Anti-SEZ6L2 antibody and antibody-drug conjugate

Abstract

Provision of anti-SEZ6L2 antibodies and antibody-drug conjugates. [Solution] This specification discloses anti-seizure-associated 6-homologous-like 2 (SEZ6L2) antibodies and antibody-drug conjugates (ADCs), including compositions and methods using the said antibodies and ADCs. In one embodiment, the disclosure provides an anti-hSEZ6L2 antibody, ADC, or antigen-binding fragment thereof that inhibits tumor growth by at least about 50% compared to a human IgG antibody in an in vivo human small cell lung cancer (SCLC) xenograft assay in which a human IgG antibody not specific to SEZ6L2 is administered at the same dose and frequency as an anti-human seizure-associated 6-homologous-like 2 (anti-hSEZ6L2) antibody, ADC, or antigen-binding fragment thereof.

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 438,943, filed on 23 December 2016, the entirety of which is expressly incorporated herein.

[0002] Sequence List This application is filed electronically in ASCII format and includes a sequence listing which is incorporated herein by reference in its entirety. The ASCII copy was created on 22 December 2017, has the filename 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 other two 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, Vol. 28: pp. 201-210; Shimizu-Nishikawa K et al., 1995, Biochem Biophys Res Commun, Vol. 216: pp. 382-389). There are six isoforms of SEZ6L2 produced by alternative splicing. Sequence homology between human SEZ6L2 and mouse / rat and cynomolgus monkey homologs is 96% and 99%, respectively.

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

[0005] SEZ6L2 has been shown to bind to the aspartate protease cathepsin D in mouse neurons and promote its transport from the trans-Golgi network to endosomes (Boonen M et al., 2016 J Cell Sci 129: pp. 557-568). Furthermore, cathepsin D has 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: pp. 1438-1445; Steinfeld R et al., 2006 Am J Hum Genet 78: pp. 988-998; Tyynela J et al., 2000 EMBO J 19: pp. 2786-2792). Furthermore, it has been shown that proteolytic cleavage of SEZ6L2 by cathepsin D releases a soluble N-terminal fragment that modulates neuronal differentiation (Boonen M et al., 2016 J Cell Sci 129: pp. 557-568). In addition, SEZ6L2 has been identified as a substrate for BACE2 and BACE1, proteases known as schidases, in pancreatic cells and primary neurons, respectively (Stutzer I, S et al., 2013 J Biol Chem 288: pp. 10536-10547; Hemming ML et al., 2009 PLoS One 4: p. e8477).

[0006] Several proteomics and transcriptome databases suggest that SEZ6L2 is differentially upregulated in certain tumors. In addition, a study of primary lung cancer specimens by Ishikawa et al. (Cancer Sci, Vol. 97, pp. 737-745, 2006) found that SEZ6L2 was differentially expressed in tumors compared to normal tissue. Furthermore, Ishikawa 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 that contain antibodies conjugated to cytotoxic drugs via a chemical linker. The therapeutic concept of ADCs is to combine the binding ability of an antibody with a drug, using the antibody to deliver the drug to tumor cells by binding to a target surface antigen. Therefore, there remains a need in this field 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 Vol. 28: pp. 201-210. [Non-Patent Document 2] Shimizu-Nishikawa K et al., 1995. Biochem Biophys Res Commun Vol. 216: pp. 382-389. [Non-Patent Document 3] Yu ZL et al., 2007, J Neurosci Res, Vol. 85: pp. 166-172. [Non-Patent Document 4] Kumar RA et al., 2009. PLoS One Vol. 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 Vol. 580: pp. 4057-4064. [Overview of the project] [Means for solving the problem]

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

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

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

[0012] In certain embodiments of this disclosure, the antibody or its antigen-binding moiety is K between approximately 1 pM (0.001 nM) and 50 nM, approximately 500 pM (0.5 nM) and 20 nM, approximately 1 nM and 10 nM, or approximately 1 nM and 5 nM. d Then it connects to huSEZ6L2.

[0013] In some embodiments, the antibody or its antigen-binding portion is a heavy chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 4 and a light chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 8; a heavy chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 12 and a light chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 16; a heavy chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 20 and a light chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 24; a heavy chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 28 and a light chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 31; a heavy chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 35 and a light chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 39; a heavy chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 43 and a light chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 46; a heavy chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 35 and a light chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 50; a CDR having the amino acid sequence of SEQ ID NO: 54 A heavy chain variable region containing 3 and a light chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 58; a heavy chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 62 and a light chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 66; a heavy chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 70 and a light chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 72; a heavy chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 76 and a light chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 78; the amino acid sequence of SEQ ID NO: 81 A heavy chain variable region containing CDR3 having an acid sequence and a light chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 83; a heavy chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 87 and a light chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 89; a heavy chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 93 and a light chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 95; a heavy chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 99 and a light chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 103;A heavy chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 107 and a light chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 89; a heavy chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 112 and a light chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 58; a heavy chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 70 and a light chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 119; a heavy chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 236 and a light chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 238; or a heavy chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 242 and a light chain variable region containing CDR3 having the amino acid sequence of SEQ ID NO: 245.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0056] In some embodiments, the disclosure provides an antibody or its antigen-binding moiety that binds to the same epitope as an antibody or its antigen-binding moiety described herein.

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

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

[0059] Furthermore, in certain embodiments, this disclosure provides isolated nucleic acids encoding antibodies or antigen-binding portions thereof.

[0060] In some embodiments of this disclosure, the antibody or its antigen-binding moiety includes 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 polyspecific antibody.

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

[0062] In other embodiments, the disclosure provides pharmaceutical compositions comprising an antibody or its antigen-binding moiety as described herein and a pharmaceutically acceptable carrier.

[0063] In other embodiments, the disclosure provides an antibody or its antigen-binding moiety, 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, mitotic inhibitors, antitumor antibiotics, immunomodulators, nucleic acids for gene therapy, anti-angiogenic agents, antimetabolites, boron-containing agents, chemoprotective agents, hormones, antihormone agents, corticosteroids, phototherapeutic agents, oligonucleotides, radionuclides, radiosensitizers, topoisomerase inhibitors, and tyrosine kinase inhibitors. In one embodiment, the antitumor antibiotic is pyrrolobenzodiazepine (PBD).

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

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

[0067] In some embodiments, the auristatin is monomethyl auristatin E (MMAE), and the linker is maleimide-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 an antibody-drug conjugate (ADC) comprising an antibody or its antigen-binding moiety conjugated to at least one drug, for example, pyrrolobenzodiazepine (PBD), auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody or its antigen-binding moiety 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 an antibody-drug conjugate (ADC) comprising an antibody or its antigen-binding moiety conjugated to at least one drug, for example, pyrrolobenzodiazepine (PBD), auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody or its antigen-binding moiety 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 an antibody-drug conjugate (ADC) comprising an antibody or its antigen-binding moiety conjugated to at least one drug, for example, pyrrolobenzodiazepine (PBD), auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody or its antigen-binding moiety 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 an antibody-drug conjugate (ADC) comprising an antibody or its antigen-binding moiety conjugated to at least one drug, for example, pyrrolobenzodiazepine (PBD), auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody or its antigen-binding moiety 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 an antibody-drug conjugate (ADC) comprising an antibody or its antigen-binding moiety conjugated to at least one drug, for example, pyrrolobenzodiazepine (PBD), auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody or its antigen-binding moiety 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 an antibody-drug conjugate (ADC) comprising an antibody or its antigen-binding moiety conjugated to at least one drug, for example, pyrrolobenzodiazepine (PBD), auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody or its antigen-binding moiety 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 an antibody-drug conjugate (ADC) comprising an antibody or its antigen-binding moiety conjugated to at least one drug, for example, pyrrolobenzodiazepine (PBD), auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody or its antigen-binding moiety 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 an antibody-drug conjugate (ADC) comprising an antibody or its antigen-binding moiety conjugated to at least one drug, for example, pyrrolobenzodiazepine (PBD), auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody or its antigen-binding moiety 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 an antibody-drug conjugate (ADC) comprising an antibody or its antigen-binding moiety conjugated to at least one drug, for example, pyrrolobenzodiazepine (PBD), auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody or its antigen-binding moiety 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 an antibody-drug conjugate (ADC) comprising an antibody or its antigen-binding moiety conjugated to at least one drug, for example, pyrrolobenzodiazepine (PBD), auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody or its antigen-binding moiety 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 an antibody-drug conjugate (ADC) comprising an antibody or its antigen-binding moiety conjugated to at least one drug, for example, pyrrolobenzodiazepine (PBD), auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody or its antigen-binding moiety 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 an antibody-drug conjugate (ADC) comprising an antibody or its antigen-binding moiety conjugated to at least one drug, for example, pyrrolobenzodiazepine (PBD), auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody or its antigen-binding moiety 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 an antibody-drug conjugate (ADC) comprising an antibody or its antigen-binding moiety conjugated to at least one drug, for example, pyrrolobenzodiazepine (PBD), auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody or its antigen-binding moiety 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 an antibody-drug conjugate (ADC) comprising an antibody or its antigen-binding moiety conjugated to at least one drug, for example, pyrrolobenzodiazepine (PBD), auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody or its antigen-binding moiety 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 an antibody-drug conjugate (ADC) comprising an antibody or its antigen-binding moiety conjugated to at least one drug, for example, pyrrolobenzodiazepine (PBD), auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody or its antigen-binding moiety 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 an antibody-drug conjugate (ADC) comprising an antibody or its antigen-binding moiety conjugated to at least one drug, for example, pyrrolobenzodiazepine (PBD), auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody or its antigen-binding moiety 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 an antibody-drug conjugate (ADC) comprising an antibody or its antigen-binding moiety conjugated to at least one drug, for example, pyrrolobenzodiazepine (PBD), auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody or its antigen-binding moiety 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 an antibody-drug conjugate (ADC) comprising an antibody or its antigen-binding moiety conjugated to at least one drug, for example, pyrrolobenzodiazepine (PBD), auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody or its antigen-binding moiety 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 an antibody-drug conjugate (ADC) comprising an antibody or its antigen-binding moiety conjugated to at least one drug, for example, pyrrolobenzodiazepine (PBD), auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody or its antigen-binding moiety 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 present disclosure provides an antibody-drug conjugate (ADC) comprising an antibody or its antigen-binding moiety conjugated to at least one drug, for example, pyrrolobenzodiazepine (PBD), auristatin, at least one maytansinoid, or at least one DNA alkylating agent, wherein the antibody or its antigen-binding moiety 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 of the ADC includes a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 5.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0108] In one embodiment, the ADC comprises auristatin, which is monomethyl auristatin E (MMAE). In another embodiment, the ADC comprises a meitansinoid, which is 4-methyl-4-mercapto-1-oxopentyl)-meitansin (DM4). In yet another embodiment, the ADC comprises a DNA alkylating agent, which is indolino-benzodiazepine (IGN). In one embodiment, the ADC comprises pyrrolobenzodiazepine (PBD).

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

[0110] In some embodiments, the auristatin is monomethyl auristatin E (MMAE), and the linker is maleimide-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 containing 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 to 8.

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

[0115] In another embodiment, the Disclosure provides a method for treating a subject having a SEZ6L2-related disorder, comprising administering a therapeutically effective dose of the 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, comprising administering an effective amount of the ADC of the Disclosure to the subject having the solid tumor in such a manner 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 yet another embodiment, the solid tumor is a neuroendocrine tumor. In one embodiment, the solid tumor is characterized by SEZ6L2 overexpression.

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

[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 anti-SEZ6L2 monoclonal antibody alone (black bar) or in combination with mouse Fab-ZAP secondary antibody (gray bar; 0.4 ug / ml). After 3 days, the percentage of viable cells was quantified and compared with positive controls (anti-transferrin receptor antibody (TR) (Figure 1A) or human antibody 1A1 (Figure 1B)) and negative controls (mouse IgG (mIgG) (Figure 1A) or unbound antibody 3B5 (Figure 1B)). Figure 1A shows the results for mouse antibodies 2E4, 3E2, 16H8, and 20C4, and Figure 1B shows the results for human antibodies 1A1, 3A1, 3A2, 3A3, 3A4, 3B1, 3B2, 3B3, 3B6, as well as humanized antibodies 2E4, 3E2, 16H8, and 20C4.

