Immunoconjugates for sez6l2 and methods of use

Abstract

Provided herein are anti-SEZ6L2 immunoconjugates that can be used for treating cancer.

Description

Attorney Docket No. 22419-20011.40IMMUNOCONJUGATES FOR SEZ6L2 AND METHODS OF USECROSS REFERNCE TO RELATED APPLICATIONS

[0001] This application claims priority benefit U. S. Provisional Application Nos. 63 / 725,275, 63 / 737,316, 63 / 812,704, 63 / 878,012, 63 / 885,067, and 63 / 903,768, filed November 26, 2024, December 20, 2024, May 27, 2025, September 8, 2025, September 19, 2025, and October 22, 2025, respectively, the contents of each of which are hereby incorporated by reference in their entireties.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (224192001140SEQLIST.xml; Size: 165,512 bytes; and Date of Creation: November 20, 2025) is herein incorporated by reference in its entirety.FIELD OF INVENTION

[0003] The invention relates to anti-SEZ6L2 antibodies and anti-SEZ6L2 immunoconjugates, and methods of using the same for treating cancer.BACKGROUND

[0004] Seizure Related 6 Homolog Like 2 (SEZ6L2) is a type 1 transmembrane protein that belongs to the SEZ6 family, which is composed of SEZ6, SEZ6L, and SEZ6L2. The SEZ6 family members are expressed throughout the brain and have been shown to influence synapse numbers and dendritic morphology. All SEZ6 family members contain 2-3 CUB domains and 5 complement control protein (CCP) domains, suggesting that they may be involved in complement regulation.

[0005] Though the normal physiologic role of SEZ6L2 is not fully understood, genetic variations in the SEZ6 family have been associated with various neurological and psychiatric disorders including febrile seizures, bipolar disorder I, and autism. Further, several proteomic and transcriptomic databases have suggested that SEZ6L2 is differentially upregulated in certain tumors.

[0006] Current cancer treatments involve the use of cytotoxic drugs, chemotherapy, radiotherapy, and surgery, and often result in cancer recurrence. For example, cytotoxic drugs such as exatecan and its analogues are highly toxic and indiscriminate. Improved and targeted therapies are needed for targeting SEZ6L2.1MF - 363628584Attorney Docket No. 22419-20011.40BRIEF SUMMARY OF INVENTION

[0007] Provided herein are immunoconjugates (antibody-drug conjugates, or ADCs) for SEZ6L2 that address the previous limitations of cancer treatments. For example, immunoconjugates for SEZ6L2 described herein have reduced toxicity over conventional therapy and as such represent an improved therapeutic.

[0008] Described herein, in certain embodiments, are immunoconjugates having Formula (I), Ab-[S-L1-L2-L3-L4-L5-L6-L7-D]n(I)wherein:Ab is an antibody or an antigen-binding fragment thereof that binds Seizure Related 6 Homolog Like 2 (SEZ6L2), comprising:a heavy chain variable region (VH) comprising (i) a complementarity determining region (CDR) 1 having an amino acid sequence according to any one of SEQ ID NOs: 1-12; (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 13-24; and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 25-36; and a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 37-48; (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 49-60; and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 61-72;S is a sulfur atom of a cysteine of the antibody or the antigen-binding fragment thereof;L1isL2is absent,2MF - 363628584Attorney Docket No. 22419-20011.40Z1and Z2are each individually hydrogen, halogen, NO2, -O-(Ci-Ce alkyl), or Ci-Ce alkyl;L3is -(CH2)n1-C(=O)- or -(CH2CH2O)n1-(CH2)n1C(=O)-;each n1is individually an integer from 0 to 10;L4is a tetrapeptide residue;L5is absent or -[NH(CH2)n2]n3- n2is an integer from 0 to 6;n3is an integer from 0 to 2;L6is absent,HN, wherein G is a beta- glucuronic acid moiety;L7is absent,HN OD is a drug moiety; andn is an integer from 1 to 10.

[0009] In some embodiments according to any of the embodiments described above, the drug moiety is represented by Formula (II) having the structure:3MF - 363628584Attorney Docket No. 22419-20011.40(II)wherein:R1and R2are each individually selected from the group consisting of hydrogen, halogen, -CN, -OR5, -NR5R6, a substituted or an unsubstituted Ci-Ce alkyl, a substituted or unsubstituted Ci-Ce haloalkyl, a substituted or unsubstituted -O-(Ci-Ce alkyl), a substituted or unsubstituted -O-(Ci-Ce haloalkyl), and -[(CY2)pO(CY2)q]tCY3, or a substituted or unsubstituted -O-(CR5R6)m-O- such that R1and R2are taken together form a ring;R3is a hydrogen or a substituted or an unsubstituted Ci-Ce alkyl, a substituted or an unsubstituted Ci-Ce haloalkyl, or — [(CY2)PO(CY2)q]tCY3;R4is hydrogen, a substituted or an unsubstituted — (Ci-Ce alkyl)-X2, a substituted or an unsubstituted — (Ci-Ce haloalkyl)-X2, a substituted or an unsubstituted — (Ci-Ce alkenyl)-X2, a substituted or an unsubstituted — (Ci-C6haloalkenyl)-X2, a substituted or an unsubstituted — (Ci-Ce alkynyl)-X2, or a substituted or an unsubstituted — (Ci-Ce haloalkynyl)-X2;X1is — O—, — S(O)W—, — NH—, — O— (C=O)—, — NH— (C=O)—, — NH— (C=O)— O—, — NH— (C=O)— NH—, or — NH— S(O)W—;X2is —OR9, —SR9, or — NHR9;R5and R6are each individually hydrogen, halogen, a substituted or an unsubstituted Ci-Ce alkyl, a substituted or an unsubstituted Ci-Ce haloalkyl, or — [(CY2)PO(CY2)q]tCY3;m is 1 or 2;4MF - 363628584Attorney Docket No. 22419-20011.40n4and n5are each individually 0, 1 or 2, with the proviso that n4and n5are not both 0; each w is 0, 1 or 2;each Y is individually hydrogen or halogen;each p is individually 1, 2, 3, 4, 5, or 6;each q is individually 0, 1, 2, 3, 4, 5, or 6;each t is individually 1, 2, 3, 4, 5, or 6;R7is hydrogen, —COR8, — CO2R8, — (CO)— NHR8, L4, L5, L6, or L7;R8is a substituted or an unsubstituted Ci-Ce alkyl-X3, a substituted or an unsubstituted Ci-Ce haloalkyl-X3, or — [(CY2)pO(CY2)q]tCY2 — X3;R9is hydrogen, — COR8, — CO2R8, — (CO) — NHR8, L4, L5, L6, or L7, with the proviso that exactly one of R7and R9is L4, L5, L6, or L7; andeach X3is individually — H, — OH, — SH, or — NH2.

[0010] In some embodiments according to any of the embodiments described above, the drug moiety of Formula (II) is represented by:(II)wherein:R1and R2are each individually selected from the group consisting of hydrogen, halogen, -OR5, unsubstituted Ci-Ce alkyl, unsubstituted Ci-Ce haloalkyl and unsubstituted -O-(Ci-Ce alkyl), or unsubstituted -O-(CR5R6)m-O- such that R1and R2are taken together form a ring;R3is hydrogen or unsubstituted Ci-Ce alkyl;5MF - 363628584Attorney Docket No. 22419-20011.40R4is a substituted or an unsubstituted -(Ci-Ce alkyl)-X2;X1is — O—;X2is —OR9;R5and R6are each individually hydrogen;m is 1;n4is 1 or 2;n5is 0;R7is H; andR9is L4, L5, L6, or L7.

[0011] In some embodiments according to any of the embodiments described above, n4is 1.

[0012] In some embodiments according to any of the embodiments described above, n4is 2.

[0013] In some embodiments according to any of the embodiments described above, the drug moiety of Formula (II) is represented by:R1is methyl;R2is fluoro;R3is hydrogen;R4is a substituted or an unsubstituted -(C2 alkyl)-X2; andn4is 2,and wherein the remaining variables are as described herein.

[0014] In some embodiments according to any of the embodiments described above, L2is absent;n1is the integer 2 or 5;L4is gly-gly-phe-gly;6MF - 363628584Attorney Docket No. 22419-20011.40L5is -[NH(CH2)n2]n3-;n2is the integer 1;n3is the integer 1; andL7is absent,and wherein the remaining variables are as described herein.

[0015] In some embodiments according to any of the embodiments described above, the drug moiety of Formula (II) is represented by:OR9wherein R9is L4, L5, L6, or L7.

[0016] In some embodiments according to any of the embodiments described above, the drug moiety of Formula (II) is represented by:OR9wherein R9is L4, L5, L6, or L7.

[0017] In some embodiments according to any of the embodiments described above, the drug moiety of Formula (II) is represented by:7MF - 363628584Attorney Docket No. 22419-20011.40OH Owherein R9is L4, L5, L6, or L7.

[0018] In some embodiments according to any of the embodiments described above, Formula (I) is:wherein n is as described herein.

[0019] In some embodiments according to any of the embodiments described above, Formula (I) is:8MF - 363628584Attorney Docket No. 22419-20011.40, wherein n is as described herein.

[0020] In some embodiments according to any of the embodiments described above, Formula (I) is:9MF - 363628584Attorney Docket No. 22419-20011.40wherein n is as described herein.

[0021] In some embodiments according to any of the embodiments described above, Formula (I) is represented by:, wherein n is as described herein.

[0022] In some embodiments according to any of the embodiments described above, Formula (I) is represented by:10MF - 363628584Attorney Docket No. 22419-20011.40wherein n is as described herein.

[0023] Described herein, in certain embodiments, are immunoconjugates having Formula (I),Ab-[S-L1-L2-L3-L4-L5-L6-L7-D]n(I)wherein:Ab is an antibody or an antigen-binding fragment thereof that binds Seizure Related 6 Homolog Like 2 (SEZ6L2), comprising:a heavy chain variable region (VH) comprising (i) a complementarity determining region (CDR) 1 having an amino acid sequence according to any one of SEQ ID NOs: 1-12; (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 13-24; and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 25-36; anda light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 37-48; (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 49-60; and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 61-72;11MF - 363628584Attorney Docket No. 22419-20011.40S is a sulfur atom of a cysteine of the antibody or the antigen-binding fragment thereof;L1isL2is absent,z- Z1and Z2are each individually hydrogen, halogen, NO2, -O-(Ci-Ce alkyl), or Ci-Ce alkyl;L3is -(CH2)n1-C(=O)- or -(CH2CH2O)n1-(CH2)n1C(=O)-;each n1is individually an integer from 0 to 10;L4is a tetrapeptide residue;L5is absent or -[NH(CH2)n2]n3-n2is an integer from 0 to 6;n3is an integer from 0 to 2;L6is absent,HN, wherein G is a beta- glucuronic acid moiety;L7is absent,12MF - 363628584Attorney Docket No. 22419-20011.40wherein D has the structure:n is an integer from 1 to 10.

[0024] In some embodiments according to any of the embodiments described above, n is an integer from 4 to 8.

[0025] In some embodiments according to any of the embodiments described above, the VH comprises an amino acid sequence having at least about 80% sequence identity to any one of SEQ ID NOs: 73-84.

[0026] In some embodiments according to any of the embodiments described above, the VL comprises an amino acid sequence having at least about 80% sequence identity to any one of SEQ ID NOs: 85-96.

[0027] In some embodiments according to any of the embodiments described above, the VH comprises an amino acid sequence having at least about 80% sequence identity to any one of SEQ ID NOs: 73-84 and the VL comprises an amino acid sequence having at least about 80% sequence identity to any one of SEQ ID NOs: 85-96.

[0028] In some embodiments according to any of the embodiments described above, the antibody or the antigen-binding fragment thereof comprises:i) a VH comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 1, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 13, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 25; and a VL comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 37, (ii) a 13MF - 363628584Attorney Docket No. 22419-20011.40CDR2 having an amino acid sequence according to SEQ ID NO: 49, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 61;ii) a VH comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 2, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 14, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 26; and a VL comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 38, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 50, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 62;iii) a VH comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 3, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 15, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 27; and a VL comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 39, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 51, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 63;iv) a VH comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 4, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 16, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 28; and a VL comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 40, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 52, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 64;v) a VH comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 5, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 17, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 29; and a VL comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 41, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 53, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 65;vi) a VH comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 6, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 18, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 30; and a VL comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 42, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 54, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 66;vii)a VH comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 7, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 19,14MF - 363628584Attorney Docket No. 22419-20011.40and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 31; and a VL comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 43, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 55, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 67;viii) a VH comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 8, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 20, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 32; and a VL comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 44, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 56, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 68;ix) a VH comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 9, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 21, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 33; and a VL comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 45, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 57, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 69;x) a VH comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 10, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 22, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 34; and a VL comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 46, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 58, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 70;xi) a VH comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 11, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 23, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 35; and a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 47, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 59, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 71; orxii)a VH comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 12, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 24, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 36; and a VL comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 48, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 60, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 72.15MF - 363628584Attorney Docket No. 22419-20011.40

[0029] In some embodiments according to any of the embodiments described above, the antibody comprises a Fc domain comprising one or more modifications that reduces binding to an Fc receptor, reduces binding to complement component C1q, or reduces binding to an Fc receptor and reduces binding to complement component C1q.

[0030] In some embodiments according to any of the embodiments described above, the antibody comprises a Fc domain comprising the amino acid modifications L234A / L235A (LALA), L234A / L235A / P329A (LALAPA), L234A / L235A / P329S (LALAPS), or L234A / L235A / P329G (LALAPG).

[0031] In some embodiments according to any of the embodiments described above, the antibody or the antigen-binding fragment thereof binds to human SEZ6L2 with an affinity of 10’7M to 10’10M.

[0032] In some embodiments according to any of the embodiments described above, the antibody or the antigen-binding fragment thereof does not bind to SEZ6 or SEZ6L.

[0033] Described herein, in certain embodiments, are immunoconjugates having Formula (I),Ab-[S-L1-L2-L3-L4-L5-L6-L7-D]n(I)wherein:Ab is an antibody or an antigen-binding fragment thereof that binds Seizure Related 6 Homolog Like 2 (SEZ6L2), comprising:a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO: 73; anda light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO: 85;S is a sulfur atom of a cysteine of the antibody or the antigen-binding fragment thereof;L1is O;L2is absent;L3is -(CH2)n1-C(=O)-;n1is the integer 2;L4is gly-gly-phe-gly;16MF - 363628584Attorney Docket No. 22419-20011.40L5is -[NH(CH2)n2]n3-;n2is the integer 1;n3is the integer 1;L6is absent;L7is absent;D has the structure:

[0034] Described herein, in certain embodiments, are immunoconjugates having Formula (I),Ab-[S-L1-L2-L3-L4-L5-L6-L7-D]n(I)wherein:Ab is an antibody or an antigen-binding fragment thereof that binds Seizure Related 6 Homolog Like 2 (SEZ6L2), comprising:a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO: 73; anda light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO: 85;S is a sulfur atom of a cysteine of the antibody or the antigen-binding fragment thereof;L2is absent;L3is -(CH2)n1-C(=O)-;17MF - 363628584Attorney Docket No. 22419-20011.40n1is the integer 5;L4is gly-gly-phe-gly;L5is -[NH(CH2)n2]n3-;n2is the integer 1;n3is the integer 1;L6is absent;L7is absent;D has the structure:

[0035] Described herein, in certain embodiments, are pharmaceutical compositions comprising any of the immunoconjugates described herein, and a pharmaceutically acceptable excipient, salt, carrier, or diluent.

[0036] Described herein, in certain embodiments, are pharmaceutical compositions for use in treating cancer in a subject.

[0037] Described herein, in certain embodiments, are methods of treating cancer comprising administering a therapeutically effective amount of any of the immunoconjugates or any of the pharmaceutical compositions described herein to a subject in need thereof.

[0038] In some embodiments according to any of the embodiments described above, the method further comprises administering an additional anti-cancer therapy selected from the group consisting of surgery, chemotherapy, radiotherapy, and immunotherapy.

[0039] In some embodiments according to any of the embodiments described above, the method further comprises administering to the subject an immune-modulator, activated lymphocyte cell, kinase inhibitor, or a chemotherapeutic agent.

[0040] In some embodiments according to any of the embodiments described above, the cancer is selected from the group consisting of multiple myeloma, acute myeloid leukemia,18MF - 363628584Attorney Docket No. 22419-20011.40diffuse large B-cell lymphoma, hepatocellular carcinoma, small cell lung cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, sarcoma, bladder cancer, cervical cancer, esophageal squamous cell carcinoma, lung squamous cell carcinoma, triple negative breast cancer, skin cutaneous melanoma, colorectal cancer, glioblastoma, ovarian cancer, kidney renal clear cell carcinoma, breast cancer, stomach adenocarcinoma, uterine corpus endometrial carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, esophageal adenocarcinoma, low-grade glioma, prostate adenocarcinoma, pancreatic cancer, neuroendocrine cancer, colon adenocarcinoma, non-small cell lung cancer adenocarcinoma, gastroesophageal junction cancer, non-small cell lung cancer squamous cell carcinoma, and neuroblastoma.

