SCLC) xenograft assay compared to a human IgG antibody that is not specific for SEZ6L2, when administered at the same dose and dosing periodicity. In certain embodiments, the anti-SEZ6L2 antibody, ADC, or antigen-binding fragment thereof can inhibit or reduce tumor growth by about 80% to about 90%, or about 84% to about 90%, or about 88% to about 90%, compared to a human IgG antibody that is not specific for SEZ6L2 when administered at the same dose and dosing periodicity in an in vivo human small cell lung cancer (SCLC) xenograft assay. In some embodiments, an anti-SEZ6L2 antibody, ADC, or antigen-binding fragment thereof can inhibit or reduce tumor growth for more than 7 days, more than 14 days, more than 1 month, more than 2 months, more than 3 months, more than 4 months, more than 5 months, more than 6 months, or more than 1 year, or for more than 30, 40, 50, 60, 70, 80, 90, 100, or 110 days in an in vivo human small cell lung cancer (SCLC) xenograft assay when administered at the same dose and dosing periodicity, compared to a human IgG antibody that is not specific for SEZ6L2.

[0182] Antibodies having any combination of the above-described characteristics are contemplated as embodiments of the present disclosure. Additionally, ADCs, described in more detail below, may have any of the above-described characteristics.

[0183] One aspect of the present disclosure features an anti-human SEZ6L2 (anti-hSEZ6L2) antibody-drug conjugate (ADC) comprising an anti-hSEZ6L2 antibody conjugated to a drug via a linker. Exemplary anti-SEZ6L2 antibodies (and their sequences) that can be used in the ADC are described herein.

[0184] The anti-SEZ6L2 antibodies described herein have the ability to bind to SEZ6L2, and provide ADCs that can deliver a cytotoxic molecule (e.g., a microtubule inhibitor such as a DNA alkylating agent, e.g., IGN, an auristatin (e.g., MMAE), or a maytansinoid (e.g., DM4) conjugated to the antibody) to SEZ6L2-expressing cells, particularly SEZ6L2-expressing cancer cells.

[0185] Although the term "antibody" is used throughout this specification, it should be noted that antibody fragments (i.e., antigen-binding portions of anti-SEZ6L2 antibodies) are also included in this disclosure and may be included in the embodiments (methods and compositions) described throughout this specification. For example, anti-SEZ6L2 antibody fragments may be conjugated to a drug (e.g., a DNA alkylating agent, e.g., IGN, a microtubule inhibitor such as an auristatin (e.g., MMAE), or a maytansinoid (e.g., DM4)) as described herein. In certain embodiments, the anti-SEZ6L2 antibody-binding portion is a Fab, Fab', F(ab'), Fv, disulfide-linked Fv, scFv, single-domain antibody, or diabody.

[0186] II.A. Humanized Antibodies After generating 17 anti-hSEZ6L2 murine antibodies as described in Example 2 below, murine antibodies mu16H8, mu3E2, mu20C4, and Mu2E4 were selected for humanization (as described in Example 3 below), resulting in the production of four humanized antibodies (16H8, 3E2, 20C4, and 2E4). The heavy and light chain variable region amino acid sequences of these humanized antibodies are shown in Table 6.

[0187] Thus, in one embodiment, the humanized anti-hSEZ6L2 antibody or its antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of 1, 9, 17, and 25; and a light chain variable region comprising an amino acid sequence selected from the group consisting of 5, 13, 21, and 29.

[0188] In one embodiment, the humanized anti-hSEZ6L2 antibody or antigen-binding portion thereof comprises an HC CDR set (CDR1, CDR2, and CDR3) selected from the group consisting of SEQ ID NOs: 2, 3, and 4; SEQ ID NOs: 10, 11, and 12; SEQ ID NOs: 18, 19, and 20; and SEQ ID NOs: 26, 27, and 28; and an LC light chain CDR set (CDR1, CDR2, and CDR3) selected from the group consisting of SEQ ID NOs: 6, 7, and 8; SEQ ID NOs: 14, 15, and 16; SEQ ID NOs: 22, 23, and 24; and SEQ ID NOs: 30, 15, and 31.

[0189] In one embodiment, the anti-SEZ6L2 antibody, or antigen-binding portion thereof, is humanized antibody 16H8. The 16H8 antibody comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 3, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 2, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 8, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 7, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 6. In a further embodiment, disclosed herein is an antibody having a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 5.

[0190] In some embodiments, the anti-SEZ6L2 antibody or antigen-binding portion thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 1, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 1, and / or a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 5, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 5.

[0191] In one embodiment, the disclosure features an anti-SEZ6L2 antibody, or an antigen-binding portion thereof, that is humanized antibody 3E2. The 3E2 antibody comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 12, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 11, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 10, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 16, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 15, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 14. In a further embodiment, the disclosure provides an antibody having a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 13.

[0192] In some embodiments, the anti-SEZ6L2 antibody or antigen-binding portion thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 9, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 9, and / or a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 13, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 13.

[0193] In one embodiment, the disclosure features an anti-SEZ6L2 antibody, or antigen-binding portion thereof, that is humanized antibody 20C4. The 20C4 antibody comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 20, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 19, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 18, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 24, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 23, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 22. In a further embodiment, the disclosure provides an antibody having a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 17 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 21.

[0194] In some embodiments, the anti-SEZ6L2 antibody or antigen-binding portion thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 1, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 1, and / or a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 5, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 5.

[0195] In one embodiment, the disclosure features an anti-SEZ6L2 antibody, or antigen-binding portion thereof, that is humanized antibody 2E4. The 2E4 antibody comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO:28, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:27, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:26, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO:31, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:15, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:30. In a further embodiment, the disclosure provides an antibody having a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:25 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:29.

[0196] In some embodiments, the anti-SEZ6L2 antibody or antigen-binding portion thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:25, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:25, and / or a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:29, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:29.

[0197] II.B. Human Antibodies Example 4 describes the production of human SEZ6L2 antibodies by inoculating a protein composed of the extracellular portion of the human SEZ6L2 protein (SEZ6L2-his) as described in Example 2. Transgenic mice were used to generate high-affinity fully human monoclonal antibodies that bind to and / or inhibit SEZ6L2. The heavy and light chain variable region amino acid sequences of these human antibodies are shown in Table 9.

[0198] Thus, in one embodiment, the disclosure includes a human anti-hSEZ6L2 antibody or antigen-binding portion thereof comprising: a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 32, 40, 51, 59, 67, 73, 79, 84, 90, 96, 104, 109, 115, 233, and 239; and a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 36, 44, 47, 55, 63, 71, 77, 82, 88, 94, 100, 108, 113, 116, 237, and 243.

[0199] In one embodiment, the disclosure provides a HC CDR set (CDR1, CDR2, and CDR3) selected from the group consisting of SEQ ID NOs: 33, 34, and 35; SEQ ID NOs: 41, 42, and 42; SEQ ID NOs: 52, 53, and 54; SEQ ID NOs: 60, 61, and 62; SEQ ID NOs: 68, 69, and 70; SEQ ID NOs: 74, 75, and 76; SEQ ID NOs: 80, 75, and 81; SEQ ID NOs: 85, 86, and 87; SEQ ID NOs: 91, 92, and 93; SEQ ID NOs: 97, 98, and 99; SEQ ID NOs: 105, 106, and 107; SEQ ID NOs: 110, 111, and 112; SEQ ID NOs: 234, 235, and 236; and SEQ ID NOs: 240, 241, and 242;

[0200] The present invention relates to a human anti-hSEZ6L2 antibody or antigen-binding portion thereof, comprising an LC light chain CDR set (CDR1, CDR2, and CDR3) selected from the group consisting of SEQ ID NOs: 37, 38, and 39; SEQ ID NOs: 45, 38, and 46; SEQ ID NOs: 48, 49, and 50; SEQ ID NOs: 56, 57, and 58; SEQ ID NOs: 64, 65, and 66; SEQ ID NOs: 64, 65, and 72; SEQ ID NOs: 48, 49, and 78; SEQ ID NOs: 48, 49, and 83; SEQ ID NOs: 37, 38, and 89; SEQ ID NOs: 37, 38, and 95; SEQ ID NOs: 101, 102, and 103; SEQ ID NOs: 37, 38, and 89; SEQ ID NOs: 114, 57, and 58; SEQ ID NOs: 117, 118, and 119; SEQ ID NOs: 37, 38, and 238; and SEQ ID NOs: 244, 38, and 245.

[0201] In one embodiment, the disclosure features an anti-SEZ6L2 antibody, or antigen-binding portion thereof, that is human antibody 1A1. The 1A1 antibody comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 39, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37. In a further embodiment, the disclosure provides an antibody having a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 32 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36.

[0202] In some embodiments, the anti-SEZ6L2 antibody or antigen-binding portion thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 32, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 32, and / or a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 36, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 36.

[0203] In one embodiment, the disclosure features an anti-SEZ6L2 antibody, or antigen-binding portion thereof, that is antibody 1D2. The 1D2 antibody comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 43, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 42, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 41, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 46, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 45. In a further embodiment, the disclosure provides an antibody having a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 40 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 44.

[0204] In some embodiments, the anti-SEZ6L2 antibody or antigen-binding portion thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 40, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 40, and / or a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 44, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 44.

[0205] In one embodiment, the disclosure features an anti-SEZ6L2 antibody, or an antigen-binding portion thereof, that is human antibody 1E4. The 1E4 antibody comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 50, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 49, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 48. In a further embodiment, the disclosure provides an antibody having a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 32 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 47.

[0206] In some embodiments, the anti-SEZ6L2 antibody or antigen-binding portion thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 32, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 32, and / or a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 47, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 47.

[0207] In one embodiment, the disclosure features an anti-SEZ6L2 antibody, or antigen-binding portion thereof, that is human antibody 3A1. The 3A1 antibody comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 54, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 53, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 52, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 58, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 57, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 56. In a further embodiment, the disclosure provides an antibody having a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 51 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 55.

[0208] In some embodiments, the anti-SEZ6L2 antibody or antigen-binding portion thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 51, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 51, and / or a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 55, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 55.

[0209] In one embodiment, the disclosure features an anti-SEZ6L2 antibody, or antigen-binding portion thereof, that is human antibody 3B1. The 3B1 antibody comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 62, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 61, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 60, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 66, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 65, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 64. In a further embodiment, the disclosure provides an antibody having a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 59 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 63.

[0210] In some embodiments, the anti-SEZ6L2 antibody or antigen-binding portion thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 59, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 59, and / or a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 63, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 63.

[0211] In one embodiment, the disclosure features an anti-SEZ6L2 antibody, or antigen-binding portion thereof, that is human antibody 3B3. The 3B3 antibody comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO:70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:69, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:68, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO:72, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:65, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:64. In a further embodiment, the disclosure provides an antibody having a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:67 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:71.