[0120] [Figure 2]Figures 2A-2B show that the anti-SEZ6L2 antibody exhibits 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 the tumor volume reached 250 mm3, the mice were randomly assigned to treatment groups and intraperitoneally injected with either MMAE-conjugated mouse parent clone mu16H8 (mu16H8-MMAE), MMAE-conjugated mu16H8 (16H8) humanized offspring (16H8-MMAE), naked 16H8, MMAE-conjugated mouse IgG control (mIgG-MMAE), or PBS alone. Mice were injected with 5 mg / kg four times over a 10-day period and sacrificed when the tumor reached 1200 mm3 or became pathological. Figure 2A shows the ability of the conjugated SEZ6L2 antibody to delay the in vivo growth of SCLC tumors, and Figure 2B shows increased survival in mice treated with the conjugated anti-SEZ6L2 antibody.

[0121] [Figure 3] Figures 3A–3F show that the SEZ6L2 ADC modulator mediates the delivery of cytotoxic agents in SCLC and prostate cancer cell lines. Antibodies 3E2 and 1A1 conjugated to pyrrolobenzodiazepine (PBD) were tested for their effects on cells in small cell lung cancer and prostate cell lines. Results for small cell lung cancer cell lines H524 (Figure 3A), DMS79 (Figure 3B), H209 (Figure 3C), and H1048 (Figure 3D), and prostate adenocarcinoma cell lines LNCaP (Figure 3E) and 22Rv1 (Figure 3F) are shown. As shown in Figures 3A–3F, treatment of cells with anti-SEZ6L2 ADC resulted in an increased reduction in viable cell percentage compared to control hIgG in several cell lines. While hIgG IgG-PBD can be cytotoxic to cells at high concentrations, the tested anti-SEZ6L2 ADC was more potent and exhibited an immune-specific response to SEZ6L2 rather than a general response to PBD cytotoxin.

[0122] [Figure 4] Figures 4A-4B show that the SEZ6L2 ADC modulator suppresses in vivo tumor growth. Figure 4A is a graph showing that anti-SEZ6L2 antibodies 3E2 and 3A1 conjugated to MMAE 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 the detection of SEZ6L2 surface expression in engineered HEK-293 cells. Figures 5A-5L show the results of flow cytometry to evaluate whether SEZ6L2 antibody modulators immunologically specifically associate with human SEZ6L2 and whether the same modulators cross-react with SEZ6 and SEZ6L. More specifically, the antibodies disclosed herein were tested for cross-reactivity against cell lines overexpressing human homologs of SEZ6 (293-SEZ6), SEZ6L (293-SEZ6L), and SEZ6L2 (293-SEZ6L2). The graphs on the right side of Figures 5A-5L represent 293-SEZ6L2. The graphs on the left side of Figures 5A-5L represent 293-SEZ6L and 293-SEZ6. The results of 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), 20C4:red (Figure 5L). Figure 5M represents a control containing only the secondary antibody. As shown by the dataset shown in Figures 5A-M, the SEZ6L2 antibody recognizes cell lines overexpressing SEZ6L2 but does not show 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. Humanized SEZ6L2 antibody 3E2 conjugated to PBD (3E2-PBD) was tested to determine whether combination with PARP inhibitors would result in an additional reduction in cell viability. As shown in Figure 6, NCI-209 small cell lung cancer cells treated with the PARP inhibitor olaparib alone responded in a dose-dependent manner, with an increasing reduction in viable cell percentage observed as the inhibitor concentration increased. Cells incubated with both the PARP inhibitor and 3E2-PBD (10 pM) showed an increased reduction in viable cells, thereby demonstrating 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 immune-specific response to SEZ6L2 rather than a general response to PBD cytotoxin. [Modes for carrying out the invention]

[0125] Various aspects of this 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 for using the antibodies and ADCs described herein to detect human SEZ6L2, to inhibit human SEZ6L2 activity (in vitro or in vivo), and to treat SEZ6L2-related 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 To make the present invention easier to understand, certain terms will first be defined. In addition, it should be noted that whenever a parameter value or range of values ​​is stated, intermediate values ​​and intermediate ranges of the stated values ​​are also considered part of the present invention.

[0127] The terms “seizure-associated six-homologous-like two-antibody” or “anti-SEZ6L2 antibody” are used synonymously herein and refer to an antibody that specifically binds to SEZ6L2. The antibody that “binds” to the target antigen, i.e., SEZ6L2, is capable of binding to that antigen with sufficient affinity so that the antibody is useful in 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 yet 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 has 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 is a protein without the signal peptide, corresponding to 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 has 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 (the first three proteins identified to contain such domains: complement factor C1r / C1s, embryonic sea urchin protein uEGF, and bone morphogenesis protein 1), and a C-terminal transmembrane domain (Ishikawa et al., Cancer Sci 2006; Vol. 97: pp. 737-745). The three CUB domains contain amino acid residues 173-286 (CUB1), 349-459 (CUB2), and 527-638 (CUB3). The five SUSHI domains each contain amino acid residues 288-347, 462-525, 642-701, 703-766, and 769-830, respectively.

[0130] When the term “specific binding” or “specifically binding” is used herein in relation to the interaction between a SEZ6L2 antibody or ADC and a second chemical species, it means that the interaction depends on the presence of a specific structure (e.g., an antigenic determinant or epitope) in that chemical species, for example, that the antibody recognizes and binds to a specific protein structure rather than the protein in general. If the antibody or ADC is specific to epitope “A”, then in a reaction involving label “A”, the presence of a molecule and antibody containing epitope A (or free, unlabeled A) will reduce the amount of label A bound to the antibody or ADC.

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

[0132] In one embodiment, the phrase "specifically binds to hSEZ6L2" or "specifically binds to hSEZ6L2" means, as used herein, that the 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 ) refers to the ability to interact with hSEZ6L2. In another embodiment, the phrase “specifically binds to hSEZ6L2” or “specifically binds to hSEZ6L2” means, as used herein, that an anti-SEZ6L2 antibody or ADC has a dissociation constant (K) between approximately 1 pM (0.001 nM) and 50 nM, approximately 500 pM (0.5 nM) and 20 nM, approximately 1 nM and 10 nM, or approximately 1 nM and 5 nM. D ) refers to the ability to interact with hSEZ6L2. In one embodiment, K D This is determined by surface plasmon resonance. In another embodiment, K D This is determined as described in Example 4 of this specification.

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

[0134] In full-length antibodies, each heavy chain consists of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region consists of three domains: CH1, CH2, and CH3. Each light chain consists of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region consists of one domain, CL. The VH and VL regions can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs), which are scattered in more conserved regions and are named framework regions (FRs). Each VH and VL consists of three CDRs and four FRs, arranged in the order FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 from the amino terminus to the carboxy terminus. The immunoglobulin molecule 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” (or simply “antibody portion”) of an antibody, 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 carried out by fragments of a full-length antibody. Furthermore, such antibody embodiments may be bispecific, dual-specific, or multispecific, i.e., specifically binding to two or more different antigens. Examples of binding fragments included in the term "antigen-binding moiety" of an antibody include: (i) Fab fragments, i.e., monovalent fragments consisting of VL, VH, CL, and CH1 domains; (ii) F(ab')2 fragments, i.e., bivalent fragments containing two Fab fragments linked by disulfide crosslinks in the hinge region; (iii) Fd fragments consisting of VH and CH1 domains; (iv) Fv fragments consisting of VL and VH domains of a single arm of the antibody; (v) dAb fragments containing a single variable domain (Ward et al., Nature 341, pp. 544-546, 1989; Winter et al., PCT Publication WO90 / 05144A1; these publications are incorporated herein by reference); and (vi) isolated complementarity-determining regions (CDRs). Furthermore, although the two domains of the Fv fragment, VL and VH, are encoded by separate genes, they can be joined using recombination via a synthetic linker that allows the VL and VH regions to pair up to form a single protein chain that forms a monovalent molecule (known as single-chain Fv (scFv); see, e.g., Bird et al. (1988) Science vol. 242: pp. 423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA vol. 85: pp. 5879-5883). Such single-chain antibodies are also intended to be included within the term "antigen-binding portion" of the antibody. In certain embodiments, the scFv molecule may be incorporated into a fusion protein. Other forms of single-chain antibodies, such as diabodies, are also included.Diabody is a bivalent, bispecific antibody in which the VH and VL domains are expressed on a single polypeptide chain, but a linker that is too short to allow pairing between the two domains on the same chain is used, thereby forcing the above domains to pair with a complementary domain on another chain, generating two antigen-binding sites (see, for example, Holliger, P. et al. (1993) Proc. Natl. Acad. Sci. USA Vol. 90: pp. 6444-6448; Poljak, RJ et al. (1994) Structure Vol. 2: pp. 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 antigen-binding moieties disclosed herein, linked to a linker polypeptide or an immunoglobulin constant domain. A linker polypeptide comprises two or more amino acid residues joined by a peptide bond and is used to link one or more antigen-binding moieties. Such linker polypeptides are well known in the art (see, for example, Holliger, P. et al. (1993) Proc. Natl. Acad. Sci. USA Vol. 90: pp. 6444–6448; Poljak, RJ et al. (1994) Structure Vol. 2: pp. 1121–1123). An immunoglobulin constant domain refers to a heavy chain or light chain constant domain. Exemplary human IgG heavy chain and light chain constant domain amino acid sequences are well known in the art and are shown below. Sequences of the human IgG heavy chain constant domain and light chain constant domain [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 of the whole antibody. Further, antibodies, antibody portions, and immunoadhesion molecules can be obtained using standard recombinant DNA techniques as described herein.

[0138] "Isolated antibody," as used herein, is intended to refer to an antibody that is substantially free of other antibodies having 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. Further, an isolated antibody may be substantially free of other cellular materials and / or chemical substances.

[0139] The term “humanized antibody” refers to an antibody that contains 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 has been modified 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 contains a framework (FR) region having substantially the amino acid sequence of a human antibody, and a complementation-determining region (CDR) having substantially the amino acid sequence of a non-human antibody. As used herein, the term “substantially” 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 a non-human antibody CDR. A humanized antibody contains substantially all of at least one, typically two, variable domains (Fab, Fab', F(ab')2, FabC, Fv), where all or substantially all of the CDR region corresponds to the CDR region of a non-human immunoglobulin (i.e., a donor antibody), and all or substantially all of the framework region is the framework region of the human immunoglobulin consensus sequence. Preferably, the humanized antibody also contains the immunoglobulin constant region (Fc), typically at least a portion of the constant region of a human immunoglobulin. In some embodiments, the humanized antibody contains both the light chain and at least the heavy chain variable domains. The antibody may also contain the CH1, hinge, CH2, CH3, and CH4 regions of the heavy chain. In some embodiments, the humanized antibody contains only the humanized light chain. In other embodiments, the humanized antibody contains only the humanized heavy chain. In certain embodiments, the humanized antibody contains only the humanized variable domains of the light chain and / or the humanized heavy chain.

[0140] Humanized antibodies can be selected from any class of immunoglobulin, including IgM, IgG, IgD, IgA, and IgE, and any isotype, including, but not limited to, IgG1, IgG2, IgG3, and IgG4. Humanized antibodies may contain sequences derived from more than one class or isotype, and specific constant domains can be selected to optimize desired effector function using techniques well known in the art.

[0141] The terms “Kabat numbering,” “Kabat definition,” and “Kabat notation” are used synonymously herein. These terms refer to a system recognized in the art 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 its antigen-binding moiety (Kabat et al. (1971) Ann. NY Acad, Sci. Vol. 190: pp. 382–391, and Kabat, EA et al. (1991) Sequences of Proteins of Immunological Interest, 5th edition, US Department of Health and Human Services, NIH Publications 91-3242). In the case of the heavy chain variable region, the hypervariable region is the range of amino acids 31–35 in CDR1, amino acids 50–65 in CDR2, and amino acids 95–102 in CDR3. In the case of the light chain variable region, the hypervariable region is in the range of amino acids 24-34 in CDR1, in the range of amino acids 50-56 in CDR2, and in the range of amino acids 89-97 in CDR3.

[0142] As used herein, the term “CDR” refers to the complementarity-determining region within an antibody variable sequence. Each of the variable regions of the heavy chain (HC) and light chain (LC) contains three CDRs, each named CDR1, CDR2, and CDR3 (or, in particular, HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3). As used herein, the term “CDR set” refers to a group of three CDRs occurring in a single variable region capable of binding to an antigen. The precise boundaries of these CDRs are defined differently by different systems. One such system is described by Kabat et al. in *Sequences of Proteins of Immunological Interest* (National The Institutes of Health, Bethesda, Md. (1987 and 1991) not only provide a clear residue numbering system applicable to any variable region of an antibody, but also precise residue boundaries that define three CDRs. These CDRs are sometimes called Kabat CDRs. Chothia and collaborators (Chothia and Lesk, J. Mol. Biol. Vol. 196: pp. 901-917 (1987), and Chothia et al., Nature, Vol. 342: pp. 877-883 (1989)) found that certain subportions within Kabat CDRs adopt almost identical peptide skeletal conformations despite considerable diversity at the amino acid sequence level. These subportions are named L1, L2, and L3, or H1, H2, and H3, where "L" and "H" refer to the light chain 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 are described by Padlan (FASEB J. Vol. 9: pp. 133-139 (1995)) and MacCallum (J mol Biol Vol. 262 (No. 5): pp. 732-745 (1996)). Further other CDR boundary definitions may not strictly follow one of the above systems, but they overlap with Kabat CDRs, although they may be shortened or extended in light of predictions or experimental findings that certain residues or groups of residues, or even the entire CDR, do not significantly affect antigen binding. The methods used herein may use CDRs defined according to any of these systems, but in preferred embodiments, CDRs defined by Kabat or Chothia are used.