[0041] Described herein, in certain embodiments, are methods of diagnosing or prognosing cancer in a subject, the method comprising determining the expression level of SEZ6L2 in a biological sample using any of the immunoconjugates described herein.

[0042] Described herein, in certain embodiments, are uses of an effective amount of any of the immunoconjugates described herein for treating cancer in a subject in need thereof.

[0043] In some embodiments according to any of the embodiments described above, the cancer is selected from the group consisting of multiple myeloma, acute myeloid leukemia, diffuse large B-cell lymphoma, hepatocellular carcinoma, small cell lung cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, sarcoma, bladder cancer, cervical cancer, esophageal squamous cell carcinoma, lung squamous cell carcinoma, triple negative breast cancer, skin cutaneous melanoma, colorectal cancer, glioblastoma, ovarian cancer, kidney renal clear cell carcinoma, breast cancer, stomach adenocarcinoma, uterine corpus endometrial carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, esophageal adenocarcinoma, low-grade glioma, prostate adenocarcinoma, pancreatic cancer, neuroendocrine cancer, colon adenocarcinoma, non-small cell lung cancer adenocarcinoma, gastroesophageal junction cancer, non-small cell lung cancer squamous cell carcinoma, and neuroblastoma.

[0044] Described herein, in certain embodiments, are kits comprising any of the immunoconjugates described herein and instructions for use.BRIEF DESCRIPTION OF THE DRAWINGS

[0045] FIG. 1 depicts thermal stability of anti-SEZ6L2 antibodies and anti-SEZ6L2 ADCs by differential scanning calorimetry (DSC).19MF - 363628584Attorney Docket No. 22419-20011.40

[0046] FIG. 2 depicts the stability of anti-SEZ6L2 antibodies after freeze thaw by size exclusion chromatography (SEC).

[0047] FIG. 3A depicts a graph of mean tumor volume in a prostate cancer mouse model (22Rvl) and a pancreatic cancer mouse model (ASPC1) after administration of SEZL62 ADCs.

[0048] FIG. 3B depicts a graph of mean plasma antibody levels in mice after administration of SEZL62 ADCs.

[0049] FIG. 4 depicts RNA expression of SEZ6L2 in normal and tumor tissues.

[0050] FIG. 5 depicts in vivo tumor control of anti-SEZ6L2 ADCs in SCLC and neuroblastoma models described herein.

[0051] FIG. 6 depicts in vivo tumor control of anti-SEZ6L2 ADCs in other solid tumor models, covering additional indications, described herein.

[0052] FIG. 7 depicts expression of SEZ6L2 in tumors by immunohistochemistry (IHC) scoring.

[0053] FIG. 8A depicts a graph of MDCK II cell permeability of payload with Formula (II) as compared to exatecan, YL0014, tirumotecan, rezetecan, A- 1743332, and deruxtecan (DXd).

[0054] FIG. 8B depicts a graph showing topoisomerase I (TOPl)-mediated DNA relaxation activity of payload with Formula (II) to deruxtecan (DXd).

[0055] FIG. 8C depicts a schema and data relating to determination of in vitro bystander activity of payload with Formula (II) and deruxtecan (DXd) in a co-culture model using NCI-11446 cells engineered to express either TROP2 or luciferase.DETAILED DESCRIPTION

[0056] To facilitate an understanding of the present disclosure, a number of terms and phrases are defined below.

[0057] As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the content dictates otherwise. Thus, for example, reference to “an antibody” optionally includes a combination of two or more such molecules and the like.

[0058] The term “about,” as used herein, refers to the usual error range for the respective value readily known to the skilled person in this technical field; for example, ± 20%, ± 10%, or ± 5%, are within the intended meaning of the recited value.

[0059] As used herein, the term “antibody” means an isolated or recombinant binding agent that comprises the necessary variable region sequences to specifically bind an antigenic 20MF - 363628584Attorney Docket No. 22419-20011.40epitope. Therefore, an “antibody” as used herein is any form of an antibody of any class or subclass or fragment thereof that exhibits the desired biological activity, e.g., binding a specific target antigen. Thus, it is used in the broadest sense and specifically covers a monoclonal antibody (including full-length monoclonal antibodies), human antibodies, chimeric antibodies, nanobodies (Nbs), minibodies, small immunoproteins (SIPs), variable new antigen receptors (VNARs), diabodies, multispecific antibodies (e.g., bispecific antibodies), antibody fragments including but not limited to scFv, Fab, VHH, and the like so long as they exhibit the desired biological activity. In general, antibodies are multimeric proteins that contain four polypeptide chains. Two of the polypeptide chains are called immunoglobulin heavy chains (H chains), and two of the polypeptide chains are called immunoglobulin light chains (L chains). The immunoglobulin heavy and light chains are connected by an interchain disulfide bond. The immunoglobulin heavy chains are connected by interchain disulfide bonds. A light chain consists of one variable region (VL) and one constant region (CL). The heavy chain consists of one variable region (VH) and at least three constant regions (CHI, CH2 and CH3). The variable regions determine the binding specificity of the antibody. Each variable region contains three hypervariable regions known as complementarity determining regions (CDRs) flanked by four relatively conserved regions known as framework regions (FRs). The extent of the FRs and CDRs has been defined (Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U. S. Department of Health and Human Services, NIH Publication No. 91-3242; and Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917). The three CDRs in each variable region (e.g., light chain variable region or heavy chain variable region, with six CDRs total in a typical antibody format), referred to as CDR1, CDR2, and CDR3, collectively contribute to antibody binding specificity. Naturally occurring antibodies have been used as starting material for engineered antibodies, such as chimeric antibodies and humanized antibodies. Examples of antibodies that have been modified or engineered include chimeric antibodies, humanized antibodies, and multispecific antibodies (e.g., bispecific antibodies). An example of a chemically conjugated antibody is an antibody conjugated to a toxin moiety.

[0060] “Antibody fragments” comprise a portion of an intact antibody, for example, the antigen-binding or variable region of the intact antibody. Examples of antibody fragments include Fab, Fab’, F(ab’)2, and Fv fragments; diabodies; linear antibodies (e.g., Zapata et al., Protein Eng. 8(10): 1057-1062 (1995)); single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments. Papain digestion of antibodies produces two identical antigen-binding fragments, called “Fab” fragments, each with a single 21MF - 363628584Attorney Docket No. 22419-20011.40antigen-binding site, and a residual “Fc” fragment, a designation reflecting the ability to crystallize readily. Pepsin treatment yields an F(ab’)2 fragment with two antigen combining sites and is still capable of cross-linking antigen.

[0061] As used herein, the term “anti- SEZ6L2 antibody”, “antibody that binds SEZ6L2,” “antibody or antigen-binding fragment thereof that binds SEZ6L2,” “antibody that targets SEZ6L2,” or “SEZ6L2-targeting antibody,” with respect to an antibody, refers to an antibody or antigen binding fragment that binds preferentially to SEZ6L2.

[0062] As used herein, “V-region” refers to an antibody variable region domain comprising the segments of Framework 1, CDR1, Framework 2, CDR2, and Framework 3, including CDR3 and Framework 4. The heavy chain V-region, VH, is a consequence of the rearrangement of a V-gene (HV), a D-gene (HD), and a J-gene (HJ), in what is termed V(D)J recombination during B-cell differentiation. The light chain V-region, VL, is a consequence of the rearrangement of a V-gene (LV) and a J-gene (LJ).

[0063] As used herein, “complementarity-determining region (CDR)” refers to the three hypervariable regions (HVRs) in each chain that interrupt the four “framework” regions established by the light and heavy chain variable regions. The CDRs are the primary contributors to binding to an epitope of an antigen. The CDRs of each chain are referred to as CDR1, CDR2, and CDR3, numbered sequentially starting from the N-terminus, and are also identified by the chain in which the CDR is located. Thus, a VH CDR3 (CDR3) is in the variable domain of the heavy chain of the antibody in which it is found, whereas a VL CDR3 (CDR3) is the CDR3 from the variable domain of the light chain of the antibody in which it is located. The term “CDR” is used interchangeably with “HVR” when referring to CDR sequences.

[0064] The amino acid sequences of the CDRs and framework regions can be determined using various well-known definitions in the art, e.g., Kabat, Chothia, international ImMunoGeneTics database (IMGT), and AbM (see, e.g., Chothia & Lesk, 1987, Canonical structures for the hypervariable regions of immunoglobulins. J. Mol. Biol. 196, 901-917; Chothia C. et al., 1989, Conformations of immunoglobulin hypervariable regions. Nature 342, 877-883; Chothia C. et al., 1992, Structural repertoire of the human VH segments J. Mol. Biol. 227, 799-817; Al-Lazikani et al., J. Mol. Biol. 1997, 273(4)). Definitions of antigen combining sites are also described in the following: Ruiz et al., IMGT, the international ImMunoGeneTics database. Nucleic Acids Res., 28, 219-221 (2000); and Lefranc, M.-P. IMGT, the international ImMunoGeneTics database. Nucleic Acids Res. Jan l;29(l):207-9 (2001); MacCallum et al., Antibody-antigen interactions: Contact analysis and 22MF - 363628584Attorney Docket No. 22419-20011.40binding site topography, J. Mol. Biol., 262 (5), 732-745 (1996); and Martin et al, Proc. Natl Acad. Sci. USA, 86, 9268-9272 (1989); Martin et al., Methods Enzymol., 203, 121-153, (1991); Pedersen et al., Immunomethods, 1, 126, (1992); and Rees et al., In Sternberg M. J. E. (ed.), Protein Structure Prediction. Oxford University Press, Oxford, 141-172 1996).Reference to CDRs as determined by Kabat numbering is based, for example, on Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institute of Health, Bethesda, MD (1991)). Chothia CDRs are determined as defined by Chothia (see, e.g., Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)).

[0065] Table A provides the positions of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 as identified by the Kabat and Chothia schemes. For CDR-H1, residue numbering is provided using both the Kabat and Chothia numbering schemes. CDRs may be assigned, for example, using antibody numbering software, such as Abnum, available at www.bioinf.org.uk / abs / abnum / , and described in Abhinandan and Martin (2008) Immunology, 45:3832-3839, incorporated by reference in its entirety.Table A. Residues in CDRs according to Kabat and Chothia numbering schemes. CDR Kabat ChothiaLI L24-L34 L24-L34L2 L50-L56 L50-L56L3 L89-L97 L89-L97Hl (Kabat Numbering) H31-H35B H26-H32 or H34*Hl (Chothia Numbering) H31-H35 H26-H32H2 H50-H65 H52-H56H3 H95-H102 H95-H102* The C -terminus of CDR-H1, when numbered using the Kabat numbering convention, varies between H32 and H34, depending on the length of the CDR.

[0066] The “EU numbering scheme” is generally used when referring to a residue in an antibody heavy chain constant region (e.g., as reported in Kabat et al., supra). Unless stated otherwise, the EU numbering scheme is used to refer to residues in antibody heavy chain constant regions described herein.

[0067] An “Fc region” refers to the constant region of an antibody excluding the first constant region immunoglobulin domain. Thus, e.g., for human immunoglobulins, “Fc” refers to the last two constant region immunoglobulin domains of IgA, IgD, and IgG, and the last three constant region immunoglobulin domains of IgE and IgM, and the flexible hinge N-terminal to these domains. For IgA and IgM, Fc may include the J chain. For IgG, Fc23MF - 363628584Attorney Docket No. 22419-20011.40comprises immunoglobulin domains Cy2 and Cy3 and the hinge between Cyl and Cy2. It is understood in the art that the boundaries of the Fc region may vary, however, the human IgG heavy chain Fc region is usually defined to comprise residues C226 or P230 to its carboxylterminus, using the numbering according to the EU index as in Kabat et al. (1991, NIH Publication 91-3242, National Technical Information Service, Springfield, Va.). The term “Fc region” may refer to this region in isolation or this region in the context of an antibody or antibody fragment. “Fc region” includes naturally occurring allelic variants of the Fc region as well as modified Fc regions, e.g., that are modified to modulate effector function or other properties such as pharmacokinetics, stability or production properties of an antibody. Fc regions also include variants that do not exhibit alterations in biological function. For example, one or more amino acids can be deleted from the N-terminus or C-terminus of the Fc region of an immunoglobulin without substantial loss of biological function. Such variants can be selected according to general rules known in the art to have minimal effect on activity (see, e.g., Bowie et al., Science 247:306-1310, 1990). For example, for IgG4 antibodies, a single amino acid substitution (S228P according to Kabat numbering; designated IgG4Pro) may be introduced to abolish the heterogeneity observed in recombinant IgG4 antibodies (see, e.g., Angal et al., Mol Immunol 30:105-108, 1993).

[0068] An “EC50” as used herein refers to the half-maximal effective concentration, which is the concentration of an antibody that induces a response (signal generated in engagement assay) halfway between the baseline and maximum after a specified exposure time. In some embodiments, the “fold over EC50” is determined by dividing the EC50 of a reference antibody by the EC50 of the test antibody.

[0069] The term “equilibrium dissociation constant” abbreviated (KD), refers to the dissociation rate constant (kd, time-1) divided by the association rate constant (ka, time-1M-1). Equilibrium dissociation constants can be measured using any method.

[0070] The term “monovalent molecule” refers to a molecule having one antigen-binding site, e.g., a Fab or scFv.

[0071] The term “bivalent molecule” as used herein, refers to a molecule having two antigenbinding sites. In some embodiments, a bivalent molecule of the present disclosure is a bivalent antibody or a bivalent fragment thereof. In some embodiments, a bivalent molecule of the present disclosure is a bivalent antibody. In some embodiments, a bivalent molecule of the present disclosure is an IgG. In general, monoclonal antibodies have a bivalent basic structure. IgG and IgE have only one bivalent unit, while IgA and IgM consist of multiple24MF - 363628584Attorney Docket No. 22419-20011.40bivalent units (2 and 5, respectively) and thus have higher valencies. This bivalency increases the avidity of antibodies for antigens.

[0072] The terms “monovalent binding” or “monovalently binds to” as used herein refer to the binding of one antigen-binding site to its antigen.

[0073] The terms “bivalent binding” or “bivalently binds to” refer to the binding of both antigen-binding sites of a bivalent molecule to its antigen. In some embodiments, both antigen-binding sites of a bivalent molecule share the same antigen specificity.

[0074] The term “valency” refers to the number of different binding sites of an antibody for an antigen. A monovalent antibody comprises one binding site for an antigen. A bivalent antibody comprises two binding sites for the same antigen.

[0075] The term “avidity” in the context of antibody binding to an antigen refers to the combined binding strength of multiple binding sites of the antibody. Thus, “bivalent avidity” refers to the combined strength of two binding sites.

[0076] The terms “identical” or percent “identity,” in the context of two or more polynucleotide or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues that are the same (e.g., 100% identity) or have a specified percentage of nucleotides or amino acid residues are the same (e.g., at least 70%, at least 75%, at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher sequence identity; or 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)) identity over a specified region, e.g., the length of the two sequences, when compared and aligned for maximum correspondence over a comparison window or designated region. Alignment for purposes of determining percent amino acid sequence identity can be performed in various methods, including those using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Examples of algorithms that are suitable for determining percent sequence identity and sequence similarity include the BLAST 2.0 algorithms, which are described in Altschul et al., Nuc. Acids Res. 25:3389-3402 (1977) and Altschul et al., J. Mol. Biol. 215:403-410 (1990). Thus, for purposes of this disclosure, BLAST 2.0 can be used with the default parameters to determine percent sequence identity.

[0077] The terms “corresponding to,” “determined with reference to,” or “numbered with reference to” when used in the context of the identification of a given amino acid residue in a polypeptide sequence, refers to the position of the residue of a specified reference sequence when the given amino acid sequence is maximally aligned and compared to the reference 25MF - 363628584Attorney Docket No. 22419-20011.40sequence. The polypeptide that is aligned to the reference sequence need not be the same length as the reference sequence.