[0212] In some embodiments, the anti-SEZ6L2 antibody or antigen-binding portion thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 67, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 67, and / or a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 71, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 71.

[0213] In one embodiment, the disclosure features an anti-SEZ6L2 antibody, or an antigen-binding portion thereof, that is human antibody 3A2. The 3A2 antibody comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 76, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 75, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 74, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 78, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 49, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 48. In a further embodiment, the disclosure provides an antibody having a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 73 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77.

[0214] In some embodiments, the anti-SEZ6L2 antibody or antigen-binding portion thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 73, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 73, and / or a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 77, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 77.

[0215] In one embodiment, the disclosure features an anti-SEZ6L2 antibody, or antigen-binding portion thereof, that is human antibody 3A3. The 3A3 antibody comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 81, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 75, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 80, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 83, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 49, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 48. In a further embodiment, the disclosure provides an antibody having a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 79 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 82.

[0216] In some embodiments, the anti-SEZ6L2 antibody or antigen-binding portion thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 79, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 79, and / or a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 82, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 82.

[0217] In one embodiment, the disclosure features an anti-SEZ6L2 antibody, or antigen-binding portion thereof, that is human antibody 3A4. The 3A4 antibody comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 87, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 86, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 85, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 89, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37. In a further embodiment, the disclosure provides an antibody having a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 84 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 88.

[0218] In some embodiments, the anti-SEZ6L2 antibody or antigen-binding portion thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 84, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 84, and / or a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 88, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 88.

[0219] In one embodiment, the disclosure features an anti-SEZ6L2 antibody, or an antigen-binding portion thereof, that is human antibody 1C6. The 1C6 antibody comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO:93, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:92, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:91, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO:95, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:37. In a further embodiment, the disclosure provides an antibody having a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:90 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:94.

[0220] In some embodiments, the anti-SEZ6L2 antibody or antigen-binding portion thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 90, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 90, and / or a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 94, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 94.

[0221] In one embodiment, the disclosure features an anti-SEZ6L2 antibody, or antigen-binding portion thereof, that is human antibody 1C1. The 1C1 antibody comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO:99, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:98, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:97, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO:103, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:102, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:101. In a further embodiment, the disclosure provides an antibody having a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:96 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:100.

[0222] In some embodiments, the anti-SEZ6L2 antibody or antigen-binding portion thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 96, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 96, and / or a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 100, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 100.

[0223] In one embodiment, the disclosure features an anti-SEZ6L2 antibody, or an antigen-binding portion thereof, that is human antibody 1D5. The 1D5 antibody comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 107, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 106, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 105, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 89, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37. In a further embodiment, the disclosure provides an antibody having a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 104 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 108.

[0224] In some embodiments, the anti-SEZ6L2 antibody or antigen-binding portion thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 104, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 104, and / or a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 108, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 108.

[0225] In one embodiment, the disclosure features an anti-SEZ6L2 antibody, or an antigen-binding portion thereof, that is human antibody 3B6. The 3B6 antibody comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 112, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 111, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 110, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 58, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 57, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 114. In a further embodiment, the disclosure provides an antibody having a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 109 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 113.

[0226] In some embodiments, the anti-SEZ6L2 antibody or antigen-binding portion thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 109, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 109, and / or a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 113, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 113.

[0227] In one embodiment, the disclosure features an anti-SEZ6L2 antibody, or an antigen-binding portion thereof, that is human antibody 3B2. The 3B2 antibody comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 68, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 69, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 70, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 117, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 118, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 119. In a further embodiment, the disclosure provides an antibody having a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 115 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 116.

[0228] In some embodiments, the anti-SEZ6L2 antibody or antigen-binding portion thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 115, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 115, and / or a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 116, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 116.

[0229] In one embodiment, the disclosure features an anti-SEZ6L2 antibody, or antigen-binding portion thereof, that is human antibody 2M5_10A1. The 2M5_10A1 antibody comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 236, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 235, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 234, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 238, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37. In a further embodiment, the disclosure provides an antibody having a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 233 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 237.

[0230] In some embodiments, the anti-SEZ6L2 antibody or antigen-binding portion thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 233, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 233, and / or a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 237, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 237.

[0231] In one embodiment, the disclosure features an anti-SEZ6L2 antibody, or antigen-binding portion thereof, that is human antibody 2M22_10A6. The 2M22_10A6 antibody comprises a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 242, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 241, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 240, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 245, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 244. In a further embodiment, the disclosure provides an antibody having a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 239 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 243.

[0232] In some embodiments, the anti-SEZ6L2 antibody or antigen-binding portion thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 239, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 239, and / or a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 243, or a sequence having at least 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 243.

[0233] The above-described anti-SEZ6L2 antibody CDR sequences establish a novel family of SEZ6L2 binding proteins, including antigen-binding polypeptides isolated in accordance with the present disclosure that comprise the CDR sequences listed in Tables 6 and 9 and in the Sequence Summary.

[0234] To generate and select CDRs that have favorable SEZ6L2 binding and / or neutralizing activity with respect to hSEZ6L2, standard methods known in the art can be used for generating antibodies or antigen-binding portions thereof and for assessing the SEZ6L2 binding and / or neutralizing characteristics of such antibodies or antigen-binding portions thereof, including, but not limited to, those specifically described herein.

[0235] In certain embodiments, the antibody comprises a heavy chain constant region such as an IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM, or IgD constant region. In certain embodiments, the anti-SEZ6L2 antibody or antigen-binding portion thereof comprises a heavy chain immunoglobulin constant domain selected from the group consisting of a human IgG constant domain, a human IgM constant domain, a human IgE constant domain, and a human IgA constant domain. In further embodiments, the antibody or antigen-binding portion thereof has an IgG1 heavy chain constant region, an IgG2 heavy chain constant region, an IgG3 constant region, or an IgG4 heavy chain constant region. Preferably, the heavy chain constant region is an IgG1 heavy chain constant region or an IgG4 heavy chain constant region. Furthermore, the antibody may comprise a light chain constant region of either a kappa light chain constant region or a lambda light chain constant region. Preferably, the antibody comprises a kappa light chain constant region. Alternatively, the antibody portion may be, for example, a Fab fragment or a single-chain Fv fragment.

[0236] In certain embodiments, the anti-SEZ6L2 antibody binding portion is a Fab, Fab', F(ab')2, Fv, disulfide-linked Fv, scFv, single domain antibody, or diabody.

[0237] In certain embodiments, the anti-SEZ6L2 antibody or antigen-binding portion thereof is a multispecific antibody, eg, a bispecific antibody.

[0238] Substitution of amino acid residues in the Fc portion to alter antibody effector function has been described (Winter et al., U.S. Pat. Nos. 5,648,260 and 5,624,821, incorporated herein by reference). The Fc portion of an antibody mediates several important effector functions, such as cytokine induction, ADCC, phagocytosis, complement-dependent cytotoxicity (CDC), and the half-life / clearance rate of antibodies and antigen-antibody complexes. In some cases, such effector functions are desirable for therapeutic antibodies, but in other cases, they may be unnecessary or even harmful depending on the therapeutic purpose. Certain human IgG isotypes, particularly IgG1 and IgG3, mediate ADCC and CDC by binding to FcRs and complement C1q, respectively. The neonatal Fc receptor (FcRn) is an important component determining the circulating half-life of an antibody. In yet another embodiment, at least one amino acid residue in the constant region of an antibody, e.g., the Fc region of an antibody, is substituted to alter the antibody's effector function.

[0239] One embodiment includes a labeled anti-SEZ6L2 antibody or antibody portion thereof that is derivatized or linked to one or more functional molecules (e.g., another peptide or protein). For example, a labeled antibody can be obtained by functionally linking (by chemical coupling, genetic fusion, noncovalent association, or otherwise) an antibody or antibody portion of the present disclosure to one or more other molecular entities, such as another antibody (e.g., a bispecific antibody or diabody); a detectable agent; a pharmaceutical agent; a protein or peptide capable of mediating the association of the antibody or antibody portion with another molecule (such as a streptavidin core region or a polyhistidine tag); and / or a cytotoxic or therapeutic agent selected from the group consisting of an antimitotic agent, an antitumor antibiotic, an immunomodulatory agent, a vector for gene therapy, an alkylating agent, an antiangiogenic agent, an antimetabolite, a boron-containing agent, a chemoprotectant, a hormone, an antihormonal agent, a corticosteroid, a photoactive therapeutic agent, an oligonucleotide, a radionuclide agent, a topoisomerase inhibitor, a tyrosine kinase inhibitor, a radiosensitizer, and combinations thereof.

[0240] Useful detectable agents with which antibodies or antibody portions thereof can be derivatized include fluorescent compounds. Exemplary fluorescent detectable agents include fluorescein, fluorescein isothiocyanate, rhodamine, 5-dimethylamine-1-napthalenesulfonyl chloride, phycoerythrin, and the like. Antibodies can also be derivatized with detectable enzymes, such as alkaline phosphatase, horseradish peroxidase, and glucose oxidase. When an antibody is derivatized with a detectable enzyme, the antibody is detected by adding an additional reagent that the enzyme uses to produce a detectable reaction product. For example, in the presence of the detectable agent horseradish peroxidase, the addition of hydrogen peroxide and diaminobenzidine results in a detectable colored reaction product. Antibodies can also be derivatized with biotin and detected by indirect measurement of avidin or streptavidin binding.

[0241] In one embodiment, the antibody is conjugated to an imaging agent. Examples of imaging agents that can be used in the compositions and methods described herein include, but are not limited to, radiolabels (e.g., indium), enzymes, fluorescent labels, luminescent labels, bioluminescent labels, magnetic labels, and biotin.

[0242] In one embodiment, the antibody or ADC may be, but is not limited to, indium ( 111 In). 111 Indium can be used to label the antibodies and ADCs described herein for use in identifying SEZ6L2-positive tumors. In certain embodiments, the anti-SEZ6L2 antibodies (or ADCs) described herein are labeled with a bifunctional chelator that is a bifunctional cyclohexyldiethylenetriaminepentaacetic acid (DTPA) chelate. 111I (see U.S. Patent Nos. 5,124,471, 5,434,287, and 5,286,850, each of which is incorporated herein by reference).

[0243] Another embodiment of the present disclosure provides a glycosylated binding protein in which an anti-SEZ6L2 antibody, or its antigen-binding portion, comprises one or more carbohydrate residues. Nascent in vivo protein production may undergo further processing known as post-translational modification. In particular, sugar (glycosyl) residues may be added enzymatically, a process known as glycosylation. The resulting protein with covalently linked oligosaccharide side chains is known as a glycosylated protein or glycoprotein. Antibodies are glycoproteins that contain one or more carbohydrate residues in the Fc domain as well as the variable domain. Carbohydrate residues in the Fc domain have a significant impact on the effector function of the Fc domain but have minimal impact on the antigen binding or half-life of the antibody (R. Jefferis, Biotechnol. Prog. 21 (2005), pp. 11-16). In contrast, glycosylation of the variable domain may affect the antigen-binding activity of the antibody. Glycosylation of variable domains can have a negative effect on antibody binding affinity, possibly due to steric hindrance (Co, MS et al., Mol. Immunol. (1993) 30:1361-1367), or can result in increased affinity for antigen (Wallick, SC et al., Exp. Med. (1988) 168:1099-1109; Wright, A. et al., EMBO J. (1991) 10:2717-2723).