[0143] As used herein, the term “framework” or “framework sequence” refers to the sequence remaining after removing the CDRs from the variable region. Since the precise definition of a CDR sequence can be determined by various systems, the meaning of the framework sequence is subject to correspondingly different interpretations. Furthermore, the six CDRs (CDR-L1, CDR-L2, and CDR-L3 of the light chain, and CDR-H1, CDR-H2, and CDR-H3 of the heavy chain) divide the framework regions of the light and heavy chains into four sub-regions (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. The framework region represents a combination of FRs within the variable region of a single naturally occurring immunoglobulin chain, without designating specific sub-regions as FR1, FR2, FR3, or FR4, as referred to elsewhere. As used herein, FR represents one of the four sub-regions, and FR represents two or more of the four sub-regions that constitute the framework region.

[0144] The framework and CDR regions of a humanized antibody do not need to correspond precisely to the parent sequence. For example, a donor antibody CDR or consensus framework may be mutagenic by substitution, insertion, and / or deletion of at least one amino acid residue such 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 residues in 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 the family of relevant immunoglobulin sequences (see, e.g., Winnaker, From Genes to Clones (Verlagsgesellschaft, Weinheim, Germany, 1987)). In immunoglobulin families, each position in the consensus sequence is occupied by the amino acid that occurs most frequently at that position within the family. If two amino acids occur with equal frequency, both can be included in the consensus sequence.

[0145] The “amino acid sequence identity percentage (%)” for a peptide or polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues of a particular peptide or polypeptide sequence after aligning the sequences, introducing gaps where necessary to achieve the maximum sequence identity percentage, and without considering any conservative substitutions as part of the sequence identity. Alignment for the purpose of determining the amino acid sequence identity percentage can be achieved in various ways within the art of the art 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 the alignment, including any algorithm required to achieve the maximum alignment over the entire length of the sequences being compared. In one embodiment, the present disclosure includes amino acid sequences 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 with any one of the amino acid sequences shown in SEQ ID NOs: 1-119 and 156-166.

[0146] The term “polyvalent antibody” is used herein to refer to an antibody containing two or more antigen-binding sites. In certain embodiments, a polyvalent antibody may be engineered to have three or more antigen-binding sites and is not generally a naturally occurring antibody.

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

[0148] The terms “dual variable domain” or “DVD” are used synonymously herein and refer to an antigen-binding protein that contains two or more antigen-binding sites and is a tetravalent or polyvalent 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 DVD Ig. Each half of DVD Ig contains a heavy-chain DVD polypeptide, 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, and has a total of six CDRs per antigen-binding site that are involved in antigen binding. In one embodiment, the CDRs described herein are used for anti-SEZ6L2 DVDs.

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

[0150] The terms “neuroendocrine tumor” or “NET” or “neuroendocrine carcinoma,” as used herein, include tumors that possess neuroendocrine features (genotype or phenotype). True or “standard neuroendocrine tumors” arise from cells of the endocrine system and are typically highly invasive. Neuroendocrine tumors may occur in the kidneys, urogenital tract (bladder, prostate, ovaries, cervix, and endometrium), gastrointestinal tract (stomach, colon), thyroid (medullary thyroid carcinoma), and lungs (small cell lung cancer and large cell neuroendocrine carcinoma). Neoplasms exhibiting neuroendocrine features are also considered NETs, ​​including neuroblastoma, medullary thyroid carcinoma, and carcinoid tumors. Furthermore, the antibodies disclosed herein have the advantage of being usable to treat, prevent, or diagnose pseudoneuroendocrine tumors (pNETs) that genotypefully or phenotypically mimic, include, resemble, or exhibit characteristics common to standard neuroendocrine tumors. A “pseudoneuroendocrine neoplasm” is a tumor arising from cells of the diffuse neuroendocrine system or from cells in which the neuroendocrine differentiation cascade is abnormally reactivated during the carcinogenic process. Such pNETs generally share certain genotypic, phenotypic, or biochemical features with conventionally established neuroendocrine neoplasms, including the ability to produce subsets of biologically active amines, neurotransmitters, and peptide hormones. Therefore, the terms “neuroendocrine neoplasm,” “NET,” “neuroendocrine carcinoma,” “tumor with neuroendocrine features,” or “tumor exhibiting neuroendocrine features” shall include both neuroendocrine neoplasms and pseudoneuroendocrine neoplasms.

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

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

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

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

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

[0156] As used herein, the term "competitive binding" 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 the 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 fluorescence 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 its antigen-binding moiety having an incorporated label that provides identification of the binding protein, e.g., the antibody. Preferably, the label is a detectable marker, e.g., the incorporation of a radioisotope-labeled amino acid, or the binding of a biotinyl moiety to a polypeptide that can be detected by a labeled avidin (e.g., streptavidin containing a fluorescent marker or enzymatic activity that can be detected by optical or colorimetric methods). Examples of labels on polypeptides, but not limited to, include: 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 phosphors), enzyme 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, secondary antibody binding sites, metal-binding domains, epitope tags); and magnetic agents such as gadolinium chelates.

[0159] The term “antibody-drug conjugate” or “ADC” refers to a conjugating protein, such as an antibody or its antigen-binding fragment, chemically linked to one or more chemical drugs (also referred herein as agonists), 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 enables the conjugation or binding of the drug to the antibody. Typically, an ADC contains 2, 4, 6, or 8 drug-loaded species, with 1 to 8 drugs conjugated to the antibody. Non-limiting examples of drugs that may be included in an ADC are mitotic inhibitors, antitumor antibiotics, immunomodulators, vectors for gene therapy, alkylating agents, anti-angiogenic agents, antimetabolites, boron-containing agents, chemoprotective agents, hormones, antihormone agents, corticosteroids, phototherapeutic agents, oligonucleotides, radionuclides, topoisomerase inhibitors, tyrosine kinase inhibitors, and radiosensitizers.

[0160] The terms “anti-seizure-related 6-homologous-like 2-antibody drug conjugate,” “anti-SEZ6L2 antibody drug conjugate,” or “anti-SEZ6L2 ADC” are used synonymously 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 indolino-benzodiazepine (IGN). In another embodiment, the DNA alkylating agent, such as IGN, is conjugated to the antibody via a linker, such as a cleavable peptide linker (D-Ala-L-dpa). In yet another embodiment, the anti-SEZ6L2 ADC is conjugated to pyrrolobenzodiazepine (PBD).

[0162] In another embodiment, the anti-SEZ6L2 ADC is conjugated to a microtubule inhibitor such as auristatin, e.g., monomethyl auristatin E (MMAE). In yet another embodiment, the anti-SEZ6L2 ADC is conjugated to a microtubule inhibitor such as a meitansinoid, e.g., DM4. In one embodiment, auristatin (e.g., MMAE) is conjugated to the antibody via a linker, e.g., maleimide-caproyl-valine-citrulline (MC-VC). In yet another embodiment, a meitansinoid (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 for ADCs are described in Miller et al. (2016), Molecular Cancer Therapeutics, Vol. 15 (No. 8). In one embodiment, an anti-SEZ6L2 antibody described herein is conjugated to IGN to form an anti-SEZ6L2 ADC.

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

[0165] As used herein, the term "aulistatin" refers to a family of anti-mitotic agents that function as microtubule inhibitors. Auristatin derivatives are also included within the definition of the term "aulistatin." Examples of auristatins, but not limited to these, include auristatin E (AE), monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), and synthetic analogs of drastatin. 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-to-antibody ratio" or "DAR" refers to the number of drugs, such as IGN, auristatin, or maytansinoids, that are bound to the antibodies of an ADC. The DAR of an ADC can range from 1 to 8, but higher loadings, such as 10, are possible depending on the number of antibody binding sites. The term DAR may be used in relation to the number of drugs loaded onto individual antibodies, or it may be used in relation to the average or mean DAR of a group of ADCs.

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

[0168] The term “cancer” is intended to refer to or describe a physiological condition in mammals 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, e.g., castration-resistant prostate cancer (CRPC), colon cancer, colorectal cancer, head and neck cancer, breast cancer, e.g., 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), e.g., squamous 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 another embodiment, the antibody or ADC is administered to a patient with small cell lung cancer (SCLC). In yet 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 yet 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 the tumor cell membrane, and any immunohistochemical staining higher than the background level in the tumor sample indicates that the tumor is SEZ6L2-expressing. Methods for detecting SEZ6L2 expression in tumors are known in the art. For example, using in situ hybridization (ISH) analysis, SEZ6L2 has been shown to be 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, as determined by immunohistochemical techniques, there is no SEZ6L2 membrane staining higher than the background level in the tumor sample.

[0171] The terms “overexpression,” “overexpressed,” or “overexpressed” are synonymous with a gene that is transcribed or translated at a level typically detectable in cancer cells compared to normal cells. Therefore, overexpression refers to both protein and RNA overexpression (through increased transcription, post-transcriptional processing, translation, post-translational processing, stability changes, and proteolysis changes) and localized overexpression through altered protein transport patterns (increased nuclear localization) and enhanced functional activity, such as increased enzymatic hydrolysis of substrates. Thus, overexpression refers to either the protein or RNA level. Furthermore, overexpression may be 50%, 60%, 70%, 80%, 90%, or higher compared to normal or comparison cells. In certain embodiments, an anti-SEZ6L2 antibody or ADC is used to treat solid tumors that may overexpress SEZ6L2.

[0172] The term “administer” 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 SEZ6L2-related disorder or inhibition or reduction of a tumor). Modes of administration may be parenteral, enteral, or topical. Parenteral administration is usually by injection and includes, but is not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions.

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

[0174] As used herein, the terms “effective dose” or “therapeutic effective dose” refer to a quantity of a drug, such as an antibody or ADC, sufficient to reduce or improve the severity and / or duration of a disorder, such as cancer, or one or more of its symptoms; prevent the progression of the disorder; cause regression of the disorder; prevent the recurrence, onset, initiation, or exacerbation of one or more symptoms associated with the disorder; detect the disorder; or enhance or improve the preventive or therapeutic effect (may be one or more) of another treatment (e.g., a prophylactic or therapeutic agent). An effective dose of an antibody or ADC may, for example, inhibit tumor growth (e.g., inhibit the increase of tumor volume), reduce tumor growth (e.g., reduce tumor volume), reduce the number of cancer cells, and / or alleviate one or more of the symptoms associated with cancer to some extent. An effective dose 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 cancer tumor cells, are transplanted into immunodeficient mice that do not reject human cells, either subcutaneously or within the organ type from which the tumor originates.

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

[0177] II. Anti-SEZ6L2 antibody One embodiment disclosed herein provides a humanized anti-SEZ6L2 antibody or its antigen-binding moiety. Another embodiment disclosed herein provides a human anti-SEZ6L2 antibody or its antigen-binding moiety. 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 either SEZ6 or SEZ6L. In another embodiment, the antibody disclosed herein binds to human SEZ6L expressed on tumor cells.

[0178] Another aspect disclosed herein features an anti-SEZ6L2 antibody as described herein, and an antibody-drug conjugate (ADC) comprising at least one drug, such as a DNA alkylating agent, e.g., IGN, auristatin (e.g., MMAE), a microtubule inhibitor, or a meitansinoid (e.g., DM4), or a pyrrolobenzodiazepine (PBD), but is not limited thereto. The antibodies or ADCs disclosed herein, but are characterized by 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, anti-SEZ6L2 humanized and human antibodies having the ability to inhibit SCLC tumor cell proliferation in vivo are disclosed, as described in the following examples. These novel antibodies are collectively referred to herein as “SEZ6L2 antibodies.” As described in Example 6, anti-SEZ6L2 antibodies, ADCs, or their antigen-binding fragments can inhibit or reduce tumor growth in vivo, for example, in the NCI-H524 human small cell lung cancer (SCLC) xenograft assay in nude mice. In various embodiments, anti-SEZ6L2 antibodies, ADCs, or their antigen-binding fragments can modulate the biological function of SEZ6L2. In other embodiments of the above-described aspects, the anti-SEZ6L2 antibodies, ADCs, or their antigen-binding fragments bind to SEZ6L2 on cells overexpressing SEZ6L2. In further embodiments, the anti-SEZ6L2 antibodies, ADCs, or their antigen-binding fragments do not bind to either SEZ6 or SEZ6L.