[0078] A “conservative” substitution refers to a substitution of an amino acid such that charge, polarity, hydropathy (hydrophobic, neutral, or hydrophilic), and / or size of the side group chain is maintained. Illustrative sets of amino acids that may be substituted for one another include (i) positively-charged amino acids Lys and Arg; and His at pH of about 6; (ii) negatively charged amino acids Glu and Asp; (iii) aromatic amino acids Phe, Tyr and Trp; (iv) nitrogen ring amino acids His and Trp; (v) aliphatic hydrophobic amino acids Ala, Vai, Leu and He; (vi) hydrophobic sulfur-containing amino acids Met and Cys, which are not as hydrophobic as Vai, Leu, and He; (vii) small polar uncharged amino acids Ser, Thr, Asp, and Asn (viii) small hydrophobic or neutral amino acids Gly, Ala, and Pro; (ix) amide-comprising amino acids Asn and Gin; and (xi) beta- branched amino acids Thr, Vai, and lie. Reference to the charge of an amino acid in this paragraph refers to the charge at pH 6-7.

[0079] The terms “polynucleotide,” “oligonucleotide,” and “nucleic acid” are used interchangeably to refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof, either in single-, double-, or multi- stranded form. Contemplated polynucleotides include a gene or fragment thereof.Exemplary polynucleotides include, but are not limited to, DNA, RNA, coding or non-coding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA (tRNA), ribosomal RNA (rRNA), short interfering RNA (siRNA), short-hairpin RNA (shRNA), micro-RNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, cell-free polynucleotides including cell-free DNA (cfDNA) and cell-free RNA (cfRNA), nucleic acid probes, and primers. In a polynucleotide when referring to a T, a T means U (Uracil) in RNA and T (Thymine) in DNA. A polynucleotide can be exogenous or endogenous to a cell and / or exist in a cell-free environment. The term polynucleotide encompasses modified polynucleotides (e.g., altered backbone, sugar, or nucleobase). If present, modifications to the nucleotide structure are imparted before or after assembly of the polymer. Non-limiting examples of modifications include: 5-bromouracil, peptide nucleic acid, xeno nucleic acid, morpholinos, locked nucleic acids, glycol nucleic acids, threose nucleic acids, dideoxynucleotides, cordycepin, 7-deaza-GTP, fluorophores (e.g., rhodamine or fluorescein linked to the sugar), thiol-containing nucleotides, biotin-linked nucleotides, fluorescent base analogs, CpG islands, methyl-7-guanosine, methylated nucleotides, inosine, thiouridine,26MF - 363628584Attorney Docket No. 22419-20011.40pseudouridine, dihydrouridine, queuosine, and wyosine. The sequence of nucleotides may be interrupted by non-nucleotide components.

[0080] The term “vector,” as used herein, refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes the vector as a selfreplicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced. A “vector” as used herein refers to a recombinant construct in which a nucleic acid sequence of interest is inserted into the vector. Certain vectors can direct the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as “expression vectors”.

[0081] A “substitution” denotes the replacement of one or more amino acids or nucleotides by different amino acids or nucleotides, respectively.

[0082] An “isolated” nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment. An isolated nucleic acid includes a nucleic acid molecule contained in cells that ordinarily contain the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.

[0083] “Isolated nucleic acid encoding an antibody or fragment thereof’ refers to one or more nucleic acid molecules encoding antibody heavy or light chains (or fragments thereof), including such nucleic acid molecule(s) in a single vector or separate vectors, and such nucleic acid molecule(s) present at one or more locations in a host cell.

[0084] The terms “host cell,” “host cell line,” and “host cell culture” are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Thus, a host cell is a recombinant host cell and includes the primary transformed cell and progeny derived therefrom without regard to the number of passages.

[0085] The term “cancer cell” or “tumor cell” as used herein refers to a neoplastic cell. The term includes cells from tumors that are benign as well as malignant. Neoplastic transformation is associated with phenotypic changes of the tumor cell relative to the cell type from which it is derived. The changes can include loss of contact inhibition, morphological changes, and unregulated cell growth.

[0086] The terms “inhibiting growth of a tumor” and “inhibiting growth of a cancer” are interchangeable and refer to slowing growth and / or reducing the cancer cell burden of a patient that has cancer. “Inhibiting growth of a cancer” thus includes killing cancer cells, as27MF - 363628584Attorney Docket No. 22419-20011.40well as decreasing the rate of tumor growth, tumor size, invasion, and / or metastasis by direct or indirect effects on tumor cells.

[0087] As used herein, the terms “treatment,” “treating,” and the like, in some embodiments, refer to administering an agent, or carrying out a procedure, for the purposes of obtaining an effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or may be therapeutic in terms of affecting a partial or complete cure for a disease and / or symptoms of the disease. “Treatment,” as used herein, may include treatment of a disease or disorder (e.g., cancer) in a mammal, particularly in a human, and includes: (a) preventing the disease or a symptom of a disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it (e.g., including diseases that may be associated with or caused by a primary disease; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression of the disease. Treating may refer to any indicia of success in the treatment or amelioration or prevention of a cancer, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms; or making the disease condition more tolerable to the patient; slowing in the rate of degeneration or decline; or making the final point of degeneration less debilitating. The treatment or amelioration of symptoms is based on one or more objective or subjective parameters; including the results of an examination by a physician. Accordingly, the term “treating” includes the administration of the compounds or agents of the present disclosure to prevent, delay, alleviate, arrest or inhibit development of the symptoms or conditions associated with diseases (e.g., cancer). The term "therapeutic effect" refers to the reduction, elimination, or prevention of the disease, symptoms of the disease, or side effects of the disease in the subject.

[0088] The terms “subject,” “recipient,” “individual,” “host,” and “patient,” are used interchangeably herein and in some embodiments, refer to any mammalian subject for whom diagnosis, treatment, or therapy is desired, particularly humans. “Mammal” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and laboratory, zoo, sports, or pet animals, such as dogs, horses, cats, cows, sheep, goats, pigs, mice, rats, rabbits, guinea pigs, monkeys etc. In some embodiments, the mammal is human. None of these terms require the supervision of medical personnel.

[0089] A “variant” of a reference antibody refers to an antibody that typically differs from the reference antibody in one or more substitutions, deletions, additions, and / or insertions in the amino acid sequence of the heavy and / or light chain.28MF - 363628584Attorney Docket No. 22419-20011.40ANTI-SEZ6L2 ANTIBODIES

[0090] Described herein, in certain embodiments, are antibodies and antigen-binding fragments thereof that bind SEZ6L2 (i.e., anti-SEZ6L2 antibodies). The anti-SEZ6L2 antibodies described herein are also described in US 2023 / 0331839 Al, the contents of which are hereby incorporated by reference in its entirety.

[0091] In some embodiments, an anti-SEZ6L2 antibody comprises a) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 1-12, (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 13-24, and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 25-36; and b) a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 37-48, (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 49-60, and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 61-72.

[0092] In some embodiments, an anti-SEZ6L2 antibody comprises a CDR1 having an amino acid sequence according to SEQ ID NOs: 1-12 or a variant CDR1 in which 1, 2, 3, 4, or 5 amino acids are substituted relative to the sequence; a CDR2 having an amino acid sequence according to SEQ ID NOs: 13-24, or a variant CDR2 in which 1, 2, 3, 4, or 5 amino acids are substituted relative to the sequence; and a CDR3 having an amino acid sequence according SEQ ID NOs: 25-36 or a variant CDR3 in which 1, 2, 3, 4, or 5 amino acids are substituted relative to the sequence. In some embodiments, an anti-SEZ6L2 antibody comprises a light chain variable region comprising: a CDR1 having an amino acid sequence according to SEQ ID NOs: 37-48, or a variant CDR1 in which 1, 2, 3, 4, or 5 amino acids are substituted relative to the sequence; a CDR2 having an amino acid sequence according to SEQ ID NOs: 49-60, or variant CDR2 in which 1, 2, or 3 amino acids are substituted relative to the sequence; and a CDR3 having an amino acid sequence according to SEQ ID NOs: 61-72, or a variant CDR3 in which 1, 2, 3, 4, or 5 amino acids are substituted relative to the sequence.

[0093] In some embodiments an anti-SEZ6L2 antibody comprises a heavy chain variable (VH) region and a light chain variable (VL) region. The VH region has an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical to SEQ ID NOs: 73-84; and comprises a CDR1 having an amino acid sequence according to SEQ ID NOs: 1-12, or the CDR1 of SEQ ID NOs: 1-12 in which 1, 2, 3, 4, or 5 amino acids are substituted; a CDR2 having an amino acid sequence according to SEQ ID NOs: 13-24, or the CDR2 of SEQ ID NOs: 13-24 in which 1, 2, 3, 4, or 5 amino acids are substituted; a CDR3 having an amino acid sequence according to SEQ ID NOs: 25- 29MF - 363628584Attorney Docket No. 22419-20011.4036 or the CDR3 of SEQ ID NOs: 25-36 in which 1, 2, 3, 4, or 5 amino acids are substituted. The VL region has an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical to SEQ ID NOs: 85-96, and comprises a CDR1 having an amino acid sequence according to SEQ ID NOs: 37-48 or the CDR1 of SEQ ID NOs: 37-48 in which 1, 2, 3, 4, or 5 amino acids are substituted; a CDR2 having an amino acid sequence according to SEQ ID NOs: 49-60, or the CDR2 of SEQ ID NOs: 49-60 in which 1, 2, or 3 amino acids are substituted; a CDR3 having an amino acid sequence according to SEQ ID NOs: 61-72 or the CDR3 of SEQ ID NOs: 61-72 in which 1, 2, 3, 4, or 5 amino acids are substituted.

[0094] In some embodiments an anti-SEZ6L2 antibody comprises a VH region and VL region. The VH region has an amino acid sequence that is at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% identical to SEQ ID NOs: 73-84; and comprises a CDR1 having an amino acid sequence according to SEQ ID NOs: 1-12, or the CDR1 of SEQ ID NOs: 1-12 in which 1, 2, 3, 4, or 5 amino acids are substituted; a CDR2 having an amino acid sequence according to SEQ ID NOs: 13-24, or the CDR2 of SEQ ID NOs: 13-24 in which 1, 2, 3, 4, or 5 amino acids are substituted; a CDR3 having an amino acid sequence according to SEQ ID NOs: 25-36 or the CDR3 of SEQ ID NOs: 25-36 in which 1, 2, 3, 4, or 5 amino acids are substituted. The VL region has an amino acid sequence that is at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% identical to SEQ ID NOs: 85-96, and comprises a CDR1 having an amino acid sequence according to SEQ ID NOs: 37-48 or the CDR1 of SEQ ID NOs: 37-48 in which 1, 2, 3, 4, or 5 amino acids are substituted; a CDR2 having an amino acid sequence according to SEQ ID NOs: 49-60, or the CDR2 of SEQ ID NOs: 49-60 in which 1, 2, or 3 amino acids are substituted; a CDR3 having an amino acid sequence according to SEQ ID NOs: 61-72 or the CDR3 of SEQ ID NOs: 61-72 in which 1, 2, 3, 4, or 5 amino acids are substituted.

[0095] In some embodiments, an anti-SEZ6L2 antibody of the present disclosure has one, two, or three CDRs of a VL sequence (CDRs) having an amino acid sequence according to a sequence set forth in Table 2. In some embodiments, the anti-SEZ6L2 antibody has at least one mutation and no more than 10, 20, 30, 40 or 50 mutations in the VL amino acid sequences compared to a VL sequence set forth in Table 3. In some embodiments, the anti-SEZ6L2 antibody has a VL amino acid sequence set forth in Table 3. In some embodiments, the VL amino acid sequence may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid insertions or deletions compared to a VL sequence set forth in Table 3. In some embodiments, the VL 30MF - 363628584Attorney Docket No. 22419-20011.40amino acid sequence may comprise a deletion or insertion, e.g., a 1, 2, 3, 4, 5, 6, or 7 amino acid deletion or insertion, relative to a CDR sequence shown in Table 2. In some embodiments, the VL region comprises a CDR1 having 1 or 2 substitutions in relative to a CDR1 sequence shown in Table 2. In some embodiments, a CDR1 has 3, 4, or 5 substitutions relative to a CDR1 sequence shown in Table 2. In some embodiments, the VL region comprises a CDR2 that has 1, 2, or 3 substitutions relative to the CDR2 sequence shown in Table 2. In some embodiments, the VL region comprises a CDR3 that has 1, 2, 3, or 4 substitutions relative to a CDR3 sequence shown in Table 2. In some embodiments, an anti-SEZ6L2 antibody of the present disclosure comprises a CDR1, CDR2, and CDR3, each having at least 70% identity to a CDR1, CDR2, and CDR3 as shown in Table 2. In some embodiments, an anti-SEZ6L2 antibody of the present disclosure comprises a CDR1, CDR2, and CDR3, each having at least 75% identity to a CDR1, CDR2, and CDR3 as shown in Table 2. In some embodiments, an anti-SEZ6L2 antibody of the present disclosure comprises a CDR1, CDR2, and CDR3, each having at least 80% identity to a CDR1, CDR2, and CDR3 as shown in Table 2. In some embodiments, an anti-SEZ6L2 antibody of the present disclosure comprises a CDR1, CDR2, and CDR3, each having at least 85% identity to a CDR1, CDR2, and CDR3 as shown in Table 2. In some embodiments, an anti-SEZ6L2 antibody of the present disclosure comprises a CDR1, CDR2, and CDR3, each having at least 90% identity to a CDR1, CDR2, and CDR3 as shown in Table 2. In some embodiments, an anti-SEZ6L2 antibody of the present disclosure comprises a CDR1, CDR2, and CDR3, each having at least 95% identity to a CDR1, CDR2, and CDR3 as shown in Table 2. In some embodiments, an anti-SEZ6L2 antibody of the present disclosure comprises a CDR1, CDR2, and CDR3, each having at least about 75% identity to a CDR1, CDR2, and CDR3 as shown in Table 2. In some embodiments, an anti-SEZ6L2 antibody of the present disclosure comprises a CDR1, CDR2, and CDR3, each having at least about 80% identity to a CDR1, CDR2, and CDR3 as shown in Table 2. In some embodiments, an anti-SEZ6L2 antibody of the present disclosure comprises a CDR1, CDR2, and CDR3, each having at least about 85% identity to a CDR1, CDR2, and CDR3 as shown in Table 2. In some embodiments, an anti-SEZ6L2 antibody of the present disclosure comprises a CDR1, CDR2, and CDR3, each having at least about 90% identity to a CDR1, CDR2, and CDR3 as shown in Table 2. In some embodiments, an anti-SEZ6L2 antibody of the present disclosure comprises a CDR1, CDR2, and CDR3, each having at least about 95% identity to a CDR1, CDR2, and CDR3 as shown in Table 2. In some embodiments, an anti-SEZ6L2 antibody of the present disclosure31MF - 363628584Attorney Docket No. 22419-20011.40comprises a CDR1, CDR2, and CDR3, each having 100% identity to a CDR1, CDR2, and CDR3 as shown in Table 2.

[0096] In some embodiments, an anti-SEZ6L2 antibody of the present disclosure has one, two, or three CDRs of a VH sequence (CDRs) having an amino acid sequence according to a sequence set forth in Table 1. In some embodiments, the anti-SEZ6L2 antibody has at least one mutation and no more than 10, 20, 30, 40 or 50 mutations in the VH amino acid sequences compared to a VH sequence set forth in Table 3. In some embodiments, the anti-SEZ6L2 antibody has a VH amino acid sequence set forth in Table 3. In some embodiments, the VH amino acid sequence may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid insertions or deletions compared to a VH sequence set forth in Table 3. In some embodiments, the VH amino acid sequence may comprise a deletion or insertion, e.g., a 1, 2, 3, 4, 5, 6, or 7 amino acid deletion or insertion, relative to a CDR sequence shown in Table 1. In some embodiments, the VH region comprises a CDR1 having 1 or 2 substitutions in relative to a CDR1 sequence shown in Table 1. In some embodiments, a CDR1 has 3, 4, or 5 substitutions relative to a CDR1 sequence shown in Table 1. In some embodiments, the VH region comprises a CDR2 that has 1, 2, or 3 substitutions relative to the CDR2 sequence shown in Table 1. In some embodiments, the VH region comprises a CDR3 that has 1, 2, 3, or 4 substitutions relative to a CDR3 sequence shown in Table 1. In some embodiments, an anti-SEZ6L2 antibody of the present disclosure comprises a CDR1, CDR2, and CDR3, each having at least 70% identity to a CDR1, CDR2, and CDR3 as shown in Table 1. In some embodiments, an anti-SEZ6L2 antibody of the present disclosure comprises a CDR1, CDR2, and CDR3, each having at least 75% identity to a CDR1, CDR2, and CDR3 as shown in Table 1. In some embodiments, an anti-SEZ6L2 antibody of the present disclosure comprises a CDR1, CDR2, and CDR3, each having at least 80% identity to a CDR1, CDR2, and CDR3 as shown in Table 1. In some embodiments, an anti-SEZ6L2 antibody of the present disclosure comprises a CDR1, CDR2, and CDR3, each having at least 85% identity to a CDR1, CDR2, and CDR3 as shown in Table 1. In some embodiments, an anti-SEZ6L2 antibody of the present disclosure comprises a CDR1, CDR2, and CDR3, each having at least 90% identity to a CDR1, CDR2, and CDR3 as shown in Table 1. In some embodiments, an anti-SEZ6L2 antibody of the present disclosure comprises a CDR1, CDR2, and CDR3, each having at least 95% identity to a CDR1, CDR2, and CDR3 as shown in Table 1. In some embodiments, an anti-SEZ6L2 antibody of the present disclosure comprises a CDR1, CDR2, and CDR3, each having at least about 75% identity to a CDR1, CDR2, and CDR3 as shown in Table 1. In some embodiments, an anti-SEZ6L2 antibody of the present disclosure32MF - 363628584Attorney Docket No. 22419-20011.40comprises a CDR1, CDR2, and CDR3, each having at least about 80% identity to a CDR1, CDR2, and CDR3 as shown in Table 1. In some embodiments, an anti-SEZ6L2 antibody of the present disclosure comprises a CDR1, CDR2, and CDR3, each having at least about 85% identity to a CDR1, CDR2, and CDR3 as shown in Table 1. In some embodiments, an anti-SEZ6L2 antibody of the present disclosure comprises a CDR1, CDR2, and CDR3, each having at least about 90% identity to a CDR1, CDR2, and CDR3 as shown in Table 1. In some embodiments, an anti-SEZ6L2 antibody of the present disclosure comprises a CDR1, CDR2, and CDR3, each having at least about 95% identity to a CDR1, CDR2, and CDR3 as shown in Table 1. In some embodiments an anti-SEZ6L2 antibody of the present disclosure comprises a CDR1, CDR2, and CDR3, each having 100% identity to a CDR1, CDR2, and CDR3 as shown in Table 1.