[0244] One aspect of the present disclosure relates to the generation of glycosylation site mutants in which the O- or N-linked glycosylation site of a binding protein is mutated. Those skilled in the art can generate such mutants using standard, well-known techniques. Glycosylation site mutants that retain biological activity but have increased or decreased binding activity are another object of the present disclosure.

[0245] In yet another embodiment, the glycosylation of the anti-SEZ6L2 antibody or antigen-binding portion is modified. For example, an aglycoslated antibody can be generated (i.e., the antibody lacks glycosylation). For example, glycosylation can be altered to increase the affinity of the antibody for the antigen. Such carbohydrate modifications can be achieved, for example, by altering one or more sites of glycosylation within the antibody sequence. For example, one or more variable region glycosylation sites can be removed, thereby making one or more amino acid substitutions that result in the removal of glycosylation at that site. Such aglycosylation can increase the affinity of the antibody for the antigen. Such techniques are described in further detail in PCT Publication WO2003016466A2 and U.S. Patent Nos. 5,714,350 and 6,350,861, each of which is incorporated herein by reference in its entirety.

[0246] Additionally or alternatively, modified anti-SEZ6L2 antibodies can be generated with altered types of glycosylation, such as hypofucosylated antibodies with reduced amounts of fucosyl residues or antibodies with increased bisected GlcNAc structures. Such altered glycosylation patterns have been demonstrated to increase the ADCC ability of antibodies. Such carbohydrate modifications can be achieved, for example, by expressing the antibody in a host cell with altered glycosylation machinery. Cells with altered glycosylation machinery have been described in the art and can be used as host cells to express recombinant antibodies, thereby producing antibodies with altered glycosylation. See, e.g., Shields, R.L. et al. (2002) J. Biol. Chem. 277:26733-26740; Umana et al. (1999) Nat. Biotech. 17:176-1, as well as European Patent No. EP 1,176,195; PCT Publication No. WO 03 / 035835; WO 99 / 54342 80, each of which is incorporated herein by reference in its entirety.

[0247] Protein glycosylation depends on the amino acid sequence of the protein of interest and the host cell in which the protein is expressed. Different organisms may produce different glycosylation enzymes (e.g., glycosyltransferases and glycosidases) and may have different substrates (nucleotide sugars) available. Due to such factors, protein glycosylation patterns and glycosyl residue compositions may vary depending on the host system in which a particular protein is expressed. Useful glycosyl residues include, but are not limited to, glucose, galactose, mannose, fucose, n-acetylglucosamine, and sialic acid. Preferably, glycosylated binding proteins contain glycosyl residues such that the glycosylation pattern is human.

[0248] Different protein glycosylation can result in different protein characteristics. For example, the efficacy of a therapeutic protein produced in a microbial host, such as yeast, and glycosylated using the yeast's endogenous pathway may be reduced compared to the efficacy of the same protein expressed in mammalian cells, such as a CHO cell line. Furthermore, such glycoproteins may be immunogenic in humans and exhibit reduced in vivo half-life after administration. Specific receptors in humans and other animals may recognize specific glycosyl residues and promote rapid clearance of the protein from the bloodstream. Other adverse effects may include changes in protein folding, solubility, susceptibility to proteases, transport, compartmentalization, secretion, recognition by other proteins or factors, antigenicity, or allergenicity. Therefore, experts may prefer therapeutic proteins with specific glycosylation compositions and patterns, e.g., glycosylation compositions and patterns that are identical to or at least similar to those produced in human cells or species-specific cells of the intended target animal.

[0249] The expression of glycosylated proteins that differ from the glycosylated proteins of host cells can be achieved by genetically modifying host cells to express heterologous glycosylation enzymes.Specialists can use recombinant technology to produce antibodies or antigen-binding portions thereof that exhibit human protein glycosylation.For example, yeast strains are genetically modified to express non-naturally occurring glycosylation enzymes, so that the glycosylated proteins (glycoproteins) produced by these yeast strains exhibit the same protein glycosylation as that of animal cells, particularly human cells (US Patent Application Publication Nos. 20040018590 and 20020137134 and PCT Publication No. WO2005100584A2).

[0250] Antibodies can be produced by any of a number of techniques, such as expression from host cells in which expression vector(s) encoding the heavy and light chains have been transfected by standard techniques. The various forms of the term "transfection" are intended to encompass a wide variety of techniques commonly used to introduce foreign DNA into prokaryotic or eukaryotic host cells, such as electroporation, calcium phosphate precipitation, and DEAE-dextran transfection. While antibodies can be expressed in either prokaryotic or eukaryotic host cells, expression of antibodies in eukaryotic cells is preferred, with mammalian host cells being most preferred, since such eukaryotic cells (and particularly mammalian cells) are more likely than prokaryotic cells to assemble and secrete correctly folded, immunologically active antibodies.

[0251] Preferred mammalian host cells for expressing the recombinant antibodies disclosed herein include Chinese hamster ovary (CHO) cells (e.g., including dhfr-CHO cells described in Urlaub and Chasin (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220, used with a DHFR selectable marker as described in RJ Kaufman and PA Sharp (1982) Mol. Biol. 159:601-621), NS0 myeloma cells, COS cells, and SP2 cells. When a recombinant expression vector encoding an antibody gene is introduced into a mammalian host cell, the antibody is produced by culturing the host cell for a period sufficient to allow expression of the antibody in the host cell, or more preferably, secretion of the antibody into the culture medium in which the host cell is grown. The antibody can be recovered from the culture medium using standard protein purification methods.

[0252] Host cells can also be used to produce functional antibody fragments, such as Fab fragments or scFv molecules. Variations on the above procedures are understood to be within the scope of the present disclosure. For example, it may be desirable to transfect host cells with DNA encoding functional fragments of either the antibody light and / or heavy chains. Recombinant DNA technology can also be used to delete some or all of the DNA encoding either or both of the light and heavy chains that is not necessary for binding to the antigen of interest. Molecules expressed from such truncated DNA molecules are also encompassed by the antibodies of the present disclosure. Additionally, antibodies of the present disclosure can be crosslinked to a second antibody using standard chemical crosslinking methods to produce bifunctional antibodies in which one heavy chain and one light chain are an antibody of the present disclosure and the other heavy and light chains are specific for an antigen other than the antigen of interest.

[0253] In a preferred system for recombinantly expressing an antibody or its antigen-binding portion, a recombinant expression vector encoding both the antibody heavy chain and the antibody light chain is introduced into dhfr-CHO cells by calcium phosphate-mediated transfection. Within the recombinant expression vector, the antibody heavy and light chain genes are each operably linked to a CMV enhancer / AdMLP promoter regulatory element to drive high levels of gene transcription. The recombinant expression vector also contains a DHFR gene, allowing CHO cells transfected with the vector to be selected using methotrexate selection / amplification. Selected transformant host cells are cultured to allow expression of the antibody heavy and light chains, and intact antibody is recovered from the culture medium. Standard molecular biology techniques are used to prepare the recombinant expression vector, transfect the host cells, select for transformants, culture the host cells, and recover the antibody from the culture medium. Furthermore, the present disclosure provides a method for synthesizing recombinant antibodies by culturing host cells in a suitable culture medium until the recombinant antibody is synthesized. Recombinant antibodies can be produced using nucleic acid molecules corresponding to the amino acid sequences disclosed herein. In one embodiment, the nucleic acid molecules set forth in SEQ ID NOs: 120-155 and 246-249 (as set forth in the Sequence Summary) are used to produce the recombinant antibody. The method may further comprise isolating the recombinant antibody from the culture medium.

[0254] III. Anti-SEZ6L2 Antibody Drug Conjugates (ADCs) The anti-SEZ6L2 antibodies described herein can be conjugated to a drug moiety to form an anti-SEZ6L2 antibody-drug conjugate (ADC). Antibody-drug conjugates (ADCs) can increase the therapeutic efficacy of antibodies in treating diseases, such as cancer, due to the ability of the ADC to selectively deliver one or more drug moieties to target tissues, such as tumor-associated antigens, e.g., SEZ6L2-expressing tumors. Thus, in certain embodiments, the present disclosure provides anti-SEZ6L2 ADCs for use in therapy, e.g., for treating cancer (including, but not limited to, lung cancer, prostate cancer, and neuroendocrine tumors).

[0255] An anti-SEZ6L2 ADC comprises an anti-SEZ6L2 antibody, i.e., an antibody that specifically binds to SEZ6L2, linked to one or more drug moieties. The specificity of the ADC is defined by the specificity of the antibody, i.e., anti-SEZ6L2. In one embodiment, the anti-SEZ6L2 antibody is linked to one or more cytotoxic drugs that are delivered to the interior of cancer cells that express SEZ6L2.

[0256] Examples of drugs that can be used in anti-SEZ6L2 ADCs are provided below. Linkers that can be used to conjugate an antibody and one or more drugs are also provided below. The terms "drug," "agent," and "drug moiety" are used interchangeably herein. The terms "linked" and "conjugated" are also used interchangeably herein to indicate that an antibody and a moiety are covalently linked.

[0257] In some embodiments, the ADC has the following formula (Formula I): Ab-(LD) n (I) wherein Ab is an anti-SEZ6L2 antibody described herein, and (LD) is a linker-drug moiety. The linker-drug moiety is made up of a linker, L-, and a drug moiety, -D, that has, e.g., cytostatic, cytotoxic, or otherwise therapeutic activity against a target cell, e.g., a cell expressing SEZ6L2, and n is an integer from 1 to 20. In some embodiments, n ranges from 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, or is 1. The DAR of the ADC corresponds to "n" as referenced in Formula I.

[0258] In one embodiment, the ADC has the formula Ab-(LD) nwherein Ab is an anti-SEZ6L2 antibody, L is a linker, e.g., maleimido-caproyl-valine-citrulline (MC-VC), D is a drug, e.g., an auristatin such as MMAE, and n is 2, 4, 6, or 8 (corresponding to a DAR of 2, 4, 6, or 8). In another embodiment, n is 0 to 8 (corresponding to a DAR of 0 to 8). In one embodiment, the ADC is used to treat neuroendocrine tumors.