[0180] Accordingly, this 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 antibody, ADC, or antigen-binding fragment thereof does not bind to either 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, for example, in the NCI-H524 human small cell lung cancer (SCLC) xenograft assay in nude mice. For example, the antibody, or its antigen-binding moiety, can inhibit tumor growth by at least about 50% compared to a human IgG antibody that is not specific to SEZ6L2 in an in vivo human small cell lung cancer (SCLC) xenograft assay. In a particular embodiment, the anti-SEZ6L2 antibody, ADC, or its antigen-binding fragment 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% compared to a human IgG antibody that is not specific to SEZ6L2 in an in vivo human small cell lung cancer (SCLC) xenograft assay when administered at the same dose and dosage cycle. In certain embodiments, anti-SEZ6L2 antibodies, ADCs, or their antigen-binding fragments can inhibit or reduce tumor growth by approximately 80% to approximately 90%, or approximately 84% to approximately 90%, or approximately 88% to approximately 90%, compared to human IgG antibodies that are not specific to SEZ6L2, in in vivo human small cell lung cancer (SCLC) xenograft assays when administered at the same dose and dosage cycle. In some embodiments, anti-SEZ6L2 antibodies, ADCs, or their antigen-binding fragments can inhibit or reduce tumor growth for longer periods than 7 days, 14 days, 1 month, 2 months, 3 months, 4 months, 5 months, 5 months, 60, 70, 80, 90, 100, or 110 days, compared to human IgG antibodies that are not specific to SEZ6L2, when administered at the same dose and dosage cycle in an in vivo human small cell lung cancer (SCLC) xenograft assay.

[0182] Antibodies having any combination of the above-described features are intended as embodiments of this disclosure. Furthermore, ADCs described in more detail below may have any of the above-described features.

[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 ADCs are described herein.

[0184] The anti-SEZ6L2 antibodies described herein have the ability to bind to SEZ6L2 and provide an ADC that can deliver a cytotoxic molecule (e.g., a DNA alkylating agent, e.g., IGN, auristatin (e.g., MMAE), or a meitansinoid (e.g., DM4), or other microtubule inhibitor) 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., the antigen-binding portion of an anti-SEZ6L2 antibody) are also included in this disclosure and may be included in the embodiments (methods and compositions) described throughout this specification. For example, an anti-SEZ6L2 antibody fragment may be conjugated to a drug (e.g., a DNA alkylating agent, such as IGN, auristatin (e.g., MMAE), or a microtubule inhibitor such as a meitansinoid (e.g., DM4)) as described herein. In certain embodiments, the anti-SEZ6L2 antibody-binding portion may be Fab, Fab', F(ab')2, Fv, disulfide-linked Fv, scFv, a single-domain antibody, or a diabody.

[0186] II.A. Humanized Antibodies After producing 17 anti-hSEZ6L2 mouse antibodies as described in Example 2 below, the mouse 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 chain and light chain variable region amino acid sequences of these humanized antibodies are shown in Table 6.

[0187] Accordingly, in one embodiment, the humanized anti-hSEZ6L2 antibody or its antigen-binding moiety includes 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 its antigen-binding moiety 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 its antigen-binding moiety is a humanized antibody 16H8. The 16H8 antibody includes a heavy chain variable region including a CDR3 domain containing the amino acid sequence of SEQ ID NO: 4, a CDR2 domain containing the amino acid sequence of SEQ ID NO: 3, and a CDR1 domain containing the amino acid sequence of SEQ ID NO: 2, as well as a light chain variable region including a CDR3 domain containing the amino acid sequence of SEQ ID NO: 8, a CDR2 domain containing the amino acid sequence of SEQ ID NO: 7, and a CDR1 domain containing the amino acid sequence of SEQ ID NO: 6. In a further embodiment, an antibody having a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 5 is disclosed herein.

[0190] In some embodiments, the anti-SEZ6L2 antibody or its antigen-binding moiety includes a heavy chain containing the amino acid sequence shown in SEQ ID NO: 1, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 1, and / or a heavy chain containing the amino acid sequence shown in SEQ ID NO: 5, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 5.

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

[0192] In some embodiments, the anti-SEZ6L2 antibody or its antigen-binding moiety includes a heavy chain containing the amino acid sequence shown in SEQ ID NO: 9, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 9, and / or a heavy chain containing the amino acid sequence shown in SEQ ID NO: 13, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 13.

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

[0194] In some embodiments, the anti-SEZ6L2 antibody or its antigen-binding moiety includes a heavy chain containing the amino acid sequence shown in SEQ ID NO: 1, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 1, and / or a heavy chain containing the amino acid sequence shown in SEQ ID NO: 5, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 5.

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

[0196] In some embodiments, the anti-SEZ6L2 antibody or its antigen-binding moiety includes a heavy chain containing the amino acid sequence shown in SEQ ID NO: 25, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 25, and / or a heavy chain containing the amino acid sequence shown in SEQ ID NO: 29, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with 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. Using transgenic mice, high-affinity, fully human monoclonal antibodies that bind to and / or inhibit SEZ6L2 were generated. The heavy chain and light chain variable region amino acid sequences of these human antibodies are shown in Table 9.

[0198] Accordingly, in one embodiment, the present disclosure includes a human anti-hSEZ6L2 antibody or its antigen-binding moiety 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 an 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 comprises a human anti-hSEZ6L2 antibody or its antigen-binding moiety, which includes 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, which is a human antibody 1A1, or its antigen-binding moiety. The 1A1 antibody includes a heavy chain variable region including a CDR3 domain containing the amino acid sequence of SEQ ID NO: 35, a CDR2 domain containing the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain containing the amino acid sequence of SEQ ID NO: 33, and a light chain variable region including a CDR3 domain containing the amino acid sequence of SEQ ID NO: 39, a CDR2 domain containing the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain containing the amino acid sequence of SEQ ID NO: 37. In a further embodiment, the disclosure provides an antibody having a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 32 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 36.

[0202] In some embodiments, the anti-SEZ6L2 antibody or its antigen-binding moiety includes a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 32, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 32, and / or a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 36, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 36.

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

[0204] In some embodiments, the anti-SEZ6L2 antibody or its antigen-binding moiety includes a heavy chain containing the amino acid sequence shown in SEQ ID NO: 40, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 40, and / or a heavy chain containing the amino acid sequence shown in SEQ ID NO: 44, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 44.

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

[0206] In some embodiments, the anti-SEZ6L2 antibody or its antigen-binding moiety includes a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 32, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 32, and / or a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 47, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 47.

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

[0208] In some embodiments, the anti-SEZ6L2 antibody or its antigen-binding moiety includes a heavy chain containing the amino acid sequence shown in SEQ ID NO: 51, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 51, and / or a heavy chain containing the amino acid sequence shown in SEQ ID NO: 55, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 55.

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

[0210] In some embodiments, the anti-SEZ6L2 antibody or its antigen-binding moiety includes a heavy chain containing the amino acid sequence shown in SEQ ID NO: 59, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 59, and / or a heavy chain containing the amino acid sequence shown in SEQ ID NO: 63, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 63.

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

[0212] In some embodiments, the anti-SEZ6L2 antibody or its antigen-binding moiety includes a heavy chain containing the amino acid sequence shown in SEQ ID NO: 67, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 67, and / or a heavy chain containing the amino acid sequence shown in SEQ ID NO: 71, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 71.

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

[0214] In some embodiments, the anti-SEZ6L2 antibody or its antigen-binding moiety includes a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 73, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 73, and / or a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 77, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 77.

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

[0216] In some embodiments, the anti-SEZ6L2 antibody or its antigen-binding moiety includes a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 79, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 79, and / or a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 82, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 82.

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

[0218] In some embodiments, the anti-SEZ6L2 antibody or its antigen-binding moiety includes a heavy chain containing the amino acid sequence shown in SEQ ID NO: 84, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 84, and / or a heavy chain containing the amino acid sequence shown in SEQ ID NO: 88, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 88.

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

[0220] In some embodiments, the anti-SEZ6L2 antibody or its antigen-binding moiety includes a heavy chain containing the amino acid sequence shown in SEQ ID NO: 90, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 90, and / or a heavy chain containing the amino acid sequence shown in SEQ ID NO: 94, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 94.

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

[0222] In some embodiments, the anti-SEZ6L2 antibody or its antigen-binding moiety includes a heavy chain containing the amino acid sequence shown in SEQ ID NO: 96, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 96, and / or a heavy chain containing the amino acid sequence shown in SEQ ID NO: 100, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 100.

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

[0224] In some embodiments, the anti-SEZ6L2 antibody or its antigen-binding moiety includes a heavy chain containing the amino acid sequence shown in SEQ ID NO: 104, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 104, and / or a heavy chain containing the amino acid sequence shown in SEQ ID NO: 108, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 108.

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

[0226] In some embodiments, the anti-SEZ6L2 antibody or its antigen-binding moiety includes a heavy chain containing the amino acid sequence shown in SEQ ID NO: 109, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 109, and / or a heavy chain containing the amino acid sequence shown in SEQ ID NO: 113, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 113.

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

[0228] In some embodiments, the anti-SEZ6L2 antibody or its antigen-binding moiety includes a heavy chain containing the amino acid sequence shown in SEQ ID NO: 115, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 115, and / or a heavy chain containing the amino acid sequence shown in SEQ ID NO: 116, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 116.

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

[0230] In some embodiments, the anti-SEZ6L2 antibody or its antigen-binding moiety includes a heavy chain containing the amino acid sequence shown in SEQ ID NO: 233, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 233, and / or a heavy chain containing the amino acid sequence shown in SEQ ID NO: 237, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 237.

[0231] In one embodiment, the disclosure features an anti-SEZ6L2 antibody, which is a human antibody 2M22_10A6, or its antigen-binding moiety. The 2M22_10A6 antibody includes a heavy chain variable region comprising a CDR3 domain containing the amino acid sequence of SEQ ID NO: 242, a CDR2 domain containing the amino acid sequence of SEQ ID NO: 241, and a CDR1 domain containing the amino acid sequence of SEQ ID NO: 240, as well as a light chain variable region comprising a CDR3 domain containing the amino acid sequence of SEQ ID NO: 245, a CDR2 domain containing the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain containing 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 its antigen-binding moiety includes a heavy chain containing the amino acid sequence shown in SEQ ID NO: 239, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 239, and / or a heavy chain containing the amino acid sequence shown in SEQ ID NO: 243, or a sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 243.

[0233] The aforementioned anti-SEZ6L2 antibody CDR sequences establish a novel family of SEZ6L2-binding proteins, including antigen-binding polypeptides containing the CDR sequences listed in Tables 6 and 9 and the Sequence Summary, which were isolated in accordance with this disclosure.

[0234] To generate and select CDRs having a preferred SEZ6L2 binding and / or neutralizing activity with respect to hSEZ6L2, standard methods known in the art for generating antibodies or their antigen-binding moieties, evaluating SEZ6L2 binding, and / or neutralizing the characteristics of such antibodies or their antigen-binding moieties can be used, including, but not limited to, those specifically described herein.

[0235] In certain embodiments, the antibody includes a heavy chain constant region such as IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM, or IgD constant regions. In certain embodiments, the anti-SEZ6L2 antibody or its antigen-binding moiety includes 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 its antigen-binding moiety 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 include either a kappa light chain constant region or a lambda light chain constant region. Preferably, the antibody includes a kappa light chain constant region. Alternatively, the antibody moiety may be, for example, a Fab fragment or a single-chain Fv fragment.

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

[0237] In certain embodiments, the anti-SEZ6L2 antibody or its antigen-binding moiety is a multispecific antibody, such as a bispecific antibody.

[0238] Substitutions of amino acid residues in the Fc moiety to alter antibody effector function have been described (Winter et al., U.S. Patents 5,648,260 and 5,624,821; these publications are incorporated herein by reference). The Fc moiety of an antibody mediates several important effector functions, such as cytokine induction, ADCC, phagocytosis, complement-dependent cell-mediated cytotoxicity (CDC), and the half-life / clearance rate of antibodies and antigen-antibody complexes. In some cases, these effector functions are desirable for therapeutic antibodies, but in others, they may be unnecessary or even harmful depending on the therapeutic purpose. Certain human IgG isotypes, particularly IgG1 and IgG3, mediate ADCC and CDC, respectively, by binding to Fc□Rs and complement C1q. The neonatal Fc receptor (FcRn) is a key component that determines 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 so that the effector function of the antibody is altered.