[0097] The sequences of the anti-SEZ6L2 antibodies described herein are shown in Tables 1-6.

[0098] In some embodiments, an anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence at least 70% identical to any one of SEQ ID NOs: 73-84. In some embodiments, an anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence at least 75% identical to any one of SEQ ID NOs: 73-84. In some embodiments, an anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence at least 80% identical to any one of SEQ ID NOs: 73-84. In some embodiments, an anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence at least 85% identical to any one of SEQ ID NOs: 73-84. In some embodiments, an anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence at least 90% identical to any one of SEQ ID NOs: 73-84. In some embodiments, an anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence at least 95% identical to any one of SEQ ID NOs: 73-84. In some embodiments, an anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence at least 96% identical to any one of SEQ ID NOs: 73-84. In some embodiments, an anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence at least 97% identical to any one of SEQ ID NOs: 73-84. In some embodiments, an anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence at least 98% identical to any one of SEQ ID NOs: 73-84. In some embodiments, an anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence at least 99% identical to any one of SEQ ID NOs:33MF - 363628584Attorney Docket No. 22419-20011.4073-84. In some embodiments, an anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid identical to any one of SEQ ID NOs: 73-84.

[0099] In some embodiments, an anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence at least about 70% identical to any one of SEQ ID NOs: 73-84. In some embodiments, an anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence at least about 75% identical to any one of SEQ ID NOs: 73-84. In some embodiments, an anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence at least about 80% identical to any one of SEQ ID NOs: 73-84. In some embodiments, an anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence at least about 85% identical to any one of SEQ ID NOs: 73-84. In some embodiments, an anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence at least about 90% identical to any one of SEQ ID NOs: 73-84. In some embodiments, an anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence at least about 95% identical to any one of SEQ ID NOs: 73-84. In some embodiments, an anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence at least about 96% identical to any one of SEQ ID NOs: 73-84. In some embodiments, an anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence at least about 97% identical to any one of SEQ ID NOs: 73-84. In some embodiments, an anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence at least about 98% identical to any one of SEQ ID NOs: 73-84. In some embodiments, an anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence at least about 99% identical to any one of SEQ ID NOs: 73-84.

[0100] In some embodiments, an anti-SEZ6L2 antibody comprises a light chain variable region comprising an amino acid sequence at least 70% identical to any one of SEQ ID NOs: 85-96. In some embodiments, an anti-SEZ6L2 antibody comprises a light chain variable region comprising an amino acid sequence at least 75% identical to any one of SEQ ID NOs: 85-96. In some embodiments, an anti-SEZ6L2 antibody comprises a light chain variable region comprising an amino acid sequence at least 80% identical to any one of SEQ ID NOs: 85-96. In some embodiments, an anti-SEZ6L2 antibody comprises a light chain variable region comprising an amino acid sequence at least 85% identical to any one of SEQ ID NOs: 85-96. In some embodiments, an anti-SEZ6L2 antibody comprises a light chain variable region comprising an amino acid sequence at least 90% identical to any one of SEQ ID NOs:34MF - 363628584Attorney Docket No. 22419-20011.4085-96. In some embodiments, an anti-SEZ6L2 antibody comprises a light chain variable region comprising an amino acid sequence at least 95% identical to any one of SEQ ID NOs: 85-96. In some embodiments, an anti-SEZ6L2 antibody comprises a light chain variable region comprising an amino acid sequence at least 96% identical to any one of SEQ ID NOs: 85-96. In some embodiments, an anti-SEZ6L2 antibody comprises a light chain variable region comprising an amino acid sequence at least 97% identical to any one of SEQ ID NOs: 85-96. In some embodiments, an anti-SEZ6L2 antibody comprises a light chain variable region comprising an amino acid sequence at least 98% identical to any one of SEQ ID NOs: 85-96. In some embodiments, an anti-SEZ6L2 antibody comprises a light chain variable region comprising an amino acid sequence at least 99% identical to any one of SEQ ID NOs: 85-96. In some embodiments, an anti-SEZ6L2 antibody comprises a light chain variable region comprising an amino acid sequence identical to any one of SEQ ID NOs: 85-96.

[0101] In some embodiments, an anti-SEZ6L2 antibody comprises a light chain variable region comprising an amino acid sequence at least about 70% identical to any one of SEQ ID NOs: 85-96. In some embodiments, an anti-SEZ6L2 antibody comprises a light chain variable region comprising an amino acid sequence at least about 75% identical to any one of SEQ ID NOs: 85-96. In some embodiments, an anti-SEZ6L2 antibody comprises a light chain variable region comprising an amino acid sequence at least about 80% identical to any one of SEQ ID NOs: 85-96. In some embodiments, an anti-SEZ6L2 antibody comprises a light chain variable region comprising an amino acid sequence at least about 85% identical to any one of SEQ ID NOs: 85-96. In some embodiments, an anti-SEZ6L2 antibody comprises a light chain variable region comprising an amino acid sequence at least about 90% identical to any one of SEQ ID NOs: 85-96. In some embodiments, an anti-SEZ6L2 antibody comprises a light chain variable region comprising an amino acid sequence at least about 95% identical to any one of SEQ ID NOs: 85-96. In some embodiments, an anti-SEZ6L2 antibody comprises a light chain variable region comprising an amino acid sequence at least about 96% identical to any one of SEQ ID NOs: 85-96. In some embodiments, an anti-SEZ6L2 antibody comprises a light chain variable region comprising an amino acid sequence at least about 97% identical to any one of SEQ ID NOs: 85-96. In some embodiments, an anti-SEZ6L2 antibody comprises a light chain variable region comprising an amino acid sequence at least about 98% identical to any one of SEQ ID NOs: 85-96. In some embodiments, an anti-SEZ6L2 antibody comprises a light chain variable region comprising an amino acid sequence at least about 99% identical to any one of SEQ ID NOs: 85-96.35MF - 363628584Attorney Docket No. 22419-20011.40

[0102] In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region (VH) that comprises an amino acid sequence at least 60% (e.g., at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the heavy chain variable region (VH) of an anti-SEZ6L2 antibody disclosed in Table 3, and a light chain variable region (VL) that comprises an amino acid sequence at least 60% (e.g., at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the light chain variable region (VL) of the same anti-SEZ6L2 antibody disclosed in Table 3.

[0103] In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region (VH) that comprises an amino acid sequence at least about 60% (e.g., at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100%) identical to the heavy chain variable region (VH) of an anti-SEZ6L2 antibody disclosed in Table 3, and a light chain variable region (VL) that comprises an amino acid sequence at least about 60% (e.g., at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100%) identical to the light chain variable region (VL) of the same anti-SEZ6L2 antibody disclosed in Table 3.

[0104] In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least about 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 73-84; and a light chain variable region comprising an amino acid sequence having at least about 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 85-96. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 73-84; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 85-96. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to 36MF - 363628584Attorney Docket No. 22419-20011.40any one of SEQ ID NOs: 73-84; and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 85-96. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 73-84; and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 85-96. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 73-84; and a light chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 85-96. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 73-84; and a light chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 85-96. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 73-84; and a light chain variable region comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 85-96. In some embodiments, the Anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 73-84 and a light chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 85-96. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 73-84; and a light chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according any one of SEQ ID NOs: 85-96. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence according to any one of SEQ ID NOs: 73-84; and a light chain variable region comprising an amino acid sequence according to any one of SEQ ID NOs: 85-96.37MF - 363628584Attorney Docket No. 22419-20011.40

[0105] In some embodiments, the anti-SEZ6L2 antibody comprises one, two, three, four, five, six, seven, or eight framework (FW) region sequences selected from the group consisting of: (a) a FWH1 comprising an amino acid sequence of any one of SEQ ID NOs: 121-128, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid insertions, deletions, or substitutions; (b) a FWH2 comprising an amino acid sequence of SEQ ID NO: 129-136, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid insertions, deletions, or substitutions; (c) a FWH3 comprising an amino acid sequence of SEQ ID NO: 137-146, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid insertions, deletions, or substitutions; (d) a FWH4 comprising an amino acid sequence of SEQ ID NO: 147-150, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid insertions, deletions, or substitutions; (e) a FWL1 comprising an amino acid sequence of any one of SEQ ID NOs: 151-157, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid insertions, deletions, or substitutions; (f) a FWL2 comprising an amino acid sequence of any one of SEQ ID NOs: 158-162, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid insertions, deletions, or substitutions; (g) a FWL3 comprising an amino acid sequence of any one of SEQ ID NOs: 163-170, or a variant thereof comprising up to about (such as about any of 1, 2, 3, 4, or 5) amino acid insertions, deletions, or substitutions; and (h) a FWL4 comprising an amino acid sequence of any one of SEQ ID NOs: 171-177, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid insertions, deletions, or substitutions.

[0106] In some embodiments, the anti-SEZ6L2 antibody comprises (a) a FWH1 comprising an amino acid sequence of any one of SEQ ID NOs: 121-128; (b) a FWH2 comprising an amino acid sequence of SEQ ID NO: 129-136; (c) a FWH3 comprising an amino acid sequence of SEQ ID NO: 137-146; (d) a FWH4 comprising an amino acid sequence of SEQ ID NO: 147-150; (e) a FWL1 comprising an amino acid sequence of any one of SEQ ID NOs: 151-157; (f) a FWL2 comprising an amino acid sequence of any one of SEQ ID NOs: 158-162; (g) a FWL3 comprising an amino acid sequence of any one of SEQ ID NOs: 163-170; and (h) a FWL4 comprising an amino acid sequence of any one of SEQ ID NOs: 171-177. The amino acid sequences of the FW regions of the anti-SEZ6L2 antibodies of the present disclosure are shown in Tables 5-6.

[0107] In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%,38MF - 363628584Attorney Docket No. 22419-20011.4097%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 73; and a light chain variable region comprising an amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 85. In some embodiments, the anti-SEZ6L2 antibody comprises a VH comprising a CDR1 having an amino acid sequence according to SEQ ID NO: 1, a CDR2 having an amino acid sequence according to SEQ ID NO: 13, and a CDR3 having an amino acid sequence according to SEQ ID NO: 25, and a VL comprising a CDR1 having an amino acid sequence according to SEQ ID NO: 37, a CDR2 having an amino acid sequence according to SEQ ID NO: 49, and a CDR3 having an amino acid sequence according to SEQ ID NO: 61, and one or more FW region sequences selected from the group consisting of (a) a FWH1 comprising an amino acid sequence of SEQ ID NO: 121; (b) a FWH2 comprising an amino acid sequence of SEQ ID NO: 130; (c) a FWH3 comprising an amino acid sequence of SEQ ID NO: 137; (d) a FWH4 comprising an amino acid sequence of SEQ ID NO: 147; (e) a FWL1 comprising an amino acid sequence of SEQ ID NO: 151; (f) a FWL2 comprising an amino acid sequence of SEQ ID NO: 158; (g) a FWL3 comprising an amino acid sequence of SEQ ID NO: 163; and / or (h) a FWL4 comprising an amino acid sequence of SEQ ID NO: 171. In some embodiments, the anti-SEZ6L2 antibody comprises (a) a FWH1 comprising an amino acid sequence of SEQ ID NO: 121; (b) a FWH2 comprising an amino acid sequence of SEQ ID NO: 130; (c) a FWH3 comprising an amino acid sequence of SEQ ID NO: 137; (d) a FWH4 comprising an amino acid sequence of SEQ ID NO: 147; (e) a FWL1 comprising an amino acid sequence of SEQ ID NO: 151; (f) a FWL2 comprising an amino acid sequence of SEQ ID NO: 158; (g) a FWL3 comprising an amino acid sequence of SEQ ID NO: 163; and (h) a FWL4 comprising an amino acid sequence of SEQ ID NO: 171. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 73; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 85. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 73; and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 85. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity 39MF - 363628584Attorney Docket No. 22419-20011.40with an amino acid sequence according to SEQ ID NO: 73; and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 85. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 73; and a light chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 85. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 73; and a light chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 85. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 73; and a light chain variable region comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 85. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 73; and a light chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 85. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according to SEQ ID NO: 73; and a light chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according SEQ ID NO: 85. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 73; and a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 85. In some embodiments, the anti-SEZ6L2 antibody comprises a HC comprising an amino acid sequence having at least about 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 97; and a LC comprising an amino acid sequence having at least about 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 109. In some embodiments, the anti-SEZ6L2 antibody comprises an HC comprising an amino acid sequence according to SEQ ID NO: 97; and a LC comprising an amino acid sequence40MF - 363628584Attorney Docket No. 22419-20011.40according to SEQ ID NO: 109. In some embodiments, the anti-SEZ6L2 antibody comprises an IgGl Fc domain comprising the amino acid modifications L234A / L235A (LALA), L234A / L235A / P329A (LALAPA), L234A / L235A / P329S (LALAPS), or L234A / L235A / P329G (LALAPG). In some embodiments, the anti-SEZ6L2 antibody comprises an IgGl Fc domain comprising the amino acid modifications L234A / L235A / P329A (LALAPA).

[0108] In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 74; and a light chain variable region comprising an amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 86. In some embodiments, the anti-SEZ6L2 antibody comprises a VH comprising a CDR1 having an amino acid sequence according to SEQ ID NO: 2, a CDR2 having an amino acid sequence according to SEQ ID NO: 14, and a CDR3 having an amino acid sequence according to SEQ ID NO: 26, and a VL comprising a CDR1 having an amino acid sequence according to SEQ ID NO: 38, a CDR2 having an amino acid sequence according to SEQ ID NO: 50, and a CDR3 having an amino acid sequence according to SEQ ID NO: 62, and one or more FW region sequences selected from the group consisting of (a) a FWH1 comprising an amino acid sequence of SEQ ID NO: 122; (b) a FWH2 comprising an amino acid sequence of SEQ ID NO: 131; (c) a FWH3 comprising an amino acid sequence of SEQ ID NO: 137; (d) a FWH4 comprising an amino acid sequence of SEQ ID NO: 148; (e) a FWL1 comprising an amino acid sequence of SEQ ID NO: 152; (f) a FWL2 comprising an amino acid sequence of SEQ ID NO: 158; (g) a FWL3 comprising an amino acid sequence of SEQ ID NO: 164; and / or (h) a FWL4 comprising an amino acid sequence of SEQ ID NO: 172. In some embodiments, the anti-SEZ6L2 antibody comprises (a) a FWH1 comprising an amino acid sequence of SEQ ID NO: 122; (b) a FWH2 comprising an amino acid sequence of SEQ ID NO: 131; (c) a FWH3 comprising an amino acid sequence of SEQ ID NO: 137; (d) a FWH4 comprising an amino acid sequence of SEQ ID NO: 148; (e) a FWL1 comprising an amino acid sequence of SEQ ID NO: 152; (f) a FWL2 comprising an amino acid sequence of SEQ ID NO: 158; (g) a FWL3 comprising an amino acid sequence of SEQ ID NO: 164; and (h) a FWL4 comprising an amino acid sequence of SEQ ID NO: 172. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 74;41MF - 363628584Attorney Docket No. 22419-20011.40and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 86. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 74; and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 86. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 74; and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 86. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 74; and a light chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 86. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 74; and a light chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 86. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 74; and a light chain variable region comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 86. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 74; and a light chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 86. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according to SEQ ID NO: 74; and a light chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according SEQ ID NO: 86. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 74; and a light chain variable 42MF - 363628584Attorney Docket No. 22419-20011.40region comprising an amino acid sequence according to SEQ ID NO: 86. In some embodiments, the anti-SEZ6L2 antibody comprises a HC comprising an amino acid sequence having at least about 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 98; and a LC comprising an amino acid sequence having at least about 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 110. In some embodiments, the anti-SEZ6L2 antibody comprises an HC comprising an amino acid sequence according to SEQ ID NO: 98; and a LC comprising an amino acid sequence according to SEQ ID NO: 110. In some embodiments, the anti-SEZ6L2 antibody comprises an IgGl Fc domain comprising the amino acid modifications L234A / L235A (LALA), L234A / L235A / P329A (LALAPA), L234A / L235A / P329S (LALAPS), or L234A / L235A / P329G (LALAPG). In some embodiments, the anti-SEZ6L2 antibody comprises an IgGl Fc domain comprising the amino acid modifications L234A / L235A / P329A (LALAPA).