[0259] In one embodiment, the ADC has the formula Ab-(LD) n wherein Ab is an anti-SEZ6L2 antibody, L is a linker, e.g., a charge-hindered disulfide (sSPDB) or a cleavable peptide linker (D-Ala-L-dpa), D is a drug, e.g., a maytansinoid such as DM4, and n is 2, 4, 6, or 8 (corresponding to a DAR of 2, 4, 6, or 8). In another embodiment, n is 0-8 (corresponding to a DAR of 0-8). In one embodiment, the ADC is used to treat neuroendocrine tumors.

[0260] In one embodiment, the ADC has the formula Ab-(LD) n wherein Ab is an anti-SEZ6L2 antibody, L is a linker, e.g., a cleavable peptide linker (D-Ala-L-dpa), D is a drug, e.g., a DNA alkylating agent such as IGN, and n is 2, 4, 6, or 8 (corresponding to a DAR of 2, 4, 6, or 8). In another embodiment, n is 0 to 8 (corresponding to a DAR of 0 to 8). In one embodiment, the ADC is used to treat small cell lung cancer (SCLC).

[0261] Additional details regarding drugs (D in Formula I) and linkers (L in Formula I) that can be used in ADCs, as well as alternative ADC structures, are provided below.

[0262] A. Anti-SEZ6L2 ADCs: Exemplary Drugs for Conjugation Anti-SEZ6L2 antibodies can be used in ADCs to target one or more drugs to cells of interest, such as cancer cells that express SEZ6L2. The anti-SEZ6L2 ADCs disclosed herein deliver one or more drugs to specific cells, providing targeted therapy that can reduce side effects often seen with anti-cancer treatments, for example.

[0263] Auristatin The anti-SEZ6L2 antibody may be conjugated to at least one auristatin. Auristatins generally represent a group of dolastatin analogs that have been shown to have anticancer activity by interfering with microtubule dynamics and GTP hydrolysis, thereby inhibiting cell division. For example, auristatin E (U.S. Pat. No. 5,635,483) is a synthetic analog of the natural marine product dolastatin 10, a compound that inhibits tubulin polymerization by binding to the same site on tubulin as the anticancer drug vincristine (GR Pettit, Prog. Chem. Org. Nat. Prod., 70, 1-79 (1997)). Dolastatin 10, auristatin PE, and auristatin E are linear peptides with four amino acids, three of which are unique to the dolastatin class of compounds. Exemplary embodiments of the auristatin subclass of antimitotic agents include, but are not limited to, the following: monomethyl auristatin D (MMAD or auristatin D derivatives), monomethyl auristatin E (MMAE or auristatin E derivatives), monomethyl auristatin F (MMAF or auristatin F derivatives), auristatin F phenylenediamine (AFP), auristatin EB (AEB), auristatin EFP (AEFP), and 5-benzoylvaleric acid-AE ester (AEVB).The synthesis and structure of auristatin derivatives are described in U.S. Patent Application Publication Nos. 2003-0083263, 2005-0238649, and 2005-0009751; International Patent Publication Nos. WO 04 / 010957, WO 02 / 088172, and U.S. Patent Publication Nos. 6,323,315; 6,239,104; 6,034,065; 5,780,588; 5,665,860; 5,663,149; 5,635,4 83; 5,599,902; 5,554,725; 5,530,097; 5,521,284; 5,504,191; 5,410,024; 5,138,036; 5,076,973; 4,986,988; 4,978,744; 4,879,278; 4,816,444; and 4,486,414, each of which is incorporated herein by reference.

[0264] In one embodiment, the anti-SEZ6L2 antibody is conjugated to at least one MMAE (monomethyl auristatin E). Monomethyl auristatin E (MMAE, vedotin) inhibits cell division by blocking tubulin polymerization. It is highly toxic and cannot be used as a drug itself. In recent cancer treatment developments, it is linked to a monoclonal antibody (mAb) that recognizes specific marker expression on cancer cells and targets MMAE to cancer cells. In one embodiment, the linker connecting MMAE to the anti-SEZ6L2 antibody is stable in extracellular fluid (i.e., the medium or environment outside the cells), but is cleaved by cathepsin when the ADC binds to a specific cancer cell antigen and enters the cancer cell, thereby releasing the toxic MMAE and activating a potent anti-mitotic mechanism.

[0265] The structure of MMAE is provided below. [ka]

[0266] In one embodiment, the antibody is coupled to a single drug and therefore has a DAR of 1. In certain embodiments, the ADC has a DAR of 2-8, or alternatively, 2-4.

[0267] Maytansinoids Anti-SEZ6L2 antibodies can be conjugated to at least one maytansinoid to form an ADC. Maytansinoids are potent antitumor agents originally isolated from members of the higher plant families Celastraceae, Rhamnaceae, and Euphorbiaceae and several species of moss (Kupchan et al., J. Am. Chem. Soc. 94:1354-1356

[1972] ; Wani et al., J. Chem. Soc. Chem. Commun. 390:

[1973] ; Powell et al., J. Nat. Prod. 46:660-666

[1983] ; Sakai et al., J. Nat. Prod. 51:845-850

[1988] ; and Suwanborirux et al., Experientia 46:117-120

[1990] ). Evidence suggests that maytansinoids inhibit mitosis by inhibiting the polymerization of the microtubule protein tubulin, thereby preventing the formation of microtubules (see, e.g., U.S. Pat. No. 6,441,163, and Remillard et al., Science 189:1002-1005 (1975)). Maytansinoids have been shown to inhibit tumor cell growth in vitro using cell culture models and in vivo using experimental animal systems, and their cytotoxicity is 1,000-fold greater than that of conventional chemotherapeutic agents, such as methotrexate, daunorubicin, and vincristine (see, e.g., U.S. Patent No. 5,208,020).

[0268] Maytansinoids include maytansine, maytansinol, C-3 esters of maytansinol, and other maytansinol analogs and derivatives (see, e.g., U.S. Pat. Nos. 5,208,020 and 6,441,163, each of which is incorporated herein by reference). C-3 esters of maytansinol may be naturally occurring or synthetically derived. Furthermore, both naturally occurring and synthetic C-3 maytansinol esters can be classified as C-3 esters with simple carboxylic acids or C-3 esters with derivatives of N-methyl-L-alanine, the latter being more cytotoxic than the former. Synthetic maytansinoid analogs are described, for example, in Kupchan et al., J. Med. Chem., 21, 31-37 (1978).

[0269] Suitable maytansinoids for use in ADCs can be isolated from natural sources, synthetically produced, or semi-synthetically produced. Furthermore, maytansinoids can be modified in any suitable manner, as long as sufficient cytotoxicity is maintained in the final conjugate molecule. In this regard, maytansinoids lack suitable functional groups that can be linked to antibodies. To link maytansinoids to antibodies to form conjugates, it is desirable to use linking moieties.

[0270] The structure of an exemplary maytansinoid, 4-methyl-4-mercapto-1-oxopentyl)-maytansine (DM4), is provided below. [ka]

[0271] Representative examples of maytansinoids include, but are not limited to, the following: DM1 (N 2 '-Deacetyl-N 2'-(3-mercapto-1-oxopropyl)-maytansine; also known as mertansine, the drug maytansinoid 1; ImmunoGen, Inc.; see also Chari et al. (1992) Cancer Res 52:127), DM2, DM3 (N 2 '-Deacetyl-N 2 '-(4-mercapto-1-oxopentyl)-maytansine), DM4 ((4-methyl-4-mercapto-1-oxopentyl)-maytansine), and maytansinol (a synthetic maytansinoid analog). Other examples of maytansinoids are described in U.S. Pat. No. 8,142,784, which is incorporated herein by reference.

[0272] Ansamitocins are a group of maytansinoid antibiotics isolated from various bacterial sources.These compounds have strong antitumor activity.Representative examples include, but are not limited to, ansamitocin P1, ansamitocin P2, ansamitocin P3, and ansamitocin P4.

[0273] In one embodiment, the anti-SEZ6L2 antibody is conjugated to at least one DM1. In one embodiment, the anti-SEZ6L2 antibody is conjugated to at least one DM2. In one embodiment, the anti-SEZ6L2 antibody is conjugated to at least one DM3. In one embodiment, the anti-SEZ6L2 antibody is conjugated to at least one DM4.

[0274] DNA alkylating agents The term "DNA alkylating agents" as used herein includes a family of DNA alkylating agents, including indolino-benzodiazepines (IGNs). IGNs have high in vitro potency against cancer cells (IC in the low pmol / L range). 50IGNs represent a chemical class of cytotoxic molecules with a cytotoxicity value (value). Examples of IGN DNA alkylating agents that can be used as cytotoxic payloads in ADCs are described in Miller et al. (2016) Molecular Cancer Therapeutics, Vol. 15 (No. 8). The IGN compounds described in Miller et al. bind to the minor groove of DNA, followed by a covalent reaction between guanine residues and two imine functional groups in the molecule, resulting in cross-linking of the DNA. The structure of an exemplary IGN is provided below. [ka]

[0275] Other drugs for conjugation Examples of drugs that can be used in ADCs, i.e., drugs that can be conjugated to anti-SEZ6L2 antibodies, are provided below and include: antimitotic agents, antitumor antibiotics, immunomodulators, gene therapy vectors, alkylating agents, antiangiogenic agents, antimetabolites, boron-containing agents, chemoprotective agents, hormonal agents, glucocorticoids, photoactive therapeutic agents, oligonucleotides, radioisotopes, radiosensitizers, topoisomerase inhibitors, tyrosine kinase inhibitors, and combinations thereof.

[0276] 1. Mitotic inhibitors In one aspect, an anti-SEZ6L2 antibody can be conjugated to one or more anti-mitotic agents to form an ADC for treating cancer. The term "anti-mitotic agent" as used herein refers to a cytotoxic and / or therapeutic agent that blocks mitosis, or cell division, a biological process particularly important to cancer cells. Anti-mitotic agents often disrupt microtubules by causing microtubule polymerization or microtubule depolymerization, thereby preventing cell division. Thus, in one embodiment, an anti-SEZ6L2 antibody is conjugated to one or more anti-mitotic agents that disrupt microtubule formation by inhibiting tubulin polymerization. In one embodiment, the anti-mitotic agent used in the ADC is Ixempra (ixabepilone). Examples of mitotic inhibitors that can be used in anti-SEZ6L2 ADCs include dolastatins, such as dolastatin 10 and dolastatin 15, and plant alkaloids, such as taxanes and vinca alkaloids, such as indesine sulfate, vincristine, vinblastine, and vinorelbine. Classes of mitotic inhibitors include the auristatins and maytansinoids described above.