[0239] One embodiment comprises a labeled anti-SEZ6L2 antibody or its antibody moiety 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 the antibody or antibody moiety of the Disclosure to one or more other molecular entities, such as (chemical coupling, gene fusion, non-covalent association, or otherwise) another antibody (e.g., a bispecific antibody or diabody); a detectable agonist; a pharmaceutical; a protein or peptide (such as a streptavidin core region or polyhistidine tag) that can mediate the association of the antibody or antibody moiety with another molecule; and / or mitotic inhibitors, antitumor antibiotics, immunomodulators, vectors for gene therapy, alkylating agents, anti-angiogenic agents, antimetabolites, boron-containing agents, chemoprotective agents, hormones, antihormone agents, corticosteroids, photoactive therapeutic agents, oligonucleotides, radionuclides, topoisomerase inhibitors, tyrosine kinase inhibitors, radiosensitizers, and combinations thereof, such as cytotoxic agents or therapeutic agents.

[0240] Fluorescent compounds are useful detectable activators that can derivatize antibodies or their antibody moieties. Exemplary fluorescent detectable activators include fluorescein, fluorescein isothiocyanate, rhodamine, 5-dimethylamine-1-naphthalenesulfonyl chloride, and phycoerythrin. Antibodies can also be derivatized with detectable enzymes such as alkaline phosphatase, horseradish peroxidase, and glucose oxidase. When antibodies are derivatized with detectable enzymes, the antibody is detected by adding additional reagents used by the enzyme to produce a detectable reaction product. For example, in the presence of the detectable activator horseradish peroxidase, a detectable colored reaction product is obtained by adding hydrogen peroxide and diaminobenzidine. Antibodies can also be derivatized with biotin and detected indirectly by measuring avidin or streptavidin binding.

[0241] In one embodiment, the antibody is conjugated with 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 is not limited to indium ( 111 It is connected to a radial marker such as (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 antibody (or ADC) described herein is chelated by a bifunctional chelating agent, which is a bifunctional cyclohexyldiethylenetriaminepentaacetic acid (DTPA) chelate. 111Labelled with I (see U.S. Patents 5,124,471, 5,434,287, and 5,286,850; each of these documents is incorporated herein by reference).

[0243] Another embodiment of this disclosure provides an anti-SEZ6L2 antibody or a glycosylated-binding protein in which the antigen-binding moiety contains one or more carbohydrate residues. The nascent in vivo protein production may undergo further processing known as post-translational modification. In particular, sugar (glycosyl) residues may be enzymatically added, which is a known process known as glycosylation. The resulting protein having a covalently linked oligosaccharide side chain is known as a glycosylated protein or glycoprotein. The antibody is a glycoprotein having one or more carbohydrate residues in the Fc domain and the variable domain. Carbohydrate residues in the Fc domain have a significant effect on the effector function of the Fc domain, but have minimal effect on the antibody's antigen binding or half-life (R. Jefferis, Biotechnol. Prog. 21 (2005), pp. 11-16). In contrast, glycosylation of the variable domain may affect the antibody's antigen-binding activity. Glycosylation of the variable domain may negatively affect antibody binding affinity, possibly due to steric hindrance (Co, MS et al., Mol. Immunol. (1993) Vol. 30: pp. 1361-1367), or it may lead to increased affinity for the antigen (Wallick, SC et al., Exp. Med. (1988) Vol. 168: pp. 1099-1109; Wright, A. et al., EMBO J. (1991) Vol. 10: pp. 2717-2723).

[0244] One aspect of this disclosure relates to the generation of glycosylation site mutants in which the O- or N-linking 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 this disclosure.

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

[0246] In addition to or instead of this, modified anti-SEZ6L2 antibodies with altered types of glycosylation can be produced, such as low-fucosylated 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 capacity of antibodies. Such carbohydrate modifications can be achieved, for example, by expressing antibodies in host cells with altered glycosylation mechanisms. Cells with altered glycosylation mechanisms have been described in the Art and can be used as host cells to express recombinant antibodies, thereby producing antibodies with altered glycosylation. For example, see Shields, RL et al. (2002) J. Biol. Chem. Vol. 277: pp. 26733-26740; Umana et al. (1999) Nat. Biotech. Vol. 17: pp. 176-171, and European Patent Nos. EP1,176,195; PCT Publication Nos. WO03 / 035835; WO99 / 54342 80. Each of these documents 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 the available substrates (nucleotide sugars) may differ. Due to such factors, the protein glycosylation pattern and the composition of glycosyl residues may vary depending on the host system in which the particular protein is expressed. Useful glycosyl residues include, but are not limited to, glucose, galactose, mannose, fucose, n-acetylglucosamine, and sialic acid. Preferably, the glycosylation-binding protein contains glycosyl residues such that the glycosylation pattern is human.

[0248] Different protein glycosylations 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 endogenous pathway may be reduced compared to the efficacy of the same protein expressed in mammalian cells such as the CHO cell line. Furthermore, such glycoproteins may be immunogenic in humans and may exhibit a reduced in vivo half-life after administration. Certain receptors in humans and other animals may recognize specific glycosyl residues, facilitating rapid clearance of the protein from the bloodstream. Other adverse effects may include changes in protein folding, solubility, sensitivity to proteases, transport, compartmentalization, secretion, recognition by other proteins or factors, antigenicity, or allergenicity. Therefore, experts may prefer therapeutic proteins with a specific glycosylation composition and pattern, e.g., one identical or at least similar to that produced in human cells or species-specific cells of the intended target animal.

[0249] The expression of glycosylated proteins different from those of host cells can be achieved by genetically modifying host cells to express heterologous glycosylation enzymes. Experts can use recombinant techniques to generate antibodies or their antigen-binding moieties that exhibit human protein glycosylation. For example, yeast strains can be genetically modified to express glycosylation enzymes that do not exist in nature, so that the glycosylated proteins (glycoproteins) produced in such yeast strains exhibit the same protein glycosylation as proteins in animal cells, particularly human cells (U.S. Patent Applications Publications 20040018590 and 20020137134 and PCT Publication WO2005100584A2).

[0250] Antibodies can be produced by any of many techniques. For example, expression from host cells transfected with an expression vector(s) encoding heavy and light chains using standard techniques. The various forms of the term “transfection” are intended to encompass a wide range of techniques commonly used to introduce exogenous 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, antibody expression in eukaryotic cells is preferred, and expression in mammalian host cells is most preferred. This is because such eukaryotic cells (and mammalian cells in particular) are more likely than prokaryotic cells to construct 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 Vol. 77: 4216-4220, used with a DHFR-selectable marker such as those described in RJ Kaufman and PA Sharp (1982) Mol. Biol. Vol. 159: pp. 601-621), NS0 myeloma cells, COS cells, and SP2 cells. When a recombinant expression vector encoding an antibody gene is introduced into mammalian host cells, the antibody is produced by culturing the host cells for a period sufficient to allow antibody expression in the host cells or, more preferably, secretion of the antibody into the culture medium in which the host cells are growing. The antibody can be recovered from the culture medium using standard protein purification methods.

[0252] Furthermore, functional antibody fragments, such as Fab fragments or scFv molecules, can be produced using host cells. Variations of the above procedure are understood to be within the scope of this disclosure. For example, it may be desirable to transfect host cells having DNA encoding a functional fragment of either the light chain and / or heavy chain of the antibody. Alternatively, recombinant DNA technology may be used to delete some or all of the DNA encoding either or both of the light and heavy chains that are not necessary for binding to the antigen of interest. Molecules expressed from such truncated DNA molecules are also included by the antibodies of this disclosure. In addition, by crosslinking the antibody of this disclosure to a second antibody using a standard chemical crosslinking method, a bifunctional antibody can be produced in which one heavy chain and one light chain are the antibody of this disclosure, and the other heavy and light chains are specific to an antigen other than the antigen of interest.

[0253] In a preferred system for recombinant expression of an antibody or its antigen-binding moiety, 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 chain and light chain genes are 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 that allows selection of CHO cells to which the vector has been transfected using methotrexate selection / amplification. Selected transformant host cells are cultured to enable expression of the antibody heavy chain and light chain, and intact antibodies are recovered from the culture medium. Using standard molecular biology techniques, the recombinant expression vector is prepared, host cells are transfected, transformants are selected, host cells are cultured, and antibodies are recovered from the culture medium. Furthermore, this disclosure provides a method for synthesizing recombinant antibodies by culturing host cells in a suitable culture medium until recombinant antibodies are synthesized. Recombinant antibodies can be produced using nucleic acid molecules corresponding to the amino acid sequences disclosed herein. In one embodiment, nucleic acid molecules shown in SEQ ID NOs. 120-155 and 246-249 (as shown in the sequence summary) are used to produce recombinant antibodies. The above method may further include isolating the recombinant antibodies 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). Because of the ADC's ability to selectively deliver one or more drug moieties to target tissues such as tumor-associated antigens, e.g., SEZ6L2-expressing tumors, the antibody-drug conjugate (ADC) can increase the therapeutic efficacy of the antibody in treating diseases, e.g., cancer. Therefore, in certain embodiments, this disclosure provides anti-SEZ6L2 ADCs for therapeutic use, e.g., for treating cancers (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, conjugated 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 conjugated to one or more cytotoxic agents that are delivered into cancer cells expressing SEZ6L2.

[0256] Examples of drugs that can be used as anti-SEZ6L2 ADCs are provided below. Linkers that can be used to conjugate antibodies and one or more drugs are also provided below. The terms “drug,” “agonist,” and “drug portion” are used synonymously herein. The terms “linked” and “conjugated” are also used synonymously herein, indicating that the antibody and portion are covalently linked.

[0257] In some embodiments, the ADC has the following formula (Formula I): Ab-(LD) n (I) In the formula, Ab is the anti-SEZ6L2 antibody described herein, and (LD) is the linker-drug moiety. The linker-drug moiety consists of L-, which is the linker, and -D, which is the drug moiety having, for example, cell proliferation inhibitory activity, cytotoxic activity, or otherwise therapeutic activity against target cells, e.g., cells expressing SEZ6L2, where n is an integer from 1 to 20. In some embodiments, n is in the range of 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1. The DAR of the ADC corresponds to "n" as referenced in Formula I.

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

[0259] In one embodiment, the ADC is given by the formula Ab-(LD) n The formula comprises, where Ab is an anti-SEZ6L2 antibody, L is a linker, such as a charged-defective disulfide (sSPDB) or a cleavable peptide linker (D-Ala-L-dpa), D is a drug, such as a meitansinoid such as DM4, and n is 2, 4, 6, or 8 (corresponding to DARs of 2, 4, 6, or 8). In another embodiment, n is 0 to 8 (corresponding to DARs of 0 to 8). In one embodiment, the above ADC is used to treat neuroendocrine tumors.

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

[0261] Further details regarding the drug (D in Formula I) and linker (L in Formula I) that can be used in ADCs, as well as alternative ADC structures, are described below.

[0262] A. Anti-SEZ6L2 ADC: Exemplary drug for conjugation Anti-SEZ6L2 antibodies can be used in ADCs to target one or more drugs to target cells of interest, such as cancer cells expressing SEZ6L2. The anti-SEZ6L2 ADCs disclosed herein provide targeted therapy that can reduce side effects often seen in anticancer treatments, for example, because one or more drugs are delivered to specific cells.

[0263] Auristatin The anti-SEZ6L2 antibody may be conjugated to at least one auristatin. Auristatins generally represent a group of drastatin 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. Patent No. 5,635,483) is a synthetic analog of the natural marine product drastatin 10, a compound that inhibits tubulin polymerization by binding to the same tubulin site as the anticancer drug vincristine (GR Pettit, Prog. Chem. Org. Nat. Prod, Vol. 70, pp. 1-79 (1997)). Drastatin 10, auristatin PE, and auristatin E are linear peptides having four amino acids, three of which are unique to compounds in the drastatin class. Exemplary embodiments of the auristatin subclass of mitotic inhibitors include, but are not limited to, 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-benzoylvalerate-AE ester (AEVB).The synthesis and structure of auristatin derivatives are described in U.S. Patent Publications 2003-0083263, 2005-0238649, and 2005-0009751; International Patent Publication WO04 / 010957, International Patent Publication WO02 / 088172, and U.S. Patent Publications 6,323,315; 6,239,104; 6,034,065; 5,780,588; 5,665,860; 5,663,149; and 5,635,4. These are listed in Nos. 83; Nos. 5,599,902; Nos. 5,554,725; Nos. 5,530,097; Nos. 5,521,284; Nos. 5,504,191; Nos. 5,410,024; Nos. 5,138,036; Nos. 5,076,973; Nos. 4,986,988; Nos. 4,978,744; Nos. 4,879,278; Nos. 4,816,444; and Nos. 4,486,414, each of which is incorporated herein by reference.