[0109] In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 75; and a light chain variable region comprising an amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 87. In some embodiments, the anti-SEZ6L2 antibody comprises a VH comprising a CDR1 having an amino acid sequence according to SEQ ID NO: 3, a CDR2 having an amino acid sequence according to SEQ ID NO: 15, and a CDR3 having an amino acid sequence according to SEQ ID NO: 27, and a VL comprising a CDR1 having an amino acid sequence according to SEQ ID NO: 39, a CDR2 having an amino acid sequence according to SEQ ID NO: 51, and a CDR3 having an amino acid sequence according to SEQ ID NO: 63, and one or more FW region sequences selected from the group consisting of (a) a FWH1 comprising an amino acid sequence of SEQ ID NO: 123; (b) a FWH2 comprising an amino acid sequence of SEQ ID NO: 132; (c) a FWH3 comprising an amino acid sequence of SEQ ID NO: 138; (d) a FWH4 comprising an amino acid sequence of SEQ ID NO: 147; (e) a FWL1 comprising an amino acid sequence of SEQ ID NO: 153; (f) a FWL2 comprising an amino acid sequence of SEQ ID NO: 159; (g) a FWL3 comprising an amino acid sequence of SEQ ID NO: 165; and / or (h) a FWL4 comprising an amino acid sequence of SEQ ID NO: 173. In some embodiments, the anti-SEZ6L2 antibody comprises (a) a FWH1 comprising an amino acid sequence of SEQ ID NO:43MF - 363628584Attorney Docket No. 22419-20011.40123; (b) a FWH2 comprising an amino acid sequence of SEQ ID NO: 132; (c) a FWH3 comprising an amino acid sequence of SEQ ID NO: 138; (d) a FWH4 comprising an amino acid sequence of SEQ ID NO: 147; (e) a FWL1 comprising an amino acid sequence of SEQ ID NO: 153; (f) a FWL2 comprising an amino acid sequence of SEQ ID NO: 159; (g) a FWL3 comprising an amino acid sequence of SEQ ID NO: 165; and (h) a FWL4 comprising an amino acid sequence of SEQ ID NO: 173. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 75; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 87. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 75; and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 87. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 75; and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 87. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 75; and a light chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 87. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 75; and a light chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 87. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 75; and a light chain variable region comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 87. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 75; and a light 44MF - 363628584Attorney Docket No. 22419-20011.40chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 87. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according to SEQ ID NO: 75; and a light chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according SEQ ID NO: 87. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 75; and a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 87. In some embodiments, the anti-SEZ6L2 antibody comprises a HC comprising an amino acid sequence having at least about 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 99; and a LC comprising an amino acid sequence having at least about 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 111. In some embodiments, the anti-SEZ6L2 antibody comprises an HC comprising an amino acid sequence according to SEQ ID NO: 99; and a LC comprising an amino acid sequence according to SEQ ID NO: 111. In some embodiments, the anti-SEZ6L2 antibody comprises an IgGl Fc domain comprising the amino acid modifications L234A / L235A (LALA), L234A / L235A / P329A (LALAPA), L234A / L235A / P329S (LALAPS), or L234A / L235A / P329G (LALAPG). In some embodiments, the anti-SEZ6L2 antibody comprises an IgGl Fc domain comprising the amino acid modifications L234A / L235A / P329A (LALAPA).

[0110] In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 76; and a light chain variable region comprising an amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 88. In some embodiments, the anti-SEZ6L2 antibody comprises a VH comprising a CDR1 having an amino acid sequence according to SEQ ID NO: 4, a CDR2 having an amino acid sequence according to SEQ ID NO: 16, and a CDR3 having an amino acid sequence according to SEQ ID NO: 28, and a VL comprising a CDR1 having an amino acid sequence according to SEQ ID NO: 40, a CDR2 having an amino acid sequence according to SEQ ID NO: 52, and a CDR3 having an amino acid sequence according to SEQ ID NO: 64, and one or more FW region sequences selected from 45MF - 363628584Attorney Docket No. 22419-20011.40the group consisting of (a) a FWH1 comprising an amino acid sequence of SEQ ID NO: 124; (b) a FWH2 comprising an amino acid sequence of SEQ ID NO: 133; (c) a FWH3 comprising an amino acid sequence of SEQ ID NO: 139; (d) a FWH4 comprising an amino acid sequence of SEQ ID NO: 147; (e) a FWL1 comprising an amino acid sequence of SEQ ID NO: 154; (f) a FWL2 comprising an amino acid sequence of SEQ ID NO: 160; (g) a FWL3 comprising an amino acid sequence of SEQ ID NO: 166; and / or (h) a FWL4 comprising an amino acid sequence of SEQ ID NO: 174. In some embodiments, the anti-SEZ6L2 antibody comprises (a) a FWH1 comprising an amino acid sequence of SEQ ID NO: 124; (b) a FWH2 comprising an amino acid sequence of SEQ ID NO: 133; (c) a FWH3 comprising an amino acid sequence of SEQ ID NO: 139; (d) a FWH4 comprising an amino acid sequence of SEQ ID NO: 147; (e) a FWL1 comprising an amino acid sequence of SEQ ID NO: 154; (f) a FWL2 comprising an amino acid sequence of SEQ ID NO: 160; (g) a FWL3 comprising an amino acid sequence of SEQ ID NO: 166; and (h) a FWL4 comprising an amino acid sequence of SEQ ID NO: 174. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 76; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 88. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 76; and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 88. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 76; and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 88. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 76; and a light chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 88. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 76; and a light chain variable region comprising an amino acid sequence having 46MF - 363628584Attorney Docket No. 22419-20011.40at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 88. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 76; and a light chain variable region comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 88. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 76; and a light chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 88. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according to SEQ ID NO: 76; and a light chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according SEQ ID NO: 88. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 76; and a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 88. In some embodiments, the anti-SEZ6L2 antibody comprises a HC comprising an amino acid sequence having at least about 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 100; and a LC comprising an amino acid sequence having at least about 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 112. In some embodiments, the anti-SEZ6L2 antibody comprises an HC comprising an amino acid sequence according to SEQ ID NO: 100; and a LC comprising an amino acid sequence according to SEQ ID NO: 112. In some embodiments, the anti-SEZ6L2 antibody comprises an IgGl Fc domain comprising the amino acid modifications L234A / L235A (LALA), L234A / L235A / P329A (LALAPA), L234A / L235A / P329S (LALAPS), or L234A / L235A / P329G (LALAPG). In some embodiments, the anti-SEZ6L2 antibody comprises an IgGl Fc domain comprising the amino acid modifications L234A / L235A / P329A (LALAPA).

[0111] In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 77; and a light chain variable region comprising an amino acid sequence having at 47MF - 363628584Attorney Docket No. 22419-20011.40least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 89. In some embodiments, the anti-SEZ6L2 antibody comprises a VH comprising a CDR1 having an amino acid sequence according to SEQ ID NO: 5, a CDR2 having an amino acid sequence according to SEQ ID NO: 17, and a CDR3 having an amino acid sequence according to SEQ ID NO: 29, and a VL comprising a CDR1 having an amino acid sequence according to SEQ ID NO: 41, a CDR2 having an amino acid sequence according to SEQ ID NO: 53, and a CDR3 having an amino acid sequence according to SEQ ID NO: 65, and one or more FW region sequences selected from the group consisting of (a) a FWH1 comprising an amino acid sequence of SEQ ID NO: 125; (b) a FWH2 comprising an amino acid sequence of SEQ ID NO: 129; (c) a FWH3 comprising an amino acid sequence of SEQ ID NO: 140; (d) a FWH4 comprising an amino acid sequence of SEQ ID NO: 147; (e) a FWL1 comprising an amino acid sequence of SEQ ID NO: 155; (f) a FWL2 comprising an amino acid sequence of SEQ ID NO: 161; (g) a FWL3 comprising an amino acid sequence of SEQ ID NO: 167; and / or (h) a FWL4 comprising an amino acid sequence of SEQ ID NO: 175. In some embodiments, the anti-SEZ6L2 antibody comprises (a) a FWH1 comprising an amino acid sequence of SEQ ID NO: 125; (b) a FWH2 comprising an amino acid sequence of SEQ ID NO: 129; (c) a FWH3 comprising an amino acid sequence of SEQ ID NO: 140; (d) a FWH4 comprising an amino acid sequence of SEQ ID NO: 147; (e) a FWL1 comprising an amino acid sequence of SEQ ID NO: 155; (f) a FWL2 comprising an amino acid sequence of SEQ ID NO: 161; (g) a FWL3 comprising an amino acid sequence of SEQ ID NO: 167; and (h) a FWL4 comprising an amino acid sequence of SEQ ID NO: 175. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 77; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 89. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 77; and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 89. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 77; and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid 48MF - 363628584Attorney Docket No. 22419-20011.40sequence according to SEQ ID NO: 89. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 77; and a light chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 89. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 77; and a light chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 89. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 77; and a light chain variable region comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 89. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 77; and a light chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 89. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according to SEQ ID NO: 77; and a light chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according SEQ ID NO: 89. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 77; and a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 89. In some embodiments, the anti-SEZ6L2 antibody comprises a HC comprising an amino acid sequence having at least about 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 101; and a LC comprising an amino acid sequence having at least about 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 113. In some embodiments, the anti-SEZ6L2 antibody comprises an HC comprising an amino acid sequence according to SEQ ID NO: 101; and a LC comprising an amino acid sequence according to SEQ ID NO: 113. In some embodiments, the anti-SEZ6L2 antibody comprises an IgGl Fc domain comprising the amino acid modifications L234A / L235A (LALA),49MF - 363628584Attorney Docket No. 22419-20011.40L234A / L235A / P329A (LALAPA), L234A / L235A / P329S (LALAPS), or L234A / L235A / P329G (LALAPG). In some embodiments, the anti-SEZ6L2 antibody comprises an IgGl Fc domain comprising the amino acid modifications L234A / L235A / P329A (LALAPA).

[0112] In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 78; and a light chain variable region comprising an amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 90. In some embodiments, the anti-SEZ6L2 antibody comprises a VH comprising a CDR1 having an amino acid sequence according to SEQ ID NO: 6, a CDR2 having an amino acid sequence according to SEQ ID NO: 18, and a CDR3 having an amino acid sequence according to SEQ ID NO: 30, and a VL comprising a CDR1 having an amino acid sequence according to SEQ ID NO: 42, a CDR2 having an amino acid sequence according to SEQ ID NO: 54, and a CDR3 having an amino acid sequence according to SEQ ID NO: 66, and one or more FW region sequences selected from the group consisting of (a) a FWH1 comprising an amino acid sequence of SEQ ID NO: 126; (b) a FWH2 comprising an amino acid sequence of SEQ ID NO: 134; (c) a FWH3 comprising an amino acid sequence of SEQ ID NO: 141; (d) a FWH4 comprising an amino acid sequence of SEQ ID NO: 149; (e) a FWL1 comprising an amino acid sequence of SEQ ID NO: 156; (f) a FWL2 comprising an amino acid sequence of SEQ ID NO: 162; (g) a FWL3 comprising an amino acid sequence of SEQ ID NO: 168; and / or (h) a FWL4 comprising an amino acid sequence of SEQ ID NO: 172. In some embodiments, the anti-SEZ6L2 antibody comprises (a) a FWH1 comprising an amino acid sequence of SEQ ID NO: 126; (b) a FWH2 comprising an amino acid sequence of SEQ ID NO: 134; (c) a FWH3 comprising an amino acid sequence of SEQ ID NO: 141; (d) a FWH4 comprising an amino acid sequence of SEQ ID NO: 149; (e) a FWL1 comprising an amino acid sequence of SEQ ID NO: 156; (f) a FWL2 comprising an amino acid sequence of SEQ ID NO: 162; (g) a FWL3 comprising an amino acid sequence of SEQ ID NO: 168; and (h) a FWL4 comprising an amino acid sequence of SEQ ID NO: 172. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 78; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 90. In some50MF - 363628584Attorney Docket No. 22419-20011.40embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 78; and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 90. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 78; and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 90. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 78; and a light chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 90. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 78; and a light chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 90. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 78; and a light chain variable region comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 90. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 78; and a light chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 90. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according to SEQ ID NO: 78; and a light chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according SEQ ID NO: 90. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 78; and a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 90. In some embodiments, the anti-SEZ6L2 antibody comprises a HC comprising an amino acid sequence 51MF - 363628584Attorney Docket No. 22419-20011.40having at least about 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 102; and a LC comprising an amino acid sequence having at least about 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 114. In some embodiments, the anti-SEZ6L2 antibody comprises an HC comprising an amino acid sequence according to SEQ ID NO: 102; and a LC comprising an amino acid sequence according to SEQ ID NO: 114. In some embodiments, the anti-SEZ6L2 antibody comprises an IgGl Fc domain comprising the amino acid modifications L234A / L235A (LALA), L234A / L235A / P329A (LALAPA), L234A / L235A / P329S (LALAPS), or L234A / L235A / P329G (LALAPG). In some embodiments, the anti-SEZ6L2 antibody comprises an IgGl Fc domain comprising the amino acid modifications L234A / L235A / P329A (LALAPA).

[0113] In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 79; and a light chain variable region comprising an amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 91. In some embodiments, the anti-SEZ6L2 antibody comprises a VH comprising a CDR1 having an amino acid sequence according to SEQ ID NO: 7, a CDR2 having an amino acid sequence according to SEQ ID NO: 19, and a CDR3 having an amino acid sequence according to SEQ ID NO: 31, and a VL comprising a CDR1 having an amino acid sequence according to SEQ ID NO: 43, a CDR2 having an amino acid sequence according to SEQ ID NO: 55, and a CDR3 having an amino acid sequence according to SEQ ID NO: 67, and one or more FW region sequences selected from the group consisting of (a) a FWH1 comprising an amino acid sequence of SEQ ID NO: 121; (b) a FWH2 comprising an amino acid sequence of SEQ ID NO: 135; (c) a FWH3 comprising an amino acid sequence of SEQ ID NO: 142; (d) a FWH4 comprising an amino acid sequence of SEQ ID NO: 148; (e) a FWL1 comprising an amino acid sequence of SEQ ID NO: 152; (f) a FWL2 comprising an amino acid sequence of SEQ ID NO: 158; (g) a FWL3 comprising an amino acid sequence of SEQ ID NO: 169; and / or (h) a FWL4 comprising an amino acid sequence of SEQ ID NO: 172. In some embodiments, the anti-SEZ6L2 antibody comprises (a) a FWH1 comprising an amino acid sequence of SEQ ID NO: 121; (b) a FWH2 comprising an amino acid sequence of SEQ ID NO: 135; (c) a FWH3 comprising an amino acid sequence of SEQ ID NO: 142; (d) a FWH4 comprising an amino 52MF - 363628584Attorney Docket No. 22419-20011.40acid sequence of SEQ ID NO: 148; (e) a FWL1 comprising an amino acid sequence of SEQ ID NO: 152; (f) a FWL2 comprising an amino acid sequence of SEQ ID NO: 158; (g) a FWL3 comprising an amino acid sequence of SEQ ID NO: 169; and (h) a FWL4 comprising an amino acid sequence of SEQ ID NO: 172. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 79; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 91. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 79; and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 91. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 79; and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 91. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 79; and a light chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 91. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 79; and a light chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 91. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 79; and a light chain variable region comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 91. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 79; and a light chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 91. In some embodiments,53MF - 363628584Attorney Docket No. 22419-20011.40the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according to SEQ ID NO: 79; and a light chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according SEQ ID NO: 91. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 79; and a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 91. In some embodiments, the anti-SEZ6L2 antibody comprises a HC comprising an amino acid sequence having at least about 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 103; and a LC comprising an amino acid sequence having at least about 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 115. In some embodiments, the anti-SEZ6L2 antibody comprises an HC comprising an amino acid sequence according to SEQ ID NO: 103; and a LC comprising an amino acid sequence according to SEQ ID NO: 115. In some embodiments, the anti-SEZ6L2 antibody comprises an IgGl Fc domain comprising the amino acid modifications L234A / L235A (LALA), L234A / L235A / P329A (LALAPA), L234A / L235A / P329S (LALAPS), or L234A / L235A / P329G (LALAPG). In some embodiments, the anti-SEZ6L2 antibody comprises an IgGl Fc domain comprising the amino acid modifications L234A / L235A / P329A (LALAPA).