[0277] The anti-SEZ6L2 antibody described herein may be conjugated to at least one taxane. As used herein, the term "taxane" refers to a class of anti-neoplastic agents that have a microtubule-acting mechanism and a structure containing a taxane ring structure and a stereospecific side chain required for cytostatic activity. The term "taxane" also includes various known derivatives, including both hydrophilic and hydrophobic derivatives. Taxane derivatives include, but are not limited to, the galactose and mannose derivatives described in International Patent Application No. 99 / 18113, the piperazino and other derivatives described in International Publication No. 99 / 14209, the taxane derivatives described in International Publication Nos. 99 / 09021, 98 / 22451, and U.S. Pat. No. 5,869,680, the 6-thio derivatives described in International Publication No. 98 / 28288, the sulfenamide derivatives described in U.S. Pat. No. 5,821,263, and the taxol derivatives described in U.S. Pat. No. 5,415,869, each of which is incorporated herein by reference. Taxane compounds have previously been disclosed in U.S. Patent Nos. 5,641,803, 5,665,671, 5,380,751, 5,728,687, 5,415,869, 5,407,683, 5,399,363, 5,424,073, 5,157,049, 5,773,464, 5, Also described in Patents 821,263, 5,840,929, 4,814,470, 5,438,072, 5,403,858, 4,960,790, 5,433,364, 4,942,184, 5,362,831, 5,705,503 and 5,278,324.All of these documents are expressly incorporated by reference.Further examples of taxanes include but are not limited to docetaxel (Taxotere; Sanofi Aventis), paclitaxel (Abraxane or Taxol; Abraxis Oncology) and nanoparticle paclitaxel (ABI-007 / Abraxane; Abraxis Bioscience).

[0278] 2. Antitumor antibiotics The anti-SEZ6L2 antibody may be conjugated to one or more antitumor antibiotics for treating cancer. As used herein, the term "antitumor antibiotic" refers to an anti-neoplastic drug made from a microorganism that blocks cell growth by interfering with DNA. In many cases, antitumor antibiotics either damage DNA strands or slow or stop DNA synthesis. Examples of antitumor antibiotics that may be included in an anti-SEZ6L2 ADC include, but are not limited to, actinomycin (e.g., pyrrolo[2,1-c][1,4]benzodiazepine), anthracycline, calicheamicin, and duocarmycin. In addition to the above, anti-SEZ6L2 Additional antitumor antibiotics that can be used in ADCs include bleomycin (Blenoxane, Bristol-Myers Squibb), mitomycin, and plicamycin (also known as mithramycin).

[0279] 3. Immunomodulators In one aspect, the anti-SEZ6L2 antibody may be conjugated to at least one immunomodulator. As used herein, the term "immunomodulator" refers to an agent capable of stimulating or modifying an immune response. In one embodiment, the immunomodulator is an immunostimulator that enhances a subject's immune response. In another embodiment, the immunomodulator is an immunosuppressant that prevents or reduces a subject's immune response. The immunomodulator can modulate myeloid cells (monocytes, macrophages, dendritic cells, megakaryocytes, and granulocytes) or lymphoid cells (T cells, B cells, and natural killer (NK) cells), and any further differentiated cells thereof. Representative examples include, but are not limited to, bacillus calmette-guerin (BCG) and levamisole (Ergamisol). Other examples of immunomodulators that can be used in ADCs include, but are not limited to, cancer vaccines and cytokines.

[0280] As used herein, the term "cancer vaccine" refers to a composition (e.g., tumor antigens and cytokines) that induces a tumor-specific immune response. The response is elicited from a subject's own immune system by administering a cancer vaccine, or in the case of the present disclosure, by administering an ADC comprising an anti-SEZ6L2 antibody and a cancer vaccine. In a preferred embodiment, the immune response results in the eradication of tumor cells (e.g., primary or metastatic tumor cells) in the body. The use of cancer vaccines generally involves administering a specific antigen or group of antigens, for example, present on the surface of specific cancer cells or on the surface of a specific infectious agent shown to promote cancer formation. In some embodiments, the use of cancer vaccines is for prophylactic purposes, while in other embodiments, the use is for therapeutic purposes. Anti-SEZ6L2 Non-limiting examples of cancer vaccines that can be used in ADCs include: recombinant bivalent human papillomavirus (HPV) types 16 and 18 vaccine (Cervarix, GlaxoSmithKline), recombinant quadrivalent human papillomavirus (HPV) types 6, 11, 16, and 18 vaccine (Gardasil, Merck & Company), and sipuleucel-T (Provenge, Dendreon). Thus, in one embodiment, the anti-SEZ6L2 antibody is conjugated to at least one cancer vaccine that is either an immunostimulatory agent or an immunosuppressant.

[0281] The anti-SEZ6L2 antibody may be conjugated to at least one cytokine. The term "cytokine" generally refers to a protein released by one cell population and acting as an intercellular mediator on another cell. Cytokines directly stimulate immune effector cells and stromal cells at the tumor site and enhance tumor cell recognition by cytotoxic effector cells (Lee and Margolin (2011) Cancers 3:3856). Numerous animal tumor model studies have demonstrated that cytokines have broad antitumor activity, which has translated into many cytokine-based approaches for cancer therapy (Lee and Margolin, supra). In recent years, many cytokines, including GM-CSF, IL-7, IL-12, IL-15, IL-18, and IL-21, have been discovered and have begun clinical trials in patients with advanced cancer (Lee and Margolin, supra).

[0282] Examples of cytokines that can be used in ADCs include, but are not limited to, parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; prorelaxin; glycoprotein hormones such as follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), and luteinizing hormone (LH); hepatic growth factor; fibroblast growth factor; prolactin; placental lactogen; tumor necrosis factor; Mullerian inhibitory substance; mouse gonadotropin-related peptide; inhibin; activin; vascular endothelial growth factor; integrins; thrombopoietin (TPO); and cytokines such as NGF. Transgenic growth factors; platelet growth factors; transforming growth factors (TGFs); insulin-like growth factors I and II; erythropoietin (EPO); osteogenic factors; interferons such as interferons α, β, and γ; colony-stimulating factors (CSFs); granulocyte-macrophage colony-stimulating factor (GM-CSF); and granulocyte-CSF (G-CSF); interleukins (ILs) such as IL-1, IL-1α, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-11, and IL-12; tumor necrosis factors; and other polypeptide factors, including LIF and kit ligand (KL). As used herein, the term cytokine includes proteins derived from natural sources or from recombinant cell culture and biologically active equivalents of native-sequence cytokines. Thus, in one embodiment, the present disclosure provides an ADC comprising an anti-SEZ6L2 antibody and a cytokine described herein.

[0283] The anti-SEZ6L2 antibody may be conjugated to at least one colony-stimulating factor (CSF). Colony-stimulating factors (CSFs) are growth factors that help bone marrow produce red blood cells. Because some cancer treatments (e.g., chemotherapy) can affect white blood cells (which help fight infection), colony-stimulating factors can be introduced to help maintain white blood cell levels and strengthen the immune system. Colony-stimulating factors can also be used to help new bone marrow start producing white blood cells after bone marrow transplantation. Representative examples of CSFs that can be used in anti-SEZ6L2 ADCs include, but are not limited to, erythropoietin (Epoetin), filgrastim (Neopogen (also known as granulocyte colony-stimulating factor (G-CSF); Amgen, Inc.)), sargramostim (leukine (granulocyte-macrophage colony-stimulating factor and GM-CSF); Genzyme Corporation), promegapoietin, and oprelvekin (recombinant IL-11; Pfizer, Inc.). Thus, in one embodiment, an ADC may comprise an anti-SEZ6L2 antibody described herein and a CSF.

[0284] 4. Alkylating agents The anti-SEZ6L2 antibody may be conjugated to one or more alkylating agents. Alkylating agents are a class of anti-neoplastic compounds that attach alkyl groups to DNA. Examples of alkylating agents that can be used in ADCs include, but are not limited to, alkyl sulfonates, ethylenimines, methylamine derivatives, epoxides, nitrogen mustards, nitrosoureas, triazines, and hydrazines.

[0285] 5. Anti-angiogenic agents In one aspect, the anti-SEZ6L2 antibody described herein is conjugated to at least one anti-angiogenic agent. Anti-angiogenic agents inhibit the growth of new blood vessels. Anti-angiogenic agents exert their effects in various ways. In some embodiments, such agents interfere with the ability of growth factors to reach their targets. For example, vascular endothelial growth factor (VEGF) is one of the key proteins involved in the initiation of angiogenesis by binding to specific receptors on the cell surface. Therefore, certain anti-angiogenic agents that prevent VEGF from interacting with its cognate receptor prevent VEGF from initiating angiogenesis. In other embodiments, such agents interfere with intracellular signaling cascades. For example, once specific receptors on the cell surface are activated, a cascade of other chemical signals is initiated, promoting blood vessel growth. Therefore, certain enzymes, such as some tyrosine kinases, that are known to promote intracellular signaling cascades that contribute to, for example, cell proliferation, are targets for cancer treatment. In other embodiments, such agents interfere with intercellular signaling cascades. In other embodiments, however, such agents neutralize specific targets that activate and promote cell growth or directly interfere with the growth of vascular cells. Angiogenesis inhibitory properties have been discovered in over 300 substances, with numerous direct and indirect inhibitory effects.

[0286] Representative examples of antiangiogenic agents that can be used in ADCs include, but are not limited to, the following: angiostatin, ABX EGF, C1-1033, PKI-166, EGF vaccine, EKB-569, GW2016, ICR-62, EMD55900, CP358, PD153035, AG1478, IMC-C225 (Erbitux, ZD1839 (Iressa)), OSI-774, erlotinib (Tarceva), angiostatin, arrestin, endostatin, BAY12-9566 and fluorouracil or doxorubicin with canstatin, carboxyamidotriozole and paclitaxel with EMD121974, S-24, vitaxin, dimethylxanthenone acetic acid, IM862, interleukin-12, interleukin-13, -2, NM-3, HuMV833, PTK787, RhuMab, angiozyme (ribozyme), IMC-1C11, neovastat, marimastat, prinomastat, BMS-275291, COL-3, MM1270, SU101, SU6668, SU11248, SU5416, with paclitaxel, with gemcitabine and cisplatin, with irinotecan and cisplatin, and with radiation, tecogalan, temozolomide and PEG-interferon alpha 2b, tetrathiomolybdate, TNP-470, thalidomide, CC-5013 and taxotere, tumstatin, 2-methoxyestradiol, VEGF trap, mTOR inhibitors (dehololimus, everolimus (Afinitor, Novartis Pharmaceutical Corporation), and temsirolimus (Torisel, Pfizer, Inc.)), tyrosine kinase inhibitors (e.g., erlotinib (Tarceva, Genentech, Inc.), imatinib (Gleevec, Novartis Pharmaceutical Corporation), gefitinib (Iressa, AstraZeneca Pharmaceuticals), dasatinib (Sprycel, Brystol-Myers Squibb), sunitinib (Sutent, Pfizer, Inc.)), nilotinib (Tasigna, Novartis Pharmaceutical Corporation), lapatinib (Tykerb, GlaxoSmithKline Pharmaceuticals), sorafenib (Nexavar, Bayer and Onyx), and phosphoinositide 3-kinase (PI3K).