[0264] In one embodiment, an 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 on its own. In recent cancer treatment developments, it is linked to a monoclonal antibody (mAb) that recognizes the expression of specific markers on cancer cells and directs the MMAE towards the cancer cells. In one embodiment, the linker linking the MMAE to the anti-SEZ6L2 antibody is stable in extracellular fluid (i.e., a medium or environment outside the cell), but once the ADC binds to a specific cancer cell antigen and enters the cancer cell, it is cleaved by cathepsin, thereby releasing the toxic MMAE and activating a potent anti-systemic 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 the DAR is 1. In a particular embodiment, the ADC has a DAR of 2 to 8, or alternatively, 2 to 4.

[0267] Maytansinoid Anti-SEZ6L2 antibodies can be conjugated to at least one meitansinoid to form ADCs. Meitansinoids are potent antitumor agents originally isolated from members of the higher plant families Celastraceae, Rhamnaceae, and Euphorbiaceae, as well as several species of mosses (Kupchan et al., J. Am. Chem. Soc. Vol. 94: pp. 1354-1356

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

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

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

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

[1990] ). There is evidence suggesting that meitansinoids inhibit mitosis by inhibiting the polymerization of the microtubule protein tubulin, thereby preventing microtubule formation (see, for example, U.S. Patent No. 6,441,163, and Remillard et al., Science, Vol. 189, pp. 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. Furthermore, the cytotoxicity of maytansinoids is 1,000 times higher than that of conventional chemotherapeutic agents such as methotrexate, daunorubicin, and vincristine (see, for example, U.S. Patent No. 5,208,020).

[0268] Examples of meitansinoids include meitansin, meitansinol, C-3 esters of meitansinol, and other meitansinol analogs and derivatives (see, for example, U.S. Patents 5,208,020 and 6,441,163; each of these publications is incorporated herein by reference). C-3 esters of meitansinol may be naturally occurring or of synthetic origin. Furthermore, both naturally occurring and synthetic C-3 meitansinol 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 meitansinoid analogs are described, for example, in Kupchan et al., J. Med. Chem., Vol. 21, pp. 31-37 (1978).

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

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

[0271] Representative examples of maytansinoids, though not limited to these, include the following: DM1(N 2 '-deacetyl-N 2'-(3-mercapto-1-oxopropyl)-meitansine; also called meltansine, drug meitansinoid 1; ImmunoGen, Inc.; see also Chari et al. (1992) Cancer Res 52: p. 127), DM2, DM3(N 2 '-deacetyl-N 2 '-(4-mercapto-1-oxopentyl)-meitansine), DM4((4-methyl-4-mercapto-1-oxopentyl)-meitansine), and meitansinol (synthetic meitansinoid analog). Other examples of meitansinoids are described in U.S. Patent No. 8,142,784, which is incorporated herein by reference.

[0272] Anthamitocins are a group of maytansinoid antibiotics isolated from various bacterial sources. These compounds possess potent antitumor activity. Representative examples, though not limited to them, include anthamitocin P1, anthamitocin P2, anthamitocin P3, and anthamitocin 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 agent The term "DNA alkylating agent," as used herein, includes a family of DNA alkylating agents, including indolino-benzodiazepines (IGN). IGN exhibits high in vitro efficacy against cancer cells (low pmol / L range IC). 50This represents a chemical class of cytotoxic molecules having a specific value. Examples of IGN DNA alkylating agents that can be used as cytotoxic payloads for ADCs are described in Miller et al. (2016) Molecular Cancer Therapeutics, Vol. 15 (No. 8). The IGN compounds described by Miller et al. bind to the minor groove of DNA, and then a covalent bond reaction occurs between the guanine residue and two imine functional groups in the molecule, resulting in DNA crosslinking. Exemplary IGN structures are 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: mitotic inhibitors, antitumor antibiotics, immunomodulators, gene therapy vectors, alkylating agents, anti-angiogenic agents, antimetabolites, boron-containing agents, chemoprotective agents, hormones, glucocorticoids, phototherapeutic agents, oligonucleotides, radioisotopes, radiosensitizers, topoisomerase inhibitors, tyrosine kinase inhibitors, and combinations thereof.

[0276] 1. Mitotic inhibitors In one embodiment, an anti-SEZ6L2 antibody can be conjugated with one or more mitotic inhibitors to form an ADC for treating cancer. The term “mitotic inhibitor,” as used herein, refers to a cytotoxic and / or therapeutic agent that inhibits mitosis or cell division, which is a particularly important biological process for cancer cells. Mitotic inhibitors often interfere with microtubules to prevent cell division by resulting in microtubule polymerization or depolymerization. Therefore, in one embodiment, the anti-SEZ6L2 antibody is conjugated with one or more mitotic inhibitors that interfere with microtubule formation by inhibiting tubulin polymerization. In one embodiment, the mitotic inhibitor used in the ADC is Ixempra (ixabepyrone). Examples of mitotic inhibitors that can be used against SEZ6L2 ADCs include drastatins, e.g., drastatin 10 and drastatin 15, and plant alkaloids, e.g., taxanes and vinca alkaloids, e.g., indesine sulfate, vincristine, vinblastine, and vinorelbine. The category of mitotic inhibitors includes auristatins and maytansinoids as described above.

[0277] The anti-SEZ6L2 antibodies described herein may be conjugated to at least one taxane. As used herein, the term "taxane" refers to a class of antineoplastic agents having a microtubule-mediated mechanism and a structure comprising a taxane ring structure and stereospecific side chains necessary for cell proliferation inhibitory activity. The term "taxane" also includes a variety of known derivatives, including both hydrophilic and hydrophobic derivatives. Examples of taxane derivatives, though not limited to these, include: galactose and mannose derivatives described in International Patent Application No. 99 / 18113; piperazino and other derivatives described in International Publication No. 99 / 14209; taxane derivatives described in International Publication No. 99 / 09021, International Publication No. 98 / 22451, and U.S. Patent No. 5,869,680; 6-thio derivatives described in International Publication No. 98 / 28288; sulfenamide derivatives described in U.S. Patent No. 5,821,263; and taxol derivatives described in U.S. Patent No. 5,415,869. Each of these documents is incorporated herein by reference. Taxane compounds were previously designated as 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, They are also mentioned in issues 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 explicitly incorporated by reference. Further examples of taxanes, but not limited to these, include 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 with one or more antitumor antibiotics for treating cancer. As used herein, the term “antitemiotic antibiotic” means an antineoplastic drug made from a microorganism that inhibits cell growth by interfering with DNA. Often, antitumor antibiotics either damage DNA strands or delay or halt DNA synthesis. Examples of antitumor antibiotics that may be included in the anti-SEZ6L2 ADC include, but are not limited to, actinomycin (e.g., pyrrolo[2,1-c][1,4]benzodiazepine), anthracyclines, calicheamicin, and duocalmycin. In addition to the above, anti-SEZ6L2 Additional antitumor antibiotics that can be used with ADCs include bleomycin (Blenoxane, Bristol-Myers Squibb), mitomycin, and plicamycin (also known as mitramycin).

[0279] 3. Immunomodulators In one embodiment, the anti-SEZ6L2 antibody may be conjugated with at least one immunomodulator. As used herein, the term “immunomodulator” refers to an agonist that can stimulate or modify an immune response. In one embodiment, the immunomodulator is an immunostimulant that enhances the immune response of a target. In another embodiment, the immunomodulator is an immunosuppressant that prevents or reduces the immune response of a target. Immunomodulators 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, but not limited to, include bacillus calmette-guerin (BCG) and levamisole (Ergamisol). Other examples of immunomodulators that can be used in ADCs, but not limited to, include 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 induced from the subject’s own immune system by administering the cancer vaccine, or, in the present disclosure, by administering an ADC containing an anti-SEZ6L2 antibody and the cancer vaccine. In preferred embodiments, the immune response results in the eradication of tumor cells in the body (e.g., primary or metastatic tumor cells). The use of cancer vaccines generally involves administering a specific antigen or group of antigens, for example, that are present on the surface of certain cancer cells or on the surface of certain infectious agents that have been shown to promote carcinogenesis. In some embodiments, the use of cancer vaccines is for preventive purposes, while in other embodiments, the use is for therapeutic purposes. Non-limiting examples of cancer vaccines that can be used in ADCs include: recombinant bivalent human papillomavirus (HPV) vaccines for types 16 and 18 (Cervarix, GlaxoSmithKline), recombinant quadrivalent human papillomavirus (HPV) vaccines for types 6, 11, 16, and 18 (Gardasil, Merck & Company), and cyproisel-T (Provenge, Dendreon). Thus, in one embodiment, an anti-SEZ6L2 antibody is conjugated to at least one cancer vaccine that is either an immunostimulant or an immunosuppressant.

[0281] Anti-SEZ6L2 antibodies may be conjugated to at least one cytokine. The term "cytokine" generally refers to a protein released by one cell population that acts as an intercellular mediator to another cell. Cytokines directly stimulate immune effector cells and stromal cells at tumor sites, enhancing tumor cell recognition by cytotoxic effector cells (Lee and Margolin (2011) Cancers 3: 3856). Numerous animal tumor model studies have demonstrated that cytokines possess broad antitumor activity, which has led to their use in various forms in many cytokine-based approaches for cancer treatment (Lee and Margolin, above). In recent years, many cytokines have been discovered, including GM-CSF, IL-7, IL-12, IL-15, IL-18, and IL-21, and clinical trials have begun in patients with advanced cancer (Lee and Margolin, above).

[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); liver growth factor; fibroblast growth factor; prolactin; placental lactogen; tumor necrosis factor; Müller inhibitors; mouse gonadotropin-related peptides; inhibin; activin; vascular endothelial growth factor; integrins; thrombopoietin (TPO); and neurotransmitters such as NGF. Transgrowth factors; platelet growth factor; transforming growth factor (TGF); insulin-like growth factor I and II; erythropoietin (EPO); bone induction factor; interferons such as interferon α, β, and γ; colony-stimulating factor (CSF); granulocyte-macrophage C-SF (GM-CSF); and granulocyte-CSF (G-CSF); interleukins (IL) 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 factor; and other polypeptide factors including LIF and kit ligand (KL). As used herein, the term cytokine includes proteins derived from natural sources or recombinant cell cultures and bioactive equivalents of naturally sequenced cytokines. Accordingly, in one embodiment, this disclosure provides an ADC comprising the anti-SEZ6L2 antibody and cytokines 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. Some cancer treatments (e.g., chemotherapy) can affect white blood cells (which help fight infection), so introducing colony-stimulating factors can help maintain white blood cell levels and strengthen the immune system. Colony-stimulating factors can also be used to help new bone marrow begin 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.)), salgramostim (leukine (granulocyte-macrophage colony-stimulating factor and GM-CSF); Genzyme Corporation), promegapoietin, and oprelbequin (recombinant IL-11; Pfizer, Inc.). Therefore, in one embodiment, the ADC may contain the anti-SEZ6L2 antibody and CSF described herein.

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

[0285] 5. Anti-angiogenic agents In one embodiment, 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 major proteins involved in initiating angiogenesis by binding to specific receptors on the cell surface. Therefore, certain anti-angiogenic agents that prevent VEGF from interacting with its cognitive receptor prevent the initiation of angiogenesis by VEGF. In other embodiments, such agents interfere with intracellular signaling cascades. For example, once a specific receptor on the cell surface is activated, a cascade of other chemical signals is initiated, promoting blood vessel growth. Therefore, certain enzymes known to promote intracellular signaling cascades that contribute to cell proliferation, such as certain tyrosine kinases, are targets for cancer treatment. In other embodiments, such agents interfere with intercellular signaling cascades. However, in other embodiments, such agents either neutralize specific targets that activate and promote cell growth, or directly interfere with the growth of vascular cells. Angiogenesis inhibitory properties have been found in more than 300 substances with numerous direct and indirect inhibitory effects.

[0286] Representative examples of anti-angiogenic 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 together with fluorouracil or doxorubicin, canstatin, carboxyamidotriozole and paclitaxel, EMD121974, S-24, vitaxin, dimethylxanthenon acetate, IM862, interleukin-12, interleukin -2, NM-3, HuMV833, PTK787, RhuMab, Angiozyme (Ribozyme), IMC-1C11, Neovastat, Marimstat, Prinomast, BMS-275291, COL-3, MM1270, SU101, SU6668, SU11248, SU5416, together with paclitaxel, together with gemcitabine and cisplatin, and together with irinotecan and cisplatin, and together with radiation, Tecogalan, Temozolomide and PEG interferon α2b, Tetrathiomolybdate, TNP-470, Thalidomide, CC-5013 and Taxotere, Tamstatin, 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), phosphoinositide 3-kinase (PI3K).