[0114] In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 80; and a light chain variable region comprising an amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 92. In some embodiments, the anti-SEZ6L2 antibody comprises a VH comprising a CDR1 having an amino acid sequence according to SEQ ID NO: 8, a CDR2 having an amino acid sequence according to SEQ ID NO: 20, and a CDR3 having an amino acid sequence according to SEQ ID NO: 32, and a VL comprising a CDR1 having an amino acid sequence according to SEQ ID NO: 44, a CDR2 having an amino acid sequence according to SEQ ID NO: 56, and a CDR3 having an amino acid sequence according to SEQ ID NO: 68, and one or more FW region sequences selected from the group consisting of (a) a FWH1 comprising an amino acid sequence of SEQ ID NO: 124; (b) a FWH2 comprising an amino acid sequence of SEQ ID NO: 133; (c) a FWH354MF - 363628584Attorney Docket No. 22419-20011.40comprising an amino acid sequence of SEQ ID NO: 143; (d) a FWH4 comprising an amino acid sequence of SEQ ID NO: 147; (e) a FWL1 comprising an amino acid sequence of SEQ ID NO: 154; (f) a FWL2 comprising an amino acid sequence of SEQ ID NO: 160; (g) a FWL3 comprising an amino acid sequence of SEQ ID NO: 166; and / or (h) a FWL4 comprising an amino acid sequence of SEQ ID NO: 173. In some embodiments, the anti-SEZ6L2 antibody comprises (a) a FWH1 comprising an amino acid sequence of SEQ ID NO: 124; (b) a FWH2 comprising an amino acid sequence of SEQ ID NO: 133; (c) a FWH3 comprising an amino acid sequence of SEQ ID NO: 143; (d) a FWH4 comprising an amino acid sequence of SEQ ID NO: 147; (e) a FWL1 comprising an amino acid sequence of SEQ ID NO: 154; (f) a FWL2 comprising an amino acid sequence of SEQ ID NO: 160; (g) a FWL3 comprising an amino acid sequence of SEQ ID NO: 166; and (h) a FWL4 comprising an amino acid sequence of SEQ ID NO: 173. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 80; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 92. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 80; and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 92. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 80; and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 92. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 80; and a light chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 92. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 80; and a light chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 92. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region 55MF - 363628584Attorney Docket No. 22419-20011.40comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 80; and a light chain variable region comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 92. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 80; and a light chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 92. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according to SEQ ID NO: 80; and a light chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according SEQ ID NO: 92. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 80; and a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 92. In some embodiments, the anti-SEZ6L2 antibody comprises a HC comprising an amino acid sequence having at least about 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 104; and a LC comprising an amino acid sequence having at least about 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 116. In some embodiments, the anti-SEZ6L2 antibody comprises an HC comprising an amino acid sequence according to SEQ ID NO: 104; and a LC comprising an amino acid sequence according to SEQ ID NO: 116. In some embodiments, the anti-SEZ6L2 antibody comprises an IgGl Fc domain comprising the amino acid modifications L234A / L235A (LALA), L234A / L235A / P329A (LALAPA), L234A / L235A / P329S (LALAPS), or L234A / L235A / P329G (LALAPG). In some embodiments, the anti-SEZ6L2 antibody comprises an IgGl Fc domain comprising the amino acid modifications L234A / L235A / P329A (LALAPA).

[0115] In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 81; and a light chain variable region comprising an amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 93. In some embodiments, the anti-SEZ6L256MF - 363628584Attorney Docket No. 22419-20011.40antibody comprises a VH comprising a CDR1 having an amino acid sequence according to SEQ ID NO: 9, a CDR2 having an amino acid sequence according to SEQ ID NO: 21, and a CDR3 having an amino acid sequence according to SEQ ID NO: 33, and a VL comprising a CDR1 having an amino acid sequence according to SEQ ID NO: 45, a CDR2 having an amino acid sequence according to SEQ ID NO: 57, and a CDR3 having an amino acid sequence according to SEQ ID NO: 69, and one or more FW region sequences selected from the group consisting of (a) a FWH1 comprising an amino acid sequence of SEQ ID NO: 121; (b) a FWH2 comprising an amino acid sequence of SEQ ID NO: 135; (c) a FWH3 comprising an amino acid sequence of SEQ ID NO: 144; (d) a FWH4 comprising an amino acid sequence of SEQ ID NO: 147; (e) a FWL1 comprising an amino acid sequence of SEQ ID NO: 151; (f) a FWL2 comprising an amino acid sequence of SEQ ID NO: 158; (g) a FWL3 comprising an amino acid sequence of SEQ ID NO: 163; and / or (h) a FWL4 comprising an amino acid sequence of SEQ ID NO: 172. In some embodiments, the anti-SEZ6L2 antibody comprises (a) a FWH1 comprising an amino acid sequence of SEQ ID NO: 121; (b) a FWH2 comprising an amino acid sequence of SEQ ID NO: 135; (c) a FWH3 comprising an amino acid sequence of SEQ ID NO: 144; (d) a FWH4 comprising an amino acid sequence of SEQ ID NO: 147; (e) a FWL1 comprising an amino acid sequence of SEQ ID NO: 151; (f) a FWL2 comprising an amino acid sequence of SEQ ID NO: 158; (g) a FWL3 comprising an amino acid sequence of SEQ ID NO: 163; and (h) a FWL4 comprising an amino acid sequence of SEQ ID NO: 172. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 81; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 93. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 81; and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 93. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 81; and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 93. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 57MF - 363628584Attorney Docket No. 22419-20011.4095% sequence identity with an amino acid sequence according to SEQ ID NO: 81; and a light chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 93. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 81; and a light chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 93. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 81; and a light chain variable region comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 93. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 81; and a light chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 93. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according to SEQ ID NO: 81; and a light chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according SEQ ID NO: 93. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 81; and a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 93. In some embodiments, the anti-SEZ6L2 antibody comprises a HC comprising an amino acid sequence having at least about 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 105; and a LC comprising an amino acid sequence having at least about 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 117. In some embodiments, the anti-SEZ6L2 antibody comprises an HC comprising an amino acid sequence according to SEQ ID NO: 105; and a LC comprising an amino acid sequence according to SEQ ID NO: 117. In some embodiments, the anti-SEZ6L2 antibody comprises an IgGl Fc domain comprising the amino acid modifications L234A / L235A (LALA), L234A / L235A / P329A (LALAPA), L234A / L235A / P329S (LALAPS), or L234A / L235A / P329G (LALAPG). In some embodiments, the anti-SEZ6L2 antibody58MF - 363628584Attorney Docket No. 22419-20011.40comprises an IgGl Fc domain comprising the amino acid modifications L234A / L235A / P329A (LALAPA).

[0116] In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 82; and a light chain variable region comprising an amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 94. In some embodiments, the anti-SEZ6L2 antibody comprises a VH comprising a CDR1 having an amino acid sequence according to SEQ ID NO: 10, a CDR2 having an amino acid sequence according to SEQ ID NO: 22, and a CDR3 having an amino acid sequence according to SEQ ID NO: 34, and a VL comprising a CDR1 having an amino acid sequence according to SEQ ID NO: 46, a CDR2 having an amino acid sequence according to SEQ ID NO: 58, and a CDR3 having an amino acid sequence according to SEQ ID NO: 70, and one or more FW region sequences selected from the group consisting of (a) a FWH1 comprising an amino acid sequence of SEQ ID NO: 127; (b) a FWH2 comprising an amino acid sequence of SEQ ID NO: 136; (c) a FWH3 comprising an amino acid sequence of SEQ ID NO: 145; (d) a FWH4 comprising an amino acid sequence of SEQ ID NO: 147; (e) a FWL1 comprising an amino acid sequence of SEQ ID NO: 151; (f) a FWL2 comprising an amino acid sequence of SEQ ID NO: 158; (g) a FWL3 comprising an amino acid sequence of SEQ ID NO: 163; and / or (h) a FWL4 comprising an amino acid sequence of SEQ ID NO: 172. In some embodiments, the anti-SEZ6L2 antibody comprises (a) a FWH1 comprising an amino acid sequence of SEQ ID NO: 127; (b) a FWH2 comprising an amino acid sequence of SEQ ID NO: 136; (c) a FWH3 comprising an amino acid sequence of SEQ ID NO: 145; (d) a FWH4 comprising an amino acid sequence of SEQ ID NO: 147; (e) a FWL1 comprising an amino acid sequence of SEQ ID NO: 151; (f) a FWL2 comprising an amino acid sequence of SEQ ID NO: 158; (g) a FWL3 comprising an amino acid sequence of SEQ ID NO: 163; and (h) a FWL4 comprising an amino acid sequence of SEQ ID NO: 172. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 82; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 94. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence 59MF - 363628584Attorney Docket No. 22419-20011.40according to SEQ ID NO: 140; and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 94. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 82; and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 94. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 82; and a light chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 94. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 82; and a light chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 94. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 82; and a light chain variable region comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 94. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 82; and a light chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 94. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according to SEQ ID NO: 82; and a light chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according SEQ ID NO: 94. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 82; and a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 94. In some embodiments, the anti-SEZ6L2 antibody comprises a HC comprising an amino acid sequence having at least about 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 106; and a LC comprising an 60MF - 363628584Attorney Docket No. 22419-20011.40amino acid sequence having at least about 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 118. In some embodiments, the anti-SEZ6L2 antibody comprises an HC comprising an amino acid sequence according to SEQ ID NO: 106; and a LC comprising an amino acid sequence according to SEQ ID NO: 118. In some embodiments, the anti-SEZ6L2 antibody comprises an IgGl Fc domain comprising the amino acid modifications L234A / L235A (LALA), L234A / L235A / P329A (LALAPA), L234A / L235A / P329S (LALAPS), or L234A / L235A / P329G (LALAPG). In some embodiments, the anti-SEZ6L2 antibody comprises an IgGl Fc domain comprising the amino acid modifications L234A / L235A / P329A (LALAPA).

[0117] In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 83; and a light chain variable region comprising an amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 95. In some embodiments, the anti-SEZ6L2 antibody comprises a VH comprising a CDR1 having an amino acid sequence according to SEQ ID NO: 11, a CDR2 having an amino acid sequence according to SEQ ID NO: 23, and a CDR3 having an amino acid sequence according to SEQ ID NO: 35, and a VL comprising a CDR1 having an amino acid sequence according to SEQ ID NO: 47, a CDR2 having an amino acid sequence according to SEQ ID NO: 59, and a CDR3 having an amino acid sequence according to SEQ ID NO: 71, and one or more FW region sequences selected from the group consisting of (a) a FWH1 comprising an amino acid sequence of SEQ ID NO: 128; (b) a FWH2 comprising an amino acid sequence of SEQ ID NO: 136; (c) a FWH3 comprising an amino acid sequence of SEQ ID NO: 145; (d) a FWH4 comprising an amino acid sequence of SEQ ID NO: 150; (e) a FWL1 comprising an amino acid sequence of SEQ ID NO: 157; (f) a FWL2 comprising an amino acid sequence of SEQ ID NO: 160; (g) a FWL3 comprising an amino acid sequence of SEQ ID NO: 170; and / or (h) a FWL4 comprising an amino acid sequence of SEQ ID NO: 176. In some embodiments, the anti-SEZ6L2 antibody comprises (a) a FWH1 comprising an amino acid sequence of SEQ ID NO: 128; (b) a FWH2 comprising an amino acid sequence of SEQ ID NO: 136; (c) a FWH3 comprising an amino acid sequence of SEQ ID NO: 145; (d) a FWH4 comprising an amino acid sequence of SEQ ID NO: 150; (e) a FWL1 comprising an amino acid sequence of SEQ ID NO: 157; (f) a FWL2 comprising an amino acid sequence of SEQ ID NO: 160; (g) a 61MF - 363628584Attorney Docket No. 22419-20011.40FWL3 comprising an amino acid sequence of SEQ ID NO: 170; and (h) a FWL4 comprising an amino acid sequence of SEQ ID NO: 176. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 83; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 95. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 83; and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 95. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 83; and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 95. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 83; and a light chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 95. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 83; and a light chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 95. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 83; and a light chain variable region comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 95. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 83; and a light chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 95. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according to 62MF - 363628584Attorney Docket No. 22419-20011.40SEQ ID NO: 83; and a light chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according SEQ ID NO: 95. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 83; and a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 95. In some embodiments, the anti-SEZ6L2 antibody comprises a HC comprising an amino acid sequence having at least about 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 107; and a LC comprising an amino acid sequence having at least about 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 119. In some embodiments, the anti-SEZ6L2 antibody comprises an HC comprising an amino acid sequence according to SEQ ID NO: 107; and a LC comprising an amino acid sequence according to SEQ ID NO: 119. In some embodiments, the anti-SEZ6L2 antibody comprises an IgGl Fc domain comprising the amino acid modifications L234A / L235A (LALA), L234A / L235A / P329A (LALAPA), L234A / L235A / P329S (LALAPS), or L234A / L235A / P329G (LALAPG). In some embodiments, the anti-SEZ6L2 antibody comprises an IgGl Fc domain comprising the amino acid modifications L234A / L235A / P329A (LALAPA).

[0118] In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 84; and a light chain variable region comprising an amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 96. In some embodiments, the anti-SEZ6L2 antibody comprises a VH comprising a CDR1 having an amino acid sequence according to SEQ ID NO: 12, a CDR2 having an amino acid sequence according to SEQ ID NO: 24, and a CDR3 having an amino acid sequence according to SEQ ID NO: 36, and a VL comprising a CDR1 having an amino acid sequence according to SEQ ID NO: 48, a CDR2 having an amino acid sequence according to SEQ ID NO: 60, and a CDR3 having an amino acid sequence according to SEQ ID NO: 72, and one or more FW region sequences selected from the group consisting of (a) a FWH1 comprising an amino acid sequence of SEQ ID NO: 121; (b) a FWH2 comprising an amino acid sequence of SEQ ID NO: 135; (c) a FWH3 comprising an amino acid sequence of SEQ ID NO: 146; (d) a FWH4 comprising an amino acid sequence of SEQ ID NO: 147; (e) a FWL1 comprising an amino acid sequence of SEQ 63MF - 363628584Attorney Docket No. 22419-20011.40ID NO: 151; (f) a FWL2 comprising an amino acid sequence of SEQ ID NO: 158; (g) a FWL3 comprising an amino acid sequence of SEQ ID NO: 163; and / or (h) a FWL4 comprising an amino acid sequence of SEQ ID NO: 177. In some embodiments, the anti-SEZ6L2 antibody comprises (a) a FWH1 comprising an amino acid sequence of SEQ ID NO: 121; (b) a FWH2 comprising an amino acid sequence of SEQ ID NO: 135; (c) a FWH3 comprising an amino acid sequence of SEQ ID NO: 146; (d) a FWH4 comprising an amino acid sequence of SEQ ID NO: 147; (e) a FWL1 comprising an amino acid sequence of SEQ ID NO: 151; (f) a FWL2 comprising an amino acid sequence of SEQ ID NO: 158; (g) a FWL3 comprising an amino acid sequence of SEQ ID NO: 163; and (h) a FWL4 comprising an amino acid sequence of SEQ ID NO: 177. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 84; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 96. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 84; and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 96. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 84; and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 96. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 84; and a light chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 96. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 84; and a light chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 96. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 84; and a light chain variable region comprising an 64MF - 363628584Attorney Docket No. 22419-20011.40amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 96. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 84; and a light chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 96. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according to SEQ ID NO: 84; and a light chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according SEQ ID NO: 96. In some embodiments, the anti-SEZ6L2 antibody comprises a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 84; and a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 96. In some embodiments, the anti-SEZ6L2 antibody comprises a HC comprising an amino acid sequence having at least about 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 108; and a LC comprising an amino acid sequence having at least about 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with an amino acid sequence according to SEQ ID NO: 120. In some embodiments, the anti-SEZ6L2 antibody comprises an HC comprising an amino acid sequence according to SEQ ID NO: 108; and a LC comprising an amino acid sequence according to SEQ ID NO: 120. In some embodiments, the anti-SEZ6L2 antibody comprises an IgGl Fc domain comprising the amino acid modifications L234A / L235A (LALA), L234A / L235A / P329A (LALAPA), L234A / L235A / P329S (LALAPS), or L234A / L235A / P329G (LALAPG). In some embodiments, the anti-SEZ6L2 antibody comprises an IgGl Fc domain comprising the amino acid modifications L234A / L235A / P329A (LALAPA).