[0287] 6. Antimetabolites The anti-SEZ6L2 antibody may be conjugated to at least one antimetabolite. An antimetabolite is a type of chemotherapy treatment that closely mimics normal substances within cells. When cells incorporate an antimetabolite into their metabolism, the results are negative for the cell, for example, the cell cannot divide. Antimetabolites are classified according to the substance they interfere with. As described in more detail below, examples of antimetabolites that can be used in ADCs include, but are not limited to, folate antagonists (e.g., methotrexate), pyrimidine antagonists (e.g., 5-fluorouracil, foxuridine, cytarabine, capecitabine, and gemcitabine), purine antagonists (e.g., 6-mercaptopurine and 6-thioguanine), and adenosine deaminase inhibitors (e.g., cladribine, fludarabine, nelarabine, and pentostatin).

[0288] 7. Boron-containing agents The anti-SEZ6L2 antibody may be conjugated with at least one boron-containing agent. The boron-containing agent comprises a class of cancer treatment compounds that interfere with cell proliferation. Representative examples of boron-containing agents include, but are not limited to, borophycin and bortezomib (Velcade, Millenium Pharmaceuticals).

[0289] 8. Chemical protectants The anti-SEZ6L2 antibody may be conjugated to at least one chemoprotectant. Chemoprotectants are a class of compounds that help protect the body from certain toxic effects of chemotherapy. Chemoprotectants can be administered with various chemotherapy regimens to protect healthy cells from the toxic effects of the chemotherapy while simultaneously allowing cancer cells to be treated with the administered chemotherapy. Representative chemoprotectants include, but are not limited to, amifostine (Ethyol, Mediimmune, Inc.), which is used to reduce nephrotoxicity associated with cumulative doses of cisplatin, dexrazoxane (Totect, Apricus Pharma; Zinecard), to treat extravasation caused by the administration of anthracyclines (Totect), and to treat cardiac complications caused by the administration of the antitumor antibiotic doxorubicin (Zinecard), and mesna (Mesnex, Bristol-Myers Squibb), which is used to prevent hemorrhagic cystitis during chemotherapy treatment with ifosfamide.

[0290] 9. Photoactive therapeutic agents The anti-SEZ6L2 antibody may be conjugated to at least one photoactive therapeutic agent. Photoactive therapeutic agents include compounds that can be configured to kill treated cells upon exposure to specific wavelengths of electromagnetic radiation. Therapeutically relevant compounds absorb electromagnetic radiation at wavelengths that penetrate tissue. In preferred embodiments, the compound is administered in a non-toxic form that, upon sufficient activation, can produce a photochemical effect that is toxic to cells or tissues. In other preferred embodiments, such compounds are retained by cancerous tissues and readily excreted from normal tissues. Non-limiting examples include various chromagens and dyes.

[0291] 10. Radionuclide drugs (radioisotopes) The anti-SEZ6L2 antibody may be conjugated to at least one radionuclide agent. Radionuclide agents include agents characterized by an unstable nucleus capable of undergoing radioactive decay. The success of radionuclide treatment depends on sufficient radionuclide concentration and long-term retention of the radionuclide by cancer cells. Other factors to consider include the radionuclide half-life, the energy of the emitted particle, and the maximum distance the emitted particle can travel. In a preferred embodiment, the therapeutic agent is 111 In, 177 Lu, 212 Bi, 213 Bi, 211 At, 62 Cu, 64 Cu, 67 Cu, 90 Y, I25 I, I31 I, 32 P, 33 P, 47 Sc, 111 Ag, 67 Ga, 142 Pr, 153 Sm, 161 Tb, 166 Dy, 166 Ho, 186 Re, 188 Re, 189 Re, 212 Pb, 223 Ra, 225 Ac, 59 Fe, 75 Se, 77 As, 89 Sr, 99 Mo, 105 Rh, I09 Pd, 143 Pr, 149 Pm, 169 Er, 194 Ir, 198 Au, 199 Au, and 211The radionuclides are preferably selected from the group consisting of Co-58, Ga-67, Br-80m, Tc-99m, Rh-103m, Pt-109, In-111, Sb-119, I-125, Ho-161, Os-189m, and Ir-192. The decay energies of useful beta particle-emitting nuclides are preferably Dy-152, At-211, Bi-212, Ra-223, Rn-219, Po-215, Bi-211, Ac-225, Fr-221, At-217, Bi-213, and Fm-255. Useful alpha particle-emitting radionuclides preferably have decay energies between 2,000 and 10,000 keV, more preferably between 3,000 and 8,000 keV, and most preferably between 4,000 and 7,000 keV. Additional potentially useful radionuclides include: 11 C. 13 N, 15 0, 75 Br, 198 Au, 224 Ac, 126 I, 133 I, 77 Br, 113m In, 95 Ru, 97 Ru, I03 Ru, 105 Ru, 107 Hg, 203 Hg, 121m Te, 122m Te, 125m Te, 165 Tm, I67 Tm, 168 Tm, 197 Pt, 109 Pd, 105 Rh, 142 Pr, 143 Pr, 161 Tb, !66 Ho, 199 Au, 57 Co, 58 Co, 51 Cr, 59 Fe, 75 Se, 201 Tl, 225 Ac, 76 Br,I69 Examples include Yb.

[0292] 11.Radiosensitizers The anti-SEZ6L2 antibody may be conjugated to at least one radiosensitizer. The term "radiosensitizer," as used herein, is defined as a molecule, preferably a low-molecular-weight molecule, administered to an animal in a therapeutically effective amount to increase the radiosensitization sensitivity of cells to electromagnetic radiation and / or to promote the treatment of diseases treatable with electromagnetic radiation. A radiosensitizer is an agent that makes cancer cells more sensitive to radiation treatment, but typically has much less effect on normal cells. Thus, a radiosensitizer can be used in combination with a radioisotope-labeled antibody or ADC. The addition of a radiosensitizer can result in enhanced efficacy compared to treatment with a radioisotope-labeled antibody or antibody fragment alone. Radiosensitizers are described in D. M. Goldberg (ed.), Cancer Therapy with Radiolabeled Antibodies, CRC Press (1995). Examples of radiosensitizers include gemcitabine, 5-fluorouracil, taxanes, and cisplatin.

[0293] Radiosensitizers can be activated by electromagnetic radiation such as X-rays. Representative examples of X-ray-activated radiosensitizers include, but are not limited to, metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C, RSU1069, SR4233, E09, RB6145, nicotinamide, 5-bromodeoxyuridine (BUdR), 5-iododeoxyuridine (IUdR), bromodeoxycytidine, fluorodeoxyuridine (FUdR), hydroxyurea, cisplatin, and their therapeutically effective analogs and derivatives. Alternatively, radiosensitizers can be activated using photodynamic therapy (PDT). Representative examples of photodynamic radiosensitizers include, but are not limited to, hematoporphyrin derivatives, photofrin(r), benzoporphyrin derivatives, NPe6, tin etioporphyrin (SnET2), pheoborbide a, bacteriochlorophyll a, naphthalocyanines, phthalocyanines, zinc phthalocyanines, and their therapeutically active analogs and derivatives.

[0294] 12. Topoisomerase inhibitors The anti-SEZ6L2 antibody may be conjugated to at least one topoisomerase inhibitor.Topoisomerase inhibitors are chemotherapeutic agents designed to interfere with the action of topoisomerase enzymes (topoisomerase I and II), which control changes in DNA structure by catalytically breaking and rejoining the phosphodiester backbone of DNA strands during the normal cell cycle.Representative examples of DNA topoisomerase I inhibitors include, but are not limited to, camptothecin and its derivative irinotecan (CPT-11, Camptosar, Pfizer, Inc.) and topotecan (Hycamtin, GlaxoSmithKline Pharmaceuticals). Representative examples of DNA topoisomerase II inhibitors include, but are not limited to, amsacrine, daunorubicin, doxotrubicin, epipodophyllotoxin, ellipticine, epirubicin, etoposide, razoxane, and teniposide.

[0295] 13. Tyrosine kinase inhibitors The anti-SEZ6L2 antibody may be conjugated to at least one tyrosine kinase inhibitor. Tyrosine kinase is an intracellular enzyme that functions to attach a phosphate group to the amino acid tyrosine. Blocking the function of protein tyrosine kinase can inhibit tumor growth. Examples of tyrosine kinase inhibitors that can be used in ADCs include, but are not limited to, axitinib, bosutinib, cediranib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sunitinib, and vandetanib.

[0296] 14. Other medications Examples of other agents that can be used in ADCs include, but are not limited to, abrin (e.g., abrin A chain), alpha toxin, Aleurites fordii proteins, amatoxin, crotin, curcin, dianthin proteins, diphtheria toxin (e.g., diphtheria A chain and non-binding active fragments of diphtheria toxin), deoxyribonuclease (Dnase), gelonin, mitogellin, modeccin A chain, momordica charantia inhibitor, neomycin, onconase, phenomycin, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), pokeweed antiviral protein, Pseudomonas endotoxin, Pseudomonas exotoxin (e.g., exotoxin A chain (from Pseudomonas aeruginosa)), restrictocin, ricin A chain, ribonuclease (Rnase), sapaonaria officinalis inhibitors, saporin, alpha-sarcin, Staphylococcal enterotoxin-A, tetanus toxin, cisplatin, carboplatin, and oxaliplatin (Eloxatin, Sanofi Aventis), proteasome inhibitors (e.g., PS-341 [bortezomib or Velcade]), HDAC inhibitors (vorinostat (Zolinza, Merck & Company, Inc.), belinostat, entinostat, mocetinostat, and panobinostat), COX-2 inhibitors, substituted ureas, heat shock protein inhibitors (e.g., geldanamycin and its numerous analogs), adrenocortical suppressants, and trichothecenes (see, e.g., WO 93 / 21232). Other agents also include asparaginase (Espar, Lundbeck Inc.), hydroxyurea, levamisole, mitotane (Lysodren, Bristol-Myers Squibb), and tretinoin (Renova, Valeant Pharmaceuticals Inc.).

[0297] In one embodiment, the agent is a pyrrolobenzodiazepine (PBD). In one embodiment, the agent is a PARP inhibitor, such as olaparib, rucaparib, niraparib, or iniparib. In one embodiment, the PARP inhibitor is olaparib. In one embodiment, the PARP inhibitor is rucaparib. In one embodiment, the PARP inhibitor is niraparib. In one embodiment, the PARP inhibitor is iniparib. In one embodiment, the agent is saporin toxin.

[0298] It should be noted that the above-described groups of drug moieties that can be used in anti-SEZ6L2 ADCs are not exclusive, in that a particular example of a drug may be found in more than one category; for example, ansamitocins are both antimitotic agents and antitumor antibiotics.

[0299] All stereoisomers of the above drug moieties, ie, any combination of R and S configurations at the chiral carbon of D, are contemplated for use herein.