[0287] 6. Antimetabolites The anti-SEZ6L2 antibody may be conjugated with at least one antimetabolite. Antimetabolites are a type of chemotherapeutic treatment that closely resembles normal substances within cells. When cells incorporate antimetabolites into their cellular metabolism, the consequences are negative for the cells; for example, the cells cannot divide. Antimetabolites are classified according to the substances they interfere with. Examples of antimetabolites that can be used in ADCs, but are not limited to these, include: 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 to at least one boron-containing agent. The boron-containing agent includes a class of cancer therapeutic compounds that interfere with cell proliferation. Representative examples of boron-containing agents, but not limited to these, include borophycin and bortezomib (Velcade, Millenium Pharmaceuticals).

[0289] 8. Chemical protective agents The anti-SEZ6L2 antibody may be conjugated with at least one chemoprotective agent. Chemoprotective agents are a class of compounds that help protect the body from the specific toxic effects of chemotherapy. Chemoprotective agents can be administered with various chemotherapy regimens to protect healthy cells from the toxic effects of chemotherapy drugs while simultaneously allowing cancer cells to be treated with the administered chemotherapy drugs. Representative chemoprotective agents, but not limited to these, include: amifostine (Ethyol, Medimmune, Inc.), used to reduce nephrotoxicity associated with the cumulative dose of cisplatin and 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 mesnex (Mesnex, Bristol-Myers Squibb), 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. Examples of photoactive therapeutic agents include compounds that can be positioned to kill treated cells upon exposure to electromagnetic radiation of a specific wavelength. The therapeutically relevant compounds absorb electromagnetic radiation of a wavelength that penetrates the tissue. In preferred embodiments, the compounds are administered in a non-toxic form capable of producing a photochemical effect that is toxic to cells or tissues once fully activated. In other preferred embodiments, such compounds are retained by cancerous tissue and readily excreted from normal tissue. Non-limiting examples include various chromagens and dyes.

[0291] 10. Radioactive radionuclides (radioisotopes) The anti-SEZ6L2 antibody may be conjugated to at least one radionuclide agent. The radionuclide agent comprises an agonist characterized by an unstable nucleus capable of undergoing radioactive decay. The basis for the success of radionuclide treatment depends on a sufficient concentration of the radionuclide and the long-term retention of the radionuclide by cancer cells. Other factors to consider include the half-life of the radionuclide, the energy of the radioactive particles, and the maximum distance the radioactive particles 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 211It is a radionuclide selected from the group consisting of Pb. Also, a radionuclide that substantially decays with Auger radiation particles is preferred. For example, Co-58, Ga-67, Br-80m, Tc-99m, Rh-103m, Pt-109, In-111 1, Sb-119, I-125, Ho-161, Os-189m, and Ir-192. The decay energy of useful beta particle-emitting radionuclides is preferably Dy-152, At-211, Bi-212, Ra-223, Rn-219, Po-215, Bi-21 1, Ac-225, Fr-221, At-217, Bi-213, and Fm-255. The decay energy of useful radionuclides that emit alpha particles is preferably 2,000 to 10,000 keV, more preferably 3,000 to 8,000 keV, and most preferably 4,000 to 7,000 keV. As further potential useful radionuclides, 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 BrI69 Examples include Yb.

[0292] 11. Radiosensitizers The anti-SEZ6L2 antibody may be conjugated with 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 dose to increase the sensitivity of cells to radiosensitization to electromagnetic radiation and / or to facilitate the treatment of diseases treatable with electromagnetic radiation. Radiosensitizers are agonists that make cancer cells more sensitive to radiotherapy but typically have a much less impact on normal cells. Therefore, radiosensitizers can be used in combination with radioisotope-labeled antibodies or ADCs. The addition of a radiosensitizer can result in enhanced efficacy compared to treatment with radioisotope-labeled antibodies or antibody fragments alone. Radiosensitizers are described in DM 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 of X-rays. Representative examples of X-ray activated radiosensitizers, but not limited to, include: 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 radiation sensitizers, though not limited to these, include: hematoporphyrin derivatives, Photofrin(r), benzoporphyrin derivatives, NPe6, tin ethithioporphyrin (SnET2), pheophorbide a, bacteriochlorophyll a, naphthalocyanines, phthalocyanines, zinc phthalocyanines, and their therapeutically effective analogs and derivatives.

[0294] 12. Topoisomerase inhibitors The anti-SEZ6L2 antibody may be conjugated to at least one topoisomerase inhibitor. A topoisomerase inhibitor is a chemotherapeutic agent designed to interfere with the action of topoisomerase enzymes (topoisomerases I and II), which, through catalytic action, regulate changes in DNA structure by disrupting and rejoining the phosphodiester backbone of DNA strands during the normal cell cycle. Representative examples of DNA topoisomerase I inhibitors, but not limited to these, include camptothecin and its derivatives irinotecan (CPT-11, Camptosar, Pfizer, Inc.) and topotecan (Hycamtin, GlaxoSmithKline Pharmaceuticals). Representative examples of DNA topoisomerase II inhibitors, though not limited to these, include amsacrin, daunorubicin, doxotrubicin, epipodophyllotoxin, ellipticin, 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 kinases are intracellular enzymes that function to attach phosphate groups to the amino acid tyrosine. Tumor growth can be inhibited by blocking the ability of protein tyrosine kinases to function. Examples of tyrosine kinases that can be used in ADCs, but are not limited to these, include axitinib, bosutinib, cedilanib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, restaurtinib, nilotinib, semaxanib, sunitinib, and vandetanib.

[0296] 14. Other medications Other drugs that can be used in ADCs include, but are not limited to, the following: abrin (e.g., abrin A chain), alpha toxin, Aleurites fordii protein, amatoxin, crotin, curcin, dianthin protein, diphtheria toxin (e.g., diphtheria A chain and unbound active fragments of diphtheria toxin), deoxyribonuclease (DNase), geronin, mitogellin, modesin A chain, momordica charantia inhibitor, neomycin, onconase, phenomycin, Phytolaca americana protein (PAPI, PAPII, and PAP-S), porkweed antiviral protein, Pseudomonas endotoxin, Pseudomonas exotoxin (e.g., exotoxin A chain (derived from Pseudomonas aeruginosa)), restrictosin, lysine A chain, ribonuclease (RNase), sapaonaria Officinalis inhibitors, saporins, 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, mosetinostat, and panobinostat), COX-2 inhibitors, urea substitutions, heat shock protein inhibitors (e.g., geldanamycin and its many analogues), corticosteroids, and tricothecene. (See, for example, WO93 / 21232). Other agents that can be used include asparaginase (Espar, Lundbeck Inc.), hydroxyurea, levamisole, mitotane (Lysodren, Bristol-Myers Squibb), and tretinoin (Renova, Valeant Pharmaceuticals Inc.).

[0297] In one embodiment, the agonist is pyrrolobenzodiazepine (PBD). In one embodiment, the agonist 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 agonist is a saporin toxin.

[0298] The aforementioned group of drug portions that can be used as anti-SEZ6L2 ADCs should be noted that certain drug examples may be found in more than one category; for example, anthamitocin is not exclusive in that it is both a mitotic inhibitor and an antitumor antibiotic.

[0299] All stereoisomers of the above drug moiety, i.e., any combination of R and S configurations at the chiral carbon of D, are intended for use herein.

[0300] Furthermore, the above-mentioned agonists (i.e., naked agonists not conjugated to an antibody) may be used in combination therapy with the anti-SEZ6L2 antibody described herein. In one embodiment, the anti-SEZ6L2 antibody or ADC is used with any of the above-mentioned agonists in combination therapy for treating cancer, in which case the agonist is administered before, simultaneously with, or after the administration of the anti-SEZ6L2 antibody or ADC to the target.

[0301] B. Anti-SEZ6L2 ADC: Exemplary linker An anti-SEZ6L2 ADC comprises an anti-SEZ6L2 antibody and at least one drug, wherein the antibody and at least one drug are conjugated by a linker. The term "linker," as used herein, refers to a chemical moiety, which may be bifunctional or polyfunctional, used to conjugate the antibody to the drug moiety. The linker may contain one conjugate component or more components.

[0302] For example, the linker may include spacers, which are portions that extend the drug linkage, for instance, to avoid shielding 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] To conjugate a drug to an antibody, two methods are generally used: alkylation of reduced interchain cysteine ​​disulfide via an enzymatically non-cleavable maleimide or a simple, cleavable disulfide linker, and acylation of lysine with a cleavable linear amino acid.

[0304] In one embodiment, the linker covalently attaches the antibody to the drug portion. The ADC is prepared using a linker having reactive functionality for binding to the antibody and drug. For example, the cysteine ​​thiol or amine side chain of the antibody, such as the N-terminus or lysine, can form a bond with the functional group of the linker.

[0305] In one embodiment, the linker has a functional group capable of reacting with free cysteine ​​present in the antibody to form a covalent bond. Non-limiting examples of such reactive functional groups include activated esters such as maleimide, haloacetamide, □-haloacetyl, succinimide esters, 4-nitrophenyl esters, pentafluorophenyl esters, and tetrafluorophenyl esters, as well as anhydrides, acid chlorides, sulfonyl chlorides, isocyanates, and isothiocyanates. For example, see the conjugation method on page 766 of Bioconjugate Chemistry, Vol. 15 (No. 4): pp. 765-773, Klussman et al. (2004).

[0306] In some embodiments, the linker has a functional group capable of reacting with electrophiles present in the antibody. Exemplary such electrophiles include, but are not limited to, aldehyde groups and ketone carbonyl groups. In some embodiments, the heteroatoms of the linker's reactive functional groups can react with the antibody's electrophiles to form covalent bonds with the antibody unit. Non-exclusive, but exemplary, such reactive functional groups include, but are not limited to, hydrazides, oximes, aminos, hydrazines, thiosemicarbazones, hydrazine carboxylates, and arylhydrazides.

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

[0308] In another embodiment, an anti-SEZ6L2 antibody is conjugated to a maytansinoid (e.g., DM4) via a charge-damaged 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 a reducing intracellular environment.

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

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

[0311] Suitable linkers include, for example, cleavable and non-cleavable linkers. The linker may be a "cleavable linker" that facilitates drug release. Non-limiting and exemplary cleavable linkers include acid-unstable linkers (e.g., containing hydrazones), protease-sensitive (e.g., peptidase-sensitive) linkers, photodissociative linkers, or disulfide-containing linkers (Chari et al., Cancer). Research, Vol. 52: pp. 127-131 (1992); U.S. Patent No. 5,208,020). Cleavable linkers are typically sensitive to cleavage under intracellular conditions. Suitable cleavable linkers include, for example, peptide linkers that can be cleaved by intracellular proteases such as lysosomal proteases 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 extracellularly in a manner sufficient to be therapeutically effective. Before transport or delivery into the cell, the ADC is preferably stable and intact, i.e., the antibody remains conjugated to the drug moiety. A linker that is stable outside the target cell can be cleaved at a certain effective rate once it enters the cell. Thus, an effective linker (i) maintains the specific binding properties of the antibody, (ii) enables delivery of the drug moiety, e.g., intracellular delivery, and (iii) maintains the therapeutic effect of the drug moiety, e.g., cytotoxic effect.

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

[0314] In other embodiments, the linker is cleavable under reducing conditions (e.g., a disulfide linker). Various disulfide linkers are known in the art and include, 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, which can be formed using these. (For example, Thorpe et al., 1987, Cancer Res. Vol. 47: pp. 5924-5931; Wawrzynczak et al., Immunoconjugates: Antibody Conjugates in Radioimagery and Therapy of Cancer (C.W. Vogel, ed., Oxford U.S. Press, 1987. See also U.S. No. 4,880,935.)

[0315] In some embodiments, the linker is cleavable by cleavage factors, such as enzymes, present in the intracellular environment (e.g., within lysosomes, endosomes, or caveoleas). The linker may be a peptidyl linker cleavable by intracellular peptidase or protease enzymes, including but not limited to lysosomal proteases or endosomal proteases. In some embodiments, the peptidyl linker is at least two amino acids long, or at least three amino acids long. Examples of cleavage factors include cathepsins B and D and plasmin, all of which are known to hydrolyze dipeptide drug derivatives, resulting in the release of active drugs within target cells (see, e.g., Dubowchik and Walker, 1999, Pharm. Therapeutics vol. 83: pp. 67-123). The most typical example is a peptidyl linker cleavable by enzymes present in SEZ6L2-expressing cells. An example of such a linker is 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, for example, U.S. Patent 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 agonist 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., Vol. 15: pp. 1387-1393), a maleimidobenzoyl linker (Lau et al., 1995, Bioorg-Med-Chem., Vol. 3 (No. 10): pp. 1299-1304), or a 3'-N-amide analog (Lau et al., 1995, Bioorg-Med-Chem., Vol. 3 (No. 10): pp. 1305-1312).