[0119] In some embodiments, the anti-SEZ6L2 antibodies or antigen-binding fragments thereof described herein are humanized.

[0120] The sequences of the anti-SEZ6L2 antibodies described herein are shown in Tables 1-6.Table 1. Heavy chain CDR sequences (Kabat)Antibody SEQ ID CDR1 SEQ CDR2 SEQ CDR3NO ID IDNO NO65MF - 363628584Attorney Docket No. 22419-20011.40Antibody 1 GYYMF 13 WINPNSGGTDYAQKF 25 DSGYDWFFD 1 QG Y Antibody 2 GYYIL 14 WINPNNGGTHYAQKF 26 DSGHDWYFD 2 QG L Antibody 3 TITMN 15 RIRSKSNNYATYYADA 27 GIFSGYVYAM 3 VKD DY Antibody 4 SYHWW 16 EIYHSGSTNYNPSLKS 28 WGRIAVADY 4 SAntibody 5 DYYMS 17 LIRNKANGYTTEYSAS 29 NGLYGLFAY 5 VKGAntibody 6 KYAMS 18 TISSGGSYTYYPDSVK 30 EGGYDEGYA 6 G MDY Antibody 7 AYYMH 19 WINPNSGGTNYAQKF 31 DSGYDWYFDI 7 QGAntibody 8 SSNWWS 20 EIYHSGSTNYNPSLKS 32 YSGSYFEY 8Antibody 9 GYYIH 21 WINPTSGGTSYAQKFQ 33 GEYSSGWSFD 9 G Y Antibody 10 SYYWS 22 YIFYSGSTNYNPSLKS 34 DSSGWYGGV 10 DY Antibody 11 AYYWS 23 EINHGGSTNYNPSLKS 35 GRYFDWLFPA 11 FDI Antibody 12 GYYMH 24 WINPNNGGTNYAQKF 36 DQNSGWLFD12 QG YTable 2. Light chain CDR sequences (Kabat)Antibody SEQ CDR1 SEQ CDR2 SEQ CDR3ID ID ID NO NO NOAntibody 37 RASQSVSSNLA 49 GASTRAT 61 QQYNNWPPFT 1Antibody 38 RASQSVSSSLA 50 DASNRAT 62 QQHSNWPPLT 2Antibody 39 RSSQSIVHSNGNTYLE 51 KVSNRFS 63 FQGSHVPYT 3Antibody 40 RASQSISSWLA 52 KASSLES 64 QQYNSYWT 4Antibody 41 RSSTSLLESSGKHRLY 53 YMSNLAS 65 MQSLEYPLT 5Antibody 42 RSSQSLVHSYGNTYLH 54 KVSNRFS 66 SQSTHFRT 6Antibody 43 RASQNISSYLA 55 DASNRAT 67 QQHSNWPPLT 7Antibody 44 RASQSISSWLA 56 KASSLES 68 QQYNSYPLT 8Antibody 45 RASQSVSSNLA 57 GASTRAT 69 QQYNDWPLT 9Antibody 46 RASQSVSSNLA 58 GASTRAT 70 QQYNNWPLT 10Antibody 47 RASQGISSYLA 59 AASTLQS 71 QQLNSYPFT1166MF - 363628584Attorney Docket No. 22419-20011.40Antibody 48 RASQSVSSNSA 60 GASTRAT 72 QQYNNWPPIT12Table 3. Heavy and light variable region sequencesAntibody SEQ VH SEQ VLID ID NO NOAntibody 73 QVQLVQSGAEVKKPGASVKVS 85 EIVMTQSPATLSVSPGERA 1 CKASGYTFTGYYMFWVRQAPG TLSCRASQSVSSNLAWYQ QGLEWLGWINPNSGGTDYAQK QKPGQAPRLLIYGASTRA FQGRVTMTRDTSISTAYMELSR TGIPARFSGSGSGTEFTLTI LRSDDTAVYYCARDSGYDWFF SSLQSEDFAVYYCQQYNN DYWGQGTLVTVSS WPPFTFGPGTKLEIKAntibody 74 QVQLVQSGAEVKKPGASVKVS 86 EIVLTQSPATLSLSPGERA 2 CKASGFTFTGYYILWMRQAPG TLSCRASQSVSSSLAWYQ QGLEWMGWINPNNGGTHYAQ QKPGQAPRLLIYDASNRA KFQGRVTMTRDTSISTAYMELS TGIPARFSGSGSGTDFTLTI RLRSDDTAVYYCARDSGHDW SSLEPEDFAVYYCQQHSN YFDLWGRGTLVTVSS WPPLTFGGGTKVEIKAntibody 75 EVQLVESGGGLVQPGGSLKLSC 87 DVVMTQSPLSLPVTVGQP 3 AASGFSFNTITMNWVRQASGK ASISCRSSQSIVHSNGNTY GLEWVGRIRSKSNNYATYYAD LEWFQQRPGQSPRVLIYK AVKDRFTISRDDSKNTAYLQM VSNRFSGVPDRFSGSGSG NSLKTEDTAVYYCVRGIFSGYV TDFTLKISRVEAEDVGVY YAMDYWGQGTLVTVSS YCFQGSHVPYTFGGGTKL EIKAntibody 76 QVQLQESGPGLVKPSGTLSLTC 88 DIQMTQSPSTLSASVGDR 4 AVSGGSISSYHWWSWVRQPPG VTITCRASQSISSWLAWY KGLEWIGEIYHSGSTNYNPSLK QQKPGKAPKLLIYKASSL SRVTISVDKSKNQFSLKLSSVTA ESGVPSRFSGSGSGTEFTL ADTAVYYCARWGRIAVADYW TISSLQPDDFATYYCQQY GQGTLVTVSS NSYWTFGQGTKVEIKAntibody 77 EVQLVESGGGLVQPGGSLRLSC 89 DIVMTQTPLSIPVTPGEPA 5 AASGFTFTDYYMSWVRQAPGK SISCRSSTSLLESSGKHRL GLEWVALIRNKANGYTTEYSA YWYLQKPGQSPQLLIYY SVKGRFTISRDNSKNSLYLQMN MSNLASGVPDRFSGSGSG SLRAEDTAVYYCARNGLYGLF TDFTLKISRVEAEDFGVY AYWGQGTLVTVSS YCMQSLEYPLTFGAGTKV EIKAntibody 78 EVKLVESGGVLVKPGGSLRLSC 90 DIVMTQSPDSLAVSLGER 6 AASGFTFSKYAMSWVRQAPGK ATINCRSSQSLVHSYGNT GLEWVSTISSGGSYTYYPDSVK YLHWYQQKPGQPPKLLIY GRFTISRDNARNSLYLQMNSLR KVSNRFSGVPDRFSGSGS AEDTAIYYCTREGGYDEGYAM GTDFTLTISSLQAEDVAV DYWGQGTTVTVSS YFCSQSTHFRTFGGGTKV EIKAntibody 79 QVQLVQSGAEVKKPGASVKVS 91 EIVLTQSPATLSLSPGERA 7 CKASGYTFTAYYMHWVRQAP TLSCRASQNISSYLAWYQ GQGLEWMGWINPNSGGTNYA QKPGQAPRLLIYDASNRA QKFQGRVTMTRDTSIDTAYLDL TGIPARFSGSGSGTDFTLTI SRLRSDDTAVYYCAKDSGYDW SSLEPEDFAVFYCQQHSNYFDIWGRGTLVTVSS WPPLTFGGGTKVEIK67MF - 363628584Attorney Docket No. 22419-20011.40Antibody 80 QVQLQESGPGLVKPSGTLSLTC 92 DIQMTQSPSTLSASVGDR 8 AVSGGSISSSNWWSWVRQPPG VTITCRASQSISSWLAWY KGLEWIGEIYHSGSTNYNPSLK QQKPGKAPKLLIYKASSL SRVTISVDKSKNQFSLKLSSVTA ESGVPSRFSGSGSGTEFTL ADTAVYYCAAYSGSYFEYWG TISSLQPDDFATYYCQQY QGTLVTVSS NSYPLTFGGGTKLEIKAntibody 81 QVQLVQSGAEVKKPGASVKVS 93 EIVMTQSPATLSVSPGERA 9 CKASGYTFTGYYIHWVRQAPG TLSCRASQSVSSNLAWYQ QGLEWMGWINPTSGGTSYAQK QKPGQAPRLLIYGASTRA FQGRVTMTRDTSISTAYMELNR TGIPARFSGSGSGTEFTLTI LRSDDTAVYYCARGEYSSGWS SSLQSEDFAVYYCQQYND FDYWGQGTLVTVSS WPLTFGGGTKVEIKAntibody 82 QVQLQESGPGLVKPSETLSLTC 94 EIVMTQSPATLSVSPGERA 10 TVSGDSISSYYWSWIRQPPGKG TLSCRASQSVSSNLAWYQ LEWIGYIFYSGSTNYNPSLKSRV QKPGQAPRLLIYGASTRA TISVDTSKNQFSLKLSSVTAADT TGIPARFSGSGSGTEFTLTI AVYYCARDSSGWYGGVDYWG SSLQSEDFAVYYCQQYNN QGTLVTVSS WPLTFGGGTKVEIKAntibody 83 QVQLQQWGAGLLKPSETLSLT 95 DIQLTQSPSFLSASVGDRV 11 CAVYGGSFSAYYWSWIRQPPG TITCRASQGISSYLAWYQ KGLEWIGEINHGGSTNYNPSLK QKPGKAPKLLIYAASTLQ SRVTISVDTSKNQFSLKLSSVTA SGVPSRFSGSGSGTEFTLT ADTAVYYCARGRYFDWLFPAF ISSLQPEDFATYYCQQLNS DIWGQGTMVTVSS YPFTFGPGTKVEIKAntibody 84 QVQLVQSGAEVKKPGASVKVS 96 EIVMTQSPATLSVSPGERA 12 CKASGYTFTGYYMHWVRQAP TLSCRASQSVSSNSAWYQ GQGLEWMGWINPNNGGTNYA QKPGQAPRLLIYGASTRA QKFQGRVTMTRDTSISTAYMEL TGIPARFSGSGSGTEFTLTI RRLRSDDTAVYYCARDQNSGW SSLQSEDFAVYYCQQYNNLFDYWGQGTLVTVSS WPPITFGQGTRLEIKTable 4. Heavy and light chain sequencesAntibody SequenceAntibody 1 HC QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMFWVRQAPGQGL SEQ EWLGWINPNSGGTDYAQKFQGRVTMTRDTSISTAYMELSRLRSDDT ID AVYYCARDSGYDWFFDYWGQGTLVTVSSASTKGPSVFPLAPSSKST NO: SGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL 97 SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK LC EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLL SEQ IYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWP ID PFTFGPGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE NO: AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH 109 KVYACEVTHQGLSSPVTKSFNRGECAntibody 2 HC QVQLVQSGAEVKKPGASVKVSCKASGFTFTGYYILWMRQAPGQGL SEQ EWMGWINPNNGGTHYAQKFQGRVTMTRDTSISTAYMELSRLRSDD ID TAVYYCARDSGHDWYFDLWGRGTLVTVSSASTKGPSVFPLAPSSKS NO: TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS98 LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP 68MF - 363628584Attorney Docket No. 22419-20011.40Antibody Sequence CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK LC EIVLTQSPATLSLSPGERATLSCRASQSVSSSLAWYQQKPGQAPRLLI SEQ YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQHSNWPP ID LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE NO: AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH 110 KVYACEVTHQGLSSPVTKSFNRGECAntibody 3 HC EVQLVESGGGLVQPGGSLKLSCAASGFSFNTITMNWVRQASGKGLE SEQ WVGRIRSKSNNYATYYADAVKDRFTISRDDSKNTAYLQMNSLKTED ID TAVYYCVRGIFSGYVYAMDYWGQGTLVTVSSASTKGPSVFPLAPSS NO: KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL 99 YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC PPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK LC DVVMTQSPLSLPVTVGQPASISCRSSQSIVHSNGNTYLEWFQQRPGQ SEQ SPRVLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQ ID GSHVPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN NO: FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA 111 DYEKHKVYACEVTHQGLSSPVTKSFNRGECAntibody 4 HC QVQLQESGPGLVKPSGTLSLTCAVSGGSISSYHWWSWVRQPPGKGL SEQ EWIGEIYHSGSTNYNPSLKSRVTISVDKSKNQFSLKLSSVTAADTAVY ID YCARWGRIAVADYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGT NO: AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV 100 TVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE AAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKALAAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK LC SEQ DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLI ID YKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYWT NO: FGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK 112 VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACEVTHQGLSSPVTKSFNRGECAntibody 5 HC EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYYMSWVRQAPGKGLE SEQ WVALIRNKANGYTTEYSASVKGRFTISRDNSKNSLYLQMNSLRAED ID TAVYYCARNGLYGLFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTS NO: GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 101 SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALAAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK LCSEQ69MF - 363628584Attorney Docket No. 22419-20011.40Antibody SequenceID DIVMTQTPLSIPVTPGEPASISCRSSTSLLESSGKHRLYWYLQKPGQSP NO: QLLIYYMSNLASGVPDRFSGSGSGTDFTLKISRVEAEDFGVYYCMQS 113 LEYPLTFGAGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD YEKHKVYACEVTHQGLSSPVTKSFNRGECAntibody 6 HC EVKLVESGGVLVKPGGSLRLSCAASGFTFSKYAMSWVRQAPGKGLE SEQ WVSTISSGGSYTYYPDSVKGRFTISRDNARNSLYLQMNSLRAEDTAI ID YYCTREGGYDEGYAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKST NO: SGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL 102 SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK LC DIVMTQSPDSLAVSLGERATINCRSSQSLVHSYGNTYLHWYQQKPG SEQ QPPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYFCS ID QSTHFRTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN NO: FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA 114 D YEKHKVYACEVTHQGLSSPVTKSFNRGECAntibody 7 HC QVQLVQSGAEVKKPGASVKVSCKASGYTFTAYYMHWVRQAPGQG SEQ LEWMGWINPNSGGTNYAQKFQGRVTMTRDTSIDTAYLDLSRLRSDD ID TAVYYCAKDSGYDWYFDIWGRGTLVTVSSASTKGPSVFPLAPSSKS NO: TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS 103 LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK LC SEQ EIVLTQSPATLSLSPGERATLSCRASQNISSYLAWYQQKPGQAPRLLI ID YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVFYCQQHSNWPP NO: LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE 115 AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH KVYACEVTHQGLSSPVTKSFNRGECAntibody 8 HC QVQLQESGPGLVKPSGTLSLTCAVSGGSISSSNWWSWVRQPPGKGL SEQ EWIGEIYHSGSTNYNPSLKSRVTISVDKSKNQFSLKLSSVTAADTAVY ID YCAAYSGSYFEYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAA NO: LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV 104 PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAA GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK ALAAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK LC DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLI SEQ YKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYPL ID TFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA NO: KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK116 VYACEVTHQGLSSPVTKSFNRGEC70MF - 363628584Attorney Docket No. 22419-20011.40Antibody SequenceAntibody 9 HC QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYIHWVRQAPGQGL SEQ EWMGWINPTSGGTSYAQKFQGRVTMTRDTSISTAYMELNRLRSDDT ID AVYYCARGEYSSGWSFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS NO: TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS 105 LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK LC EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLL SEQ IYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNDWP ID LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE NO: AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH 117 KVYACEVTHQGLSSPVTKSFNRGECAntibody HC QVQLQESGPGLVKPSETLSLTCTVSGDSISSYYWSWIRQPPGKGLEWI 10 SEQ GYIFYSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCA ID RDSSGWYGGVDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTA NO: ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT 106 VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEA AGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALAAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGK LC EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLL SEQ IYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWP ID LTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE NO: AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH 118 KVYACEVTHQGLSSPVTKSFNRGECAntibody HC QVQLQQWGAGLLKPSETLSLTCAVYGGSFSAYYWSWIRQPPGKGLE 11 SEQ WIGEINHGGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVY ID YCARGRYFDWLFPAFDIWGQGTMVTVSSASTKGPSVFPLAPSSKSTS NO: GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 107 SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALAAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK LC DIQLTQSPSFLSASVGDRVTITCRASQGISSYLAWYQQKPGKAPKLLI SEQ YAASTLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQLNSYPFT ID FGPGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK NO: VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKV 119 YACEVTHQGLSSPVTKSFNRGECAntibody HC QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQG 12 SEQ LEWMGWINPNNGGTNYAQKFQGRVTMTRDTSISTAYMELRRLRSD ID DTAVYYCARDQNSGWLFDYWGQGTLVTVSSASTKGPSVFPLAPSSK NO: STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY 108 SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP PCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLT71MF - 363628584Attorney Docket No. 22419-20011.40Antibody Sequence CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK LC SEQ EIVMTQSPATLSVSPGERATLSCRASQSVSSNSAWYQQKPGQAPRLLI ID YGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPP NO: ITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA 120 KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECTable 5. Framework sequence identifiersAntibody FWH1 FWH2 FWH3 FWH4 FWL1 FWL2 FWL3 FWL4 SEQ SEQ SEQ SEQ SEQ SEQ SEQ SEQ ID NO ID NO ID NO ID NO ID NO ID NO ID NO ID NOAntibody 1 121 130 137 147 151 158 163 171 Antibody 2 122 131 137 148 152 158 164 172 Antibody 3 123 132 138 147 153 159 165 173 Antibody 4 124 133 139 147 154 160 166 174 Antibody 5 125 129 140 147 155 161 167 175 Antibody 6 126 134 141 149 156 162 168 172 Antibody 7 121 135 142 148 152 158 169 172 Antibody 8 124 133 143 147 154 160 166 173 Antibody 9 121 135 144 147 151 158 163 172 Antibody 10 127 136 145 147 151 158 163 172 Antibody 11 128 136 145 150 157 160 170 176Antibody 12 121 135 146 147 151 158 163 177Table 6: Framework sequencesSEQ ID # Sequence121 (Antibody 1 FWH1)(Antibody 7 FWH1)(Antibody 9 FWH1)(Antibody 12 FWH1) QVQLVQSGAEVKKPGASVKVSCKASGYTFT 122 (Antibody 2 FWH1) QVQLVQSGAEVKKPGASVKVSCKASGFTFT 123 (Antibody 3 FWH1) EVQLVESGGGLVQPGGSLKLSCAASGFSFN 124 (Antibody 4 FWH1)(Antibody 8 FWH1) QVQLQESGPGLVKPSGTLSLTCAVSGGSIS 125 (Antibody 5 FWH1) EVQLVESGGGLVQPGGSLRLSCAASGFTFT 126 (Antibody 6 FWH1) EVKLVESGGVLVKPGGSLRLSCAASGFTFS 127 (Antibody 10 FWH1) QVQLQESGPGLVKPSETLSLTCTVSGDSIS128 (Antibody 11 FWH1) QVQLQQWGAGLLKPSETLSLTCAVYGGSFS 129 (Antibody 5 FWH2) WVRQAPGKGLEWVA72MF - 363628584Attorney Docket No. 22419-20011.40130 (Antibody 1 FWH2) WVRQAPGQGLEWLG131 (Antibody 2 FWH2) WMRQAPGQGLEWMG132 (Antibody 3 FWH2) WVRQASGKGLEWVG133 (Antibody 4 FWH2)(Antibody 8 FWH2) WVRQPPGKGLEWIG134 (Antibody 6 FWH2) WVRQAPGKGLEWVS135 (Antibody 7 FWH2)(Antibody 9 FWH2)(Antibody 12 FWH2) WVRQAPGQGLEWMG136 (Antibody 10 FWH2)(Antibody 11 FWH2)WIRQPPGKGLEWIG137 (Antibody 1 FWH3)(Antibody 2 FWH3) RVTMTRDTSISTAYMELSRLRSDDTAVYYCAR 138 (Antibody 3 FWH3) RFTISRDDSKNTAYLQMNSLKTEDTAVYYCVR 139 (Antibody 4 FWH3) RVTISVDKSKNQFSLKLSSVTAADTAVYYCAR 140 (Antibody 5 FWH3) RFTISRDNSKNSLYLQMNSLRAEDTAVYYCAR 141 (Antibody 6 FWH3) RFTISRDNARNSLYLQMNSLRAEDTAIYYCTR 142 (Antibody 7 FWH3) RVTMTRDTSIDTAYLDLSRLRSDDTAVYYCAK 143 (Antibody 8 FWH3) RVTISVDKSKNQFSLKLSSVTAADTAVYYCAA 144 (Antibody 9 FWH3) RVTMTRDTSISTAYMELNRLRSDDTAVYYCAR 145 (Antibody 10 FWH3)(Antibody 11 FWH3) RVTISVDTSKNQFSLKLSSVTAADTAVYYCAR 146 (Antibody 12 FWH3) RVTMTRDTSISTAYMELRRLRSDDTAVYYCAR 147 (Antibody 1 FWH4)(Antibody 3 FWH4)(Antibody 4 FWH4)(Antibody 5 FWH4)(Antibody 8 FWH4)(Antibody 9 FWH4)(Antibody 10 FWH4)(Antibody 12 FWH4) WGQGTLVTVSS148 (Antibody 2 FWH4)(Antibody 7 FWH4) WGRGTLVTVSS149 (Antibody 6 FWH4) WGQGTTVTVSS73MF - 363628584Attorney Docket No. 22419-20011.40150 (Antibody 11 FWH4) WGQGTMVTVSS151 (Antibody 1 FWL1)(Antibody 9 FWL1)(Antibody 10 FWL1)(Antibody 12 FWL1) EIVMTQSPATLSVSPGERATLSC152 (Antibody 2 FWL1)(Antibody 7 FWL1) EIVLTQSPATLSLSPGERATLSC153 (Antibody 3 FWL1) DVVMTQSPLSLPVTVGQPASISC154 (Antibody 4 FWL1)(Antibody 8 FWL1) DIQMTQSPSTLSASVGDRVTITC155 (Antibody 5 FWL1) DIVMTQTPLSIPVTPGEPASISC156 (Antibody 6 FWL1) DIVMTQSPDSLAVSLGERATINC157 (Antibody 11 FWL1) DIQLTQSPSFLSASVGDRVTITC158 (Antibody 1 FWL2)(Antibody 2 FWL2)(Antibody 7 FWL2)(Antibody 9 FWL2)(Antibody 10 FWL2)(Antibody 12 FWL2) WYQQKPGQAPRLLIY159 (Antibody 3 FWL2) WFQQRPGQSPRVLIY160 (Antibody 4 FWL2)(Antibody 8 FWL2)(Antibody 11 FWL2) WYQQKPGKAPKLLIY161 (Antibody 5 FWL2) WYLQKPGQSPQLLIY162 (Antibody 6 FWL2) WYQQKPGQPPKLLIY163 (Antibody 1 FWL3)(Antibody 9 FWL3)(Antibody 10 FWL3)(Antibody 12 FWL3) GIPARFSGSGSGTEFTLTISSLQSEDFAVYYC 164 (Antibody 2 FWL3) GIPARFSGSGSGTDFTLTISSLEPEDFAVYYC 165 (Antibody 3 FWL3) GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC 166 (Antibody 4 FWL3)(Antibody 8 FWL3) GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC 167 (Antibody 5 FWL3) GVPDRFSGSGSGTDFTLKISRVEAEDFGVYYC 168 (Antibody 6 FWL3) GVPDRFSGSGSGTDFTLTISSLQAEDVAVYFC 169 (Antibody 7 FWL3) GIPARFSGSGSGTDFTLTISSLEPEDFAVFYC74MF - 363628584Attorney Docket No. 22419-20011.40170 (Antibody 11 FWL3) GVPSRFSGSGSGTEFTLTISSLQPEDFATYYC 171 (Antibody 1 FWL4) FGPGTKLEIK172 (Antibody 2 FWL4)(Antibody 6 FWL4)(Antibody 7 FWL4)(Antibody 9 FWL4)(Antibody 10 FWL4) FGGGTKVEIK173 (Antibody 3 FWL4)(Antibody 8 FWL4) FGGGTKLEIK174 (Antibody 4 FWL4) FGQGTKVEIK175 (Antibody 5 FWL4) FGAGTKVEIK176 (Antibody 11 FWL4) FGPGTKVEIK177 (Antibody 12 FWL4) FGQGTRLEIKFc variants