[0300] The above-mentioned agents (i.e., naked agents not conjugated to an antibody) may also be used in combination therapy with the anti-SEZ6L2 antibodies described herein. In one embodiment, an anti-SEZ6L2 antibody or ADC is used with any of the above-mentioned agents in combination therapy to treat cancer, in which case the agent is administered before, simultaneously with, or after administration of the anti-SEZ6L2 antibody or ADC to a subject.

[0301] B. Anti-SEZ6L2 ADCs: Exemplary Linkers An anti-SEZ6L2 ADC comprises an anti-SEZ6L2 antibody and at least one drug, wherein the antibody and at least one drug are conjugated via a linker. The term "linker," as used herein, refers to a chemical moiety that can be bifunctional or multifunctional and is used to link an antibody to a drug moiety. The linker may contain one conjugation component or multiple components.

[0302] For example, a linker may include a spacer, which is a moiety that extends the drug linkage, e.g., to avoid blocking the active site of the antibody or to improve the solubility of the ADC. Other examples of linker components include stretcher units and amino acid units.

[0303] Two methods are commonly used to conjugate drugs to antibodies: alkylation of reduced interchain cysteine ​​disulfides via enzymatically non-cleavable maleimide or simple cleavable disulfide linkers, and acylation of lysines with cleavable linear amino acids.

[0304] In one embodiment, the linker covalently attaches the antibody to the drug moiety. ADCs are prepared using a linker with a reactive functionality for binding to the antibody and the drug. For example, a cysteine ​​thiol or amine, e.g., the N-terminus, or an amino acid side chain such as lysine, of the antibody can form a bond with the functional group of the linker.

[0305] In one embodiment, the linker has a functional group that can react with a free cysteine ​​present in an antibody to form a covalent bond. Non-limiting examples of such reactive functional groups include activated esters such as maleimide, haloacetamide, □-haloacetyl, succinimide ester, 4-nitrophenyl ester, pentafluorophenyl ester, tetrafluorophenyl ester, anhydride, acid chloride, sulfonyl chloride, isocyanate, and isothiocyanate. See, for example, Klussman et al. (2004) Bioconjugate Chemistry, 15(4):765-773, conjugation methods on page 766.

[0306] In some embodiments, the linker has a functional group capable of reacting with an electrophilic group present on an antibody. Exemplary such electrophilic groups include, but are not limited to, aldehyde groups and ketone carbonyl groups. In some embodiments, the heteroatom of the reactive functional group of the linker can react with an electrophilic group on an antibody to form a covalent bond with an antibody unit. Non-limiting exemplary such reactive functional groups include, but are not limited to, hydrazide, oxime, amino, hydrazine, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide.

[0307] In one aspect, the anti-SEZ6L2 antibody is conjugated to an auristatin, e.g., MMAE, via a linker comprising maleimidocaproyl ("mc"), valine citrulline (val-cit or "vc"). Maleimidocaproyl acts as a linker to the anti-SEZ6L2 antibody and is not cleavable. Val-cit is an amino acid unit of the linker, a dipeptide that allows cleavage of the linker by proteases, specifically the protease cathepsin B. Thus, the val-cit component of the linker provides a means for releasing the auristatin from the ADC upon exposure to the intracellular environment. In one embodiment, p-aminobenzyl alcohol (PABA) acts as a spacer within the linker and is self-immolative, allowing for release of the MMAE.

[0308] In another embodiment, the anti-SEZ6L2 antibody is conjugated to a maytansinoid (e.g., DM4) via a charge-hindered disulfide N-succinimidyl-4-(2-pyridyldithio)butanoate (sSPDB) linker. sSPDB is a cleavable linker that allows the conjugate to be cleaved within the target cell in the cytosol by the reducing intracellular environment.

[0309] In another embodiment, the anti-SEZ6L2 antibody is conjugated to a maytansinoid (eg, DM4) via a cleavable peptide linker, such as D-Ala-L-dpa.

[0310] In another embodiment, the anti-SEZ6L2 antibody is conjugated to the IGN via a cleavable peptide linker, such as D-Ala-L-dpa.

[0311] Suitable linkers include, for example, cleavable linkers and non-cleavable linkers. The linker may be a "cleavable linker" that facilitates release of the drug. Non-limiting exemplary cleavable linkers include an acid-labile linker (e.g., containing a hydrazone), a protease-sensitive (e.g., peptidase-sensitive) linker, a photolabile linker, or a disulfide-containing linker (Chari et al., Cancer Research 52:127-131 (1992); U.S. Patent No. 5,208,020. Cleavable linkers are typically susceptible to cleavage under intracellular conditions. Suitable cleavable linkers include, for example, peptide linkers that are cleavable by intracellular proteases, such as lysosomal or endosomal proteases. In exemplary embodiments, the linker may be a dipeptide linker, such as a valine-citrulline (val-cit) linker or a phenylalanine-lysine (phe-lys) linker.

[0312] The linker is preferably stable outside the cell in a manner sufficient to be therapeutically effective. Before transport or delivery into the cell, the ADC is preferably stable and remains intact, i.e., the antibody remains conjugated to the drug moiety. A linker that is stable outside the target cell can be cleaved at an effective rate once inside the cell. Thus, an effective linker (i) maintains the specific binding properties of the antibody, (ii) enables delivery, e.g., intracellular delivery, of the drug moiety, and (iii) maintains the therapeutic effect, e.g., cytotoxic effect, of the drug moiety.

[0313] In one embodiment, the linker is cleavable under intracellular conditions, and cleavage of the linker allows the drug to be sufficiently released from the antibody in the intracellular environment to be therapeutically effective. In some embodiments, the cleavable linker is pH-sensitive, i.e., sensitive to hydrolysis at a certain pH value. Typically, pH-sensitive linkers are hydrolyzable under acidic conditions. For example, acid-labile linkers (e.g., hydrazones, semicarbazones, thiosemicarbazones, cis-aconitic acid amides, orthoesters, acetals, ketals, etc.) that are hydrolyzable in lysosomes can be used. (See, e.g., U.S. Pat. Nos. 5,122,368; 5,824,805; 5,622,929; Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-123; Neville et al., 1989, Biol. Chem. 264:14653-14661.) Such linkers are relatively stable under neutral pH conditions, such as those found in blood, but are unstable at pHs below 5.5 or 5.0, the approximate pH of the lysosome. In certain embodiments, the hydrolyzable linker is a thioether linker, such as a thioether attached to a therapeutic agent via an acylhydrazone bond (see, e.g., U.S. Pat. No. 5,622,929).

[0314] In other embodiments, the linker is cleavable under reducing conditions (e.g., a disulfide linker). A variety of disulfide linkers are known in the art, including those that can be formed using, for example, SATA (N-succinimidyl-5-acetylthioacetate), SPDP (N-succinimidyl-3-(2-pyridyldithio)propionate), SPDB (N-succinimidyl-3-(2-pyridyldithio)butyrate), and SMPT (N-succinimidyloxycarbonyl-alpha-methyl-alpha-(2-pyridyl-dithio)toluene), SPDB, and SMPT. (See, e.g., Thorpe et al., 1987, Cancer Res. 47:5924-5931; Wawrzynczak et al., in Immunoconjugates: Antibody Conjugates in Radioimagery and Therapy of Cancer (C.W. Vogel, ed.), Oxford U.S. Press, 1987. See also U.S. Pat. No. 4,880,935.)

[0315] In some embodiments, the linker is cleavable by a cleavage agent, e.g., an enzyme, present in the intracellular environment (e.g., within a lysosome, endosome, or caveolae). The linker may be, for example, a peptidyl linker cleaved by an intracellular peptidase or protease enzyme, including, but not limited to, a lysosomal or endosomal protease. In some embodiments, the peptidyl linker is at least two amino acids in length or at least three amino acids in length. Cleavage agents can include cathepsins B and D and plasmin, all of which are known to hydrolyze dipeptide drug derivatives, resulting in the release of the active drug inside target cells (see, e.g., Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-123). Peptidyl linkers cleavable by enzymes present in SEZ6L2-expressing cells are most typical. Examples of such linkers are described, for example, in U.S. Patent No. 6,214,345. This document is incorporated herein by reference in its entirety for all purposes. In certain embodiments, the peptidyl linker cleavable by intracellular proteases is a Val-Cit linker or a Phe-Lys linker (see, e.g., U.S. Pat. No. 6,214,345, which describes the synthesis of doxorubicin with a val-cit linker). One advantage of using intracellular proteolytic release of therapeutic agents is that the agent is typically attenuated when conjugated, and the serum stability of the conjugate is typically high.

[0316] In other embodiments, the linker is a malonate linker (Johnson et al., 1995, Anticancer Res. 15:1387-93), a maleimidobenzoyl linker (Lau et al., 1995, Bioorg-Med-Chem. 3(10):1299-1304), or a 3'-N-amide analog (Lau et al., 1995, Bioorg-Med-Chem. 3(10):1305-12).

[0317] In yet other embodiments, the linker unit is not cleavable and the drug is released, for example, by antibody degradation. See U.S. Patent Application Publication No. 20050238649, which is incorporated herein by reference in its entirety. ADCs containing non-cleavable linkers can be designed so that the ADC remains substantially intact outside the cell, and upon interaction with certain receptors on the surface of target cells, binding of the ADC initiates (prevents) specific cell signaling pathways.

[0318] In some embodiments, the linker is a substantially hydrophilic linker (e.g., PEG4Mal and sulfo-SPDB). Hydrophilic linkers can be used to reduce the extent to which drugs can be excreted from resistant cancer cells via MDR (multidrug resistance) transporters or functionally similar transporters.

[0319] In other embodiments, the linker, upon cleavage, functions to directly or indirectly inhibit cell growth and / or cell proliferation. For example, in some embodiments, the linker, upon cleavage, can function as an intercalating agent, thereby inhibiting macromolecular biosynthesis (e.g., DNA replication, RNA transcription, and / or protein synthesis).

[0320] In other embodiments, the linker is designed to facilitate bystander killing (killing of neighboring cells) by allowing diffusion of the linker-drug and / or drug alone to neighboring cells. In others, the linker facilitates internalization into cells.

[0321] The presence of a sterically hindered disulfide can increase the stability of a particular disulfide bond and enhance the potency of an ADC. Thus, in one embodiment, the linker comprises a sterically hindered disulfide linkage. A sterically hindered disulfide refers to a disulfide bond that exists within a particular molecular environment, where the environment is typically within the same molecule or compound and is characterized by a particular spatial arrangement or orientation of atoms that prevents or at least partially inhibits reduction of the disulfide bond. Thus, the presence of bulky (or sterically hindering) chemical moieties and / or bulky amino acid side chains in proximity to a disulfide bond prevents or at least partially inhibits the disulfide bond from potential interactions that would result in reduction of the disulfide bond.