[0317] In yet another embodiment, 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 such that the ADC remains substantially intact outside the cell, and when it interacts with a specific receptor on the surface of a target cell, the binding of the ADC initiates (or prevents) a specific cellular signaling pathway.

[0318] In some embodiments, the linker is substantially hydrophilic (e.g., PEG4Mal and sulfo-SPDB). Using a hydrophilic linker can reduce the extent to which a drug can be eluted 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 insertor, thereby inhibiting macromolecule 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 diffusing the linker-drug and / or the drug alone to neighboring cells. In other embodiments, the linker facilitates internal translocation into cells.

[0321] The presence of sterically hindered disulfides can increase the stability of certain disulfide bonds and enhance the efficacy of ADCs. Therefore, in one embodiment, the linker includes a sterically hindered disulfide linkage. A sterically hindered disulfide refers to a disulfide bond present in a specific molecular environment, typically within the same molecule or compound, characterized by a specific spatial arrangement or orientation of atoms that prevents or at least partially inhibits the reduction of the disulfide bond. Thus, the disulfide bond is prevented or at least partially inhibited from potential interactions that would result in the reduction of the disulfide bond due to the presence of bulky (or sterically hindered) chemical moieties and / or bulky amino acid side chains proximal to the disulfide bond.

[0322] It should be noted that the linker types described above are not mutually exclusive. For example, in one embodiment, the linker used in the anti-SEZ6L2 ADC described herein is a non-cleaving linker that facilitates internal translocation into cells.

[0323] In some embodiments, the ADC is given by the following formula (Formula I): Ab-(LD) n (I) or having 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. The linker-drug moiety is made up of L-, which is a linker, and -D, which is a drug moiety having, for example, cell proliferation inhibitory activity, cytotoxic activity, or otherwise therapeutic activity against target cells, e.g., cells expressing SEZ6L2, where n is an integer from 1 to 20.

[0324] In some embodiments, n is in the range of 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1.

[0325] In some embodiments, the -D portion is the same. In yet another embodiment, the -D portion is different.

[0326] In some embodiments, the linker component includes an "amino acid unit." In some such embodiments, the amino acid unit enables cleavage of the linker by a protease, thereby facilitating the release of a drug from the immunoconjugate upon exposure to an intracellular protease such as a lysosomal enzyme (Doronina et al., (2003) Nat. Biotechnol. 21: pp. 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). Examples of tripeptides, though not limited to these, include glycine-valine-citrulline (gly-val-cit) and glycine-glycine-glycine (gly-gly-gly). The amino acid units may contain 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 embodiment, the amino acid unit is phenylalanine-lysine (i.e., fk). In yet another embodiment of the amino acid unit, the amino acid unit is N-methylvaline-citrulline. In yet another embodiment, the amino acid unit is 5-aminovaleric acid, homophenylalanine lysine, tetraisoquinoline carboxylate lysine, cyclohexylalanine lysine, isonepecotic acid lysine, beta-alanine lysine, glycineserine valine glutamine, and isonepecotic acid.

[0328] Another method for generating ADCs involves the use of heterobifunctional crosslinking agents to link the anti-SEZ6L2 antibody to the drug moiety. Examples of crosslinking agents that can be used include: N-succinimidyl 4-(5-nitro-2-pyridyldithio)-pentanoate or its 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 -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-dimethylcarboxamide-2-pyridyldithio)butyrate (SCPB), or N-sulfosuccinimidyl-4-(5-N,N-dimethylcarboxamide-2-pyridyldithio)butyrate (SSCPB). The antibody may be modified with the crosslinking agent 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 slightly excess of a specific drug containing the thiol moiety to obtain ADCs in excellent yield (see also U.S. Patent No. 6,913,748, which is incorporated herein by reference).

[0329] In one embodiment, a charged linker (also called a pro-charged linker) is used to conjugate an anti-SEZ6L2 antibody to a drug to form an ADC. Examples of charged linkers include those that are charged after cell processing. The presence of a charged group(s) on the linker or drug of a particular ADC after cell processing offers several advantages: for example, (i) the ADC exhibits greater water solubility; (ii) it has the ability to act at higher concentrations in aqueous solutions; (iii) it has the ability to link more drug molecules per antibody, potentially resulting in higher potency; (iv) the charged conjugate species is more likely to be retained within target cells, resulting in higher potency; and (v) it improves the sensitivity of multidrug-resistant cells, thereby preventing the charged drug species from being transported out of the cell. Some suitable charged crosslinkers or pro-charged crosslinkers and examples of their synthesis are shown in Figures 1-10 of U.S. Patent No. 8,236,319, which is incorporated herein by reference. Preferably, the charged or procharged crosslinking agent includes a sulfonate, phosphate, carboxyl, or quaternary amine substituent that significantly increases the solubility of the ADC, particularly in the case of an ADC having 2 to 20 conjugated drugs. Conjugates prepared from a linker containing a procharged moiety will produce 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 linker; maleimidocaproyl-polyethylene glycol (MC(PEG)6-OH); N-methyl-valinecitrulline; 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). Another linker for use is the avidin-biotin linkage for providing avidin-biotin-containing ADCs (U.S. Patent No. 4,676,980, PCT Publications WO1992 / 022332A2, WO1994 / 016729A1, WO1995 / 015770A1, WO1997 / 031655A2, WO1998 / 035704A1, WO1999 / 019500A1, WO2001 / 09785A2, WO2001 / 090198A1, WO2003 / 093 (See also 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 cohesion / dockerin pairs to provide cohesion-dockerin-containing ADCs (see PCT Publications WO2008 / 097866A2, WO2008 / 097870A2, WO2008 / 103947A2, and WO2008 / 103953A2).

[0331] Additional linkers may include non-peptide polymers (examples include, but are not limited to, polyethylene glycol, polypropylene glycol, polyoxyethylated polyol, polyvinyl alcohol, polysaccharide, dextran, polyvinyl ethyl ether, PLA (poly(lactic acid)), PLGA (poly(lactic acid-glycolic acid)), and combinations thereof, with polyethylene glycol being a preferred polymer) (see also PCT Publication WO2011 / 000370). Additional linkers are also described in WO2004-010957, U.S. Patent Application Publication 20060074008, U.S. Patent Int...

Claims

1. An anti-human seizure-related six-homologous 2 (anti-hSEZ6L2) antibody or its antigen-binding portion, wherein the antibody or its antigen-binding portion is A heavy chain variable region comprising a CDR3 domain containing the amino acid sequence of SEQ ID NO: 20, a CDR2 domain containing the amino acid sequence of SEQ ID NO: 19, and a CDR1 domain containing the amino acid sequence of SEQ ID NO: 18, and a light chain variable region comprising a CDR3 domain containing the amino acid sequence of SEQ ID NO: 24, a CDR2 domain containing the amino acid sequence of SEQ ID NO: 23, and a CDR1 domain containing the amino acid sequence of SEQ ID NO: 22; A heavy chain variable region comprising a CDR3 domain containing the amino acid sequence of SEQ ID NO: 28, a CDR2 domain containing the amino acid sequence of SEQ ID NO: 27, and a CDR1 domain containing the amino acid sequence of SEQ ID NO: 26, and a light chain variable region comprising a CDR3 domain containing the amino acid sequence of SEQ ID NO: 31, a CDR2 domain containing the amino acid sequence of SEQ ID NO: 15, and a CDR1 domain containing the amino acid sequence of SEQ ID NO: 30; A heavy chain variable region comprising a CDR3 domain containing the amino acid sequence of SEQ ID NO: 43, a CDR2 domain containing the amino acid sequence of SEQ ID NO: 42, and a CDR1 domain containing the amino acid sequence of SEQ ID NO: 41, and a light chain variable region comprising a CDR3 domain containing the amino acid sequence of SEQ ID NO: 46, a CDR2 domain containing the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain containing the amino acid sequence of SEQ ID NO: 45; A heavy chain variable region comprising a CDR3 domain containing the amino acid sequence of SEQ ID NO: 99, a CDR2 domain containing the amino acid sequence of SEQ ID NO: 98, and a CDR1 domain containing the amino acid sequence of SEQ ID NO: 97, and a light chain variable region comprising a CDR3 domain containing the amino acid sequence of SEQ ID NO: 103, a CDR2 domain containing the amino acid sequence of SEQ ID NO: 102, and a CDR1 domain containing the amino acid sequence of SEQ ID NO: 101; or Heavy chain variable region including a CDR3 domain containing the amino acid sequence of SEQ ID NO: 236, a CDR2 domain containing the amino acid sequence of SEQ ID NO: 235, and a CDR1 domain containing the amino acid sequence of SEQ ID NO: 234, and light chain variable region including a CDR3 domain containing the amino acid sequence of SEQ ID NO: 238, a CDR2 domain containing the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain containing the amino acid sequence of SEQ ID NO: 37 The antibody or its antigen-binding portion, wherein the antibody or its antigen-binding portion does not bind to either SEZ6 or SEZ6L.

2. The antibody or its antigen-binding portion A heavy chain variable region containing the amino acid sequence of SEQ ID NO: 17, and a light chain variable region containing the amino acid sequence of SEQ ID NO: 21; A heavy chain variable region containing the amino acid sequence of SEQ ID NO: 25, and a light chain variable region containing the amino acid sequence of SEQ ID NO: 29; A heavy chain variable region containing the amino acid sequence of SEQ ID NO: 40, and a light chain variable region containing the amino acid sequence of SEQ ID NO: 44; A heavy chain variable region containing the amino acid sequence of SEQ ID NO: 96, and a light chain variable region containing the amino acid sequence of SEQ ID NO: 100; or Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 233, and light chain variable region containing the amino acid sequence of SEQ ID NO: 237 The antibody or its antigen-binding portion according to claim 1, comprising:

3. The antibody or its antigen-binding portion A heavy chain variable region containing a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 17, and a light chain variable region containing a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 21; A heavy chain variable region containing a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 25, and a light chain variable region containing a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 29; A heavy chain variable region containing a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 40, and a light chain variable region containing a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 44; A heavy chain variable region containing a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 96, and a light chain variable region containing a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 100; or A heavy chain variable region containing a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 233, and a light chain variable region containing a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

237. The antibody or its antigen-binding portion according to claim 1, comprising:

4. An antibody or its antigen-binding moiety according to any one of claims 1 to 3, conjugated to at least one drug.

5. The antibody or antigen-binding moiety according to claim 4, wherein the at least one drug is selected from the group consisting of auristatin, meitansinoid, DNA alkylating agent, pyrrolobenzodiazepine (PBD), indolino-benzodiazepine (IGN), topoisomerase inhibitor, and topoisomerase I inhibitor.

6. The antibody or antigen-binding moiety according to claim 4 or 5, wherein at least one drug is conjugated to the antibody or its antigen-binding moiety via a linker.

7. The antibody or its antigen-binding portion according to claim 6, wherein the linker is a cleavable linker.

8. The antibody or antigen-binding portion thereof according to claim 6, wherein the linker is a non-cleavable linker.

9. The antibody or antigen-binding moiety according to claim 6, wherein the auristatin is monomethyl auristatin E (MMAE) and the linker is maleimide-caproyl-valine-citrulline (MC-VC).

10. The antibody or antigen-binding moiety according to claim 6, wherein the drug is 4-methyl-4-mercapto-1-oxopentyl)-meytansine (DM4), and the linker is D-Ala-L-dpa or sSPDB.

11. The antibody or antigen-binding moiety according to claim 6, wherein the drug is indolino-benzodiazepine (IGN) and the linker is D-Ala-L-dpa.

12. A pharmaceutical composition comprising the antibody or its antigen-binding portion according to any one of claims 1 to 11.

13. A composition comprising an anti-SEZ6L2 antibody according to any one of claims 1 to 11 or an antigen-binding portion thereof, or a pharmaceutical composition according to claim 12, for treating a subject having small cell lung cancer, characterized in that the composition or pharmaceutical composition is administered to the subject having small cell lung cancer.

14. A composition comprising an anti-SEZ6L2 antibody according to any one of claims 1 to 11 or an antigen-binding portion thereof, or a pharmaceutical composition according to claim 12, for inhibiting or reducing solid tumor growth in a subject having a solid tumor, characterized in that the composition or pharmaceutical composition is administered to the subject having the solid tumor, wherein the solid tumor is small cell lung cancer.

15. The composition or pharmaceutical composition according to claim 13 or 14, characterized in that it is administered in combination with an additional agent or additional therapy.

16. The composition or pharmaceutical composition according to claim 15, wherein the additional therapy is radiotherapy, a chemotherapeutic agent, or a PARP inhibitor.

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