[0322] Of note, the above linker types are not mutually exclusive. For example, in one embodiment, the linker used in the anti-SEZ6L2 ADCs described herein is a non-cleavable linker that facilitates internalization into cells.

[0323] In some embodiments, the ADC has the following formula (Formula I): Ab-(LD) n (I) or a pharmaceutically acceptable salt or solvate thereof, wherein Ab is an antibody, e.g., an anti-SEZ6L2 antibody, and (LD) is a linker-drug moiety made up of a linker, L-, and a drug moiety, -D, having, e.g., cytostatic, cytotoxic, or otherwise therapeutic activity against a target cell, e.g., a cell expressing SEZ6L2, and n is an integer from 1 to 20.

[0324] In some embodiments, n ranges from 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, or is 1.

[0325] In some embodiments, the -D moieties are the same. In yet other embodiments, the -D moieties are different.

[0326] In some embodiments, the linker component comprises an "amino acid unit." In some such embodiments, the amino acid unit allows for protease cleavage of the linker, thereby facilitating release of the drug from the immunoconjugate upon exposure to intracellular proteases, such as lysosomal enzymes (Doronina et al., (2003) Nat. Biotechnol. 21:778-784). Exemplary amino acid units include, but are not limited to, dipeptides, tripeptides, tetrapeptides, and pentapeptides. Exemplary dipeptides include, but are not limited to, valine-citrulline (vc or val-cit), alanine-phenylalanine (af or ala-phe), phenylalanine-lysine (fk or phe-lys), phenylalanine-homolysine (phe-homolys), and N-methyl-valine-citrulline (Me-val-cit). Exemplary tripeptides include, but are not limited to, glycine-valine-citrulline (gly-val-cit) and glycine-glycine-glycine (gly-gly-gly). The amino acid units may comprise naturally occurring amino acid residues and / or non-naturally occurring amino acid analogs, such as rare amino acids and / or citrulline amino acid units, can be designed to optimize enzymatic cleavage by specific enzymes, such as tumor-associated proteases, cathepsins B, C, and D, or plasmin proteases.

[0327] In one embodiment, the amino acid unit is valine-citrulline (vc or val-cit). In another aspect, the amino acid unit is phenylalanine-lysine (i.e., fk). In yet another aspect of the amino acid unit, the amino acid unit is N-methylvaline-citrulline. In yet another aspect, the amino acid unit is 5-aminovaleric acid, homophenylalanine lysine, tetraisoquinolinecarboxylate lysine, cyclohexylalanine lysine, isonipecotic acid lysine, beta-alanine lysine, glycine serine valine glutamine, and isonipecotic acid.

[0328] Another approach to generating ADCs involves the use of heterobifunctional crosslinkers to link anti-SEZ6L2 antibodies to drug moieties. Examples of crosslinkers that can be used include: N-succinimidyl 4-(5-nitro-2-pyridyldithio)-pentanoate or the highly water-soluble analogs N-sulfosuccinimidyl 4-(5-nitro-2-pyridyldithio)-pentanoate, N-succinimidyl-4-(2-pyridyldithio)butyrate (SPDB), N-succinimidyl-4-(5-nitro-2-pyridyldithio)butyrate (SNPB), and N-succinimidyl-4-(5-nitro-2-pyridyldithio)butyrate (SNPB). -sulfosuccinimidyl-4-(5-nitro-2-pyridyldithio)butyrate (SSNPB), N-succinimidyl-4-methyl-4-(5-nitro-2-pyridyldithio)pentanoate (SMNP), N-succinimidyl-4-(5-N,N-dimethylcarboxamido-2-pyridyldithio)butyrate (SCPB), or N-sulfosuccinimidyl 4-(5-N,N-dimethylcarboxamido-2-pyridyldithio)butyrate (SSCPB)). Antibodies may be modified with the crosslinker N-succinimidyl 4-(5-nitro-2-pyridyldithio)-pentanoate, N-sulfosuccinimidyl 4-(5-nitro-2-pyridyldithio)-pentanoate, SPDB, SNPB, SSNPB, SMNP, SCPB, or SSCPB, and then reacted with a slight excess of certain drugs containing a thiol moiety to give ADCs in excellent yields (see also U.S. Pat. No. 6,913,748, which is incorporated herein by reference).

[0329] In one embodiment, a charged linker (also referred to as a pro-charged linker) is used to conjugate an anti-SEZ6L2 antibody to a drug to form an ADC. Charged linkers include linkers that become charged after cellular processing. The presence of a charged group(s) on the linker or drug of a particular ADC after cellular processing provides several advantages: for example, (i) the ADC exhibits greater aqueous solubility; (ii) the ability to function at higher concentrations in aqueous solution; (iii) the ability to link more drug molecules per antibody, potentially resulting in higher efficacy; (iv) the charged conjugate species is more likely to be retained in target cells, resulting in higher efficacy; and (v) the sensitivity of multidrug-resistant cells is improved, thereby preventing the charged drug species from being exported from the cell. Examples of some suitable charged or pro-charged crosslinkers and their synthesis are shown in Figures 1-10 of U.S. Pat. No. 8,236,319, which is incorporated herein by reference. Preferably, the charged or pro-charged crosslinker contains a sulfonate, phosphate, carboxyl, or quaternary amine substituent, which significantly increases the solubility of the ADC, particularly for ADCs with 2 to 20 conjugated drugs. Conjugates prepared from linkers containing pro-charged moieties will yield one or more charged moieties after the conjugate is metabolized intracellularly.

[0330] Additional examples of linkers that can be used with the above compositions and methods include: valine-citrulline; maleimidocaproyl; aminobenzoic acid; p-aminobenzylcarbamoyl (PAB); lysosomal enzyme-cleavable linkers; maleimidocaproyl-polyethylene glycol (MC(PEG)6-OH); N-methyl-valine citrulline; N-succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC); N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB); and N-succinimidyl 4-(2-pyridylthio)pentanoate (SPP) (see also U.S. Patent Application Publication No. 2011 / 0076232). Alternative linkers for use include avidin-biotin linkages to provide avidin-biotin-containing ADCs (see U.S. Pat. No. 4,676,980, PCT Publications WO1992 / 022332A2, WO1994 / 016729A1, WO1995 / 015770A1, WO1997 / 031655A2, WO1998 / 035704A1, WO1999 / 019500A1, WO2001 / 09785A2, WO2001 / 090198A1, WO2003 / 093 793A2, WO2004 / 050016A2, WO2005 / 081898A2, WO2006 / 083562A2, WO2006 / 089668A1, WO2007 / 150020A1, WO2008 / 135237A1, WO2010 / 111198A1, WO2011 / 057216A1, WO2011 / 058321A1, WO2012 / 027494A1, and EP77671B1), some such linkers are resistant to biotinidase cleavage. Additional linkers that can be used include cohesin / dockerin pairs to provide cohesion-dockerin-containing ADCs (see PCT Publication Nos. WO2008 / 097866 A2, WO2008 / 097870 A2, WO2008 / 103947 A2, and WO2008 / 103953 A2).

[0331] Additional linkers may include non-peptide polymers (examples include, but are not limited to, polyethylene glycol, polypropylene glycol, polyoxyethylated polyols, polyvinyl alcohol, polysaccharides, dextran, polyvinyl ethyl ether, PLA (poly(lactic acid)), PLGA (poly(lactic-glycolic acid)), and combinations thereof, with a preferred polymer being polyethylene glycol) (see also PCT Publication WO2011 / 000370). Additional linkers are also described in WO2004-010957, U.S. Patent Application Publication No. 20060074008, U.S. Patent Application Publication No. WO20050238649, and U.S. Patent Application Publication No. 20060024317, each of which is incorporated herein by reference in its entirety).

[0332] In the case of ADCs containing maytansinoids, many positions on the maytansinoid can serve as positions for chemically linking a linking moiety. In one embodiment, the maytansinoid containing a linking moiety comprising a reactive chemical group is a C-3 ester of maytansinol and its analogs, in which the linking moiety comprises a di...

Claims

1. 1. A nucleic acid encoding an anti-human stroke-associated 6 homolog-like 2 (anti-hDLL3) antibody or antigen-binding portion thereof, said antibody or antigen-binding portion thereof comprising: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 12, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 11, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 10, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 16, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 15, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 14; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 39, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 54, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 53, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 52, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 58, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 57, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 56; or a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO:4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:3, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:2, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO:8, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:7, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:6; wherein the antibody or antigen-binding portion thereof does not bind to DLL3 or DLL3L.

2. the antibody or antigen-binding portion thereof, a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:13; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 32, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 51, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 55; or A heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

5. The nucleic acid of claim 1 , comprising:

3. the antibody or antigen-binding portion thereof, a heavy chain variable region comprising a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:9, and a light chain variable region comprising a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:13; a heavy chain variable region comprising a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 32, and a light chain variable region comprising a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 36; a heavy chain variable region comprising a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:51, and a light chain variable region comprising a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:55; or A heavy chain variable region comprising a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:1, and a light chain variable region comprising a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

5. The nucleic acid of claim 1 , comprising:

4. A vector comprising the nucleic acid of claim 1.

5. A vector comprising the nucleic acid of claim 2.

6. A vector comprising the nucleic acid of claim 3.

7. A cell comprising the vector of claim 4.

8. A cell comprising the vector of claim 5.

9. A cell comprising the vector of claim 6.

10. 1. A cell comprising at least one vector encoding an anti-human stroke-associated 6 homolog-like 2 (anti-hDLL3) antibody or antigen-binding portion thereof, wherein the antibody or antigen-binding portion thereof is: a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 12, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 11, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 10, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 16, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 15, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 14; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 39, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37; a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 54, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 53, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 52, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 58, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 57, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 56; or a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO:4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:3, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:2, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO:8, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:7, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:6; wherein the antibody or antigen-binding portion thereof does not bind to DLL3 or DLL3L.

11. the antibody or antigen-binding portion thereof, a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:13; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 32, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 51, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 55; or A heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

5. The cell of claim 10, comprising:

12. the antibody or antigen-binding portion thereof, a heavy chain variable region comprising a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:9, and a light chain variable region comprising a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:13; a heavy chain variable region comprising a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 32, and a light chain variable region comprising a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 36; a heavy chain variable region consisting of a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 51, and a light chain variable region comprising a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 55; or A heavy chain variable region comprising a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:1, and a light chain variable region comprising a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

5. The cell of claim 10, comprising:

13. 10. An in vitro method for producing an anti-human stroke-associated 6 homolog-like 2 (anti-hDLL3) antibody or an antigen-binding portion thereof, the method comprising expressing in a cell a nucleic acid of any one of claims 1 to 3 or a vector of any one of claims 4 to 6.

14. 13. An in vitro method for producing an anti-human stroke-associated 6 homolog-like 2 (anti-hDLL3) antibody or antigen-binding portion thereof, comprising expressing the antibody or antigen-binding portion thereof from a cell according to any one of claims 7 to 12.

Images