[0121] In some embodiments, the anti-SEZ6L2 antibodies disclosed herein comprise a modified Fc region (as further explained herein). Fc regions typically comprises one or more Fc chains. An IgG Fc chain typically contains two constant heavy domains (CH2 and CH3) and a hinge region connected to the CH2 domain. Fc regions may typically comprise two Fc chains which dimerize with one another; however, an Fc region may have a single chain or more than two Fc chains, e.g., as may be present in some antibody formats.

[0122] In some embodiments, the anti-SEZ6L2 antibodies comprise an IgGl Fc region (e.g., human IgGl Fc region), that is, except for having particular residue(s) at certain positions as noted herein, the Fc region has an amino acid sequence that is substantially similar to that of the Fc region within a wild type IgGl Fc. In some embodiments, the wild type IgGl Fc is a human IgGl. In some embodiments, the anti-SEZ6L2 antibodies comprise an Fc region, each Fc chain of which has an amino acid sequence that is at least 85%, at least 87.5%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to that of an Fc chain within a wild-type IgGl Fc. In some embodiments, the anti-SEZ6L2 antibodies comprise an Fc region, each Fc chain of which has an amino acid sequence that is at least about 85%, at least about 87.5%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identical to that of an Fc chain within a wild- type IgGl Fc.75MF - 363628584Attorney Docket No. 22419-20011.40

[0123] In some embodiments, the anti-SEZ6L2 antibodies comprise an IgG2 Fc region (e.g., human IgG2 Fc region), that is, except for having particular residue(s) at certain positions as noted herein, the Fc region has an amino acid sequence that is substantially similar to that of the Fc region within a wild type IgG2 Fc. In some embodiments, the wild type IgG2 Fc is a human IgG2 Fc. In some embodiments, the anti-SEZ6L2 antibodies comprise an Fc region, each Fc chain of which has an amino acid sequence that is at least 85%, at least 87.5%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to that of an Fc chain within a wild-type IgG2 Fc. In some embodiments, the anti-SEZ6L2 antibodies comprise an Fc region, each Fc chain of which has an amino acid sequence that is at least about 85%, at least about 87.5%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identical to that of an Fc chain within a wild-type IgG2 Fc.

[0124] In some embodiments, the anti-SEZ6L2 antibodies comprise an IgG4 Fc region (e.g., human IgG4 Fc region), that is, except for having particular residue(s) at certain positions as noted herein, the Fc region has an amino acid sequence that is substantially similar to that of the Fc region within a wild type IgG4 Fc. In some embodiments, the wild type IgG4 Fc is a human IgG4 Fc. In some embodiments, the anti-SEZ6L2 antibodies comprise an Fc region, each Fc chain of which has an amino acid sequence that is at least 85%, at least 87.5%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to that of an Fc chain within a wild-type IgG4 Fc. In some embodiments, the anti-SEZ6L2 antibodies comprise an Fc region, each Fc chain of which has an amino acid sequence that is at least about 85%, at least about 87.5%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identical to that of an Fc chain within a wild-type IgG4 Fc.

[0125] In certain embodiments, Fc regions are modified (e.g., substituted) at one more amino acid residues. In certain embodiments, such modifications alter the half-life of a molecule (e.g., binding protein) which comprises the Fc region by altering (e.g., enhancing) binding to an Fc receptor such as the neonatal Fc receptor (FcRn.).

[0126] Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.76MF - 363628584Attorney Docket No. 22419-20011.40

[0127] In some embodiments, one or more modifications in the modified Fc region is selected from the group consisting of: S298A, E333A, K334A, K326A, F243L, R292P, Y300L, V305I, P396L, F243L, R292P, Y300L, L235V, P396L, F243L, S239D, I332E, A330L, S267E, L328F, D265S, S239E, K326A, A327H, G237F, K326E, G236A, D270L, H268D, S324T, L234F, N325L, V266L, and S267D. In some embodiments, one or more modifications in the modified Fc region is selected from the group consisting of S228P, M252Y, S254T, T256E, T256D, T250Q, H285D, T307A, T307Q, T307R, T307W, L309D, Q411H, Q311V, A378V, E380A, M428L, N434A, N434S, N297A, D265A, L234A, L235A, and N434W.

[0128] In some embodiments, the modified Fc region comprises a specific combination of amino acid substitutions selected from the group consisting of: L234A / L235A;V234A / G237A; L235A / G237A / E318A; S228P / L236E; H268Q / V309L / A330S / A331S; C220S / C226S / C229S / P238S; C226S / C229S / E3233P / L235V / L235A; L234F / L235E / P331S; C226S / P230S; L234A / G237A; L234A / L235A / G237A; Q311R / M428L; L234A / L235A (LALA); L234A / L235A / P329G (LALAPG); L234A / L235A / P329A (LALAPA), and L234A / L235A / P329S (LALAPS). In some embodiments, the modified Fc region comprises a specific combination of amino acid substitutions consisting of L234A / L235A / P329A (LALAPA). In some embodiments, the modified Fc region comprises a specific combination of amino acid substitutions consisting of L234A / L235A / P329G (LALAPG). In some embodiments, the modified Fc region comprises a specific combination of amino acid substitutions consisting of L234A / L235A / P329S (LALAPS).

[0129] In some embodiments, the modified Fc region comprises a specific combination of amino acid substitutions selected from the group consisting of M428L / N434S (LS);M252Y / S254T / T256E (YTE); T250Q / M428L; T307A / E380A / N434A; T256D / T307Q (DQ); T256D / T307W (DW); M252Y / T256D (YD); T307Q / Q311V / A378V (QVV);T256D / H285D / T307R / Q311V / A378V (DDRVV); L309D / Q311H / N434S (DHS);S228P / L235E (SPLE); L234A / L235A (LALA); M428L / N434A (LA); L234A / G237A (LAGA); L234A / L235A / G237A (LALAGA); L234A / L235A / P329G (LALAPG);L234A / L235A / P329A (LALAPA); N297A / YTE; D265A / YTE; LALA / YTE; LAGA / YTE; LALAGA / YTE; LALAPG / YTE; N297A / LS; D265A / LS; LALA / LS; LAGA / LS;LALAGA / LS; LALAPG / LS; N297A / DHS; D265A / DHS; LALA / DHS; LAGA / DHS;LALAGA / DHS; LALAPG / DHS; SP / YTE; SPLE / YTE; SP / LS; SPLE / LS; SP / DHS;SPLE / DHS; N297A / LA; D265A / LA; LALA / LA; LAGA / LA; LALAGA / LA; LALAPG / LA; N297A / N434A; D265A / N434A; LALA / N434A; LAGA / N434A; LALAGA / N434A;77MF - 363628584Attorney Docket No. 22419-20011.40LALAPG / N434A; N297A / N434W; D265A / N434W; LALA / N434W; LAGA / N434W;LALAGA / N434W; LALAPG / N434W; N297A / DQ; D265A / DQ; LALA / DQ; LAGA / DQ; LALAGA / DQ; LALAPG / DQ; N297A / DW; D265A / DW; LALA / DW; LAGA / DW;LALAGA / DW; LALAPG / DW; N297A / YD; D265A / YD; LALA / YD; LAGA / YD;LALAGA / YD; LALAPG / YD; N297A / QVV; D265A / QVV; LALA / QVV; LAGA / QVV, LALAGA / QVV; LALAPG / QVV; N297A / DDRVV; D265A / DDRVV; LALA / DDRVV; LAGA / DDRVV; LALAGA / DDRVV; LALAPG / DDRVV; SP / Q311R / M428L;SPLE / Q311R / M428L; N297A / Q311R / M428L; D265A / Q311R / M428L;LALA / Q311R / M428L; LAGA / Q311R / M428L; LALAGA / Q311R / M428L; and LALAPG / Q311R / M428L.

[0130] In addition to the variants discussed above, there are several useful Fc amino acid modifications that can be made for a variety of reasons, including, but not limited to, altering binding to one or more FcyR receptors, altered binding to FcRn receptors and the like as discussed below. Accordingly, the antibodies provided herein (heterodimeric, as well as homodimeric) can include such amino acid modifications with or without the heterodimerization variants outlined herein (e.g., the pl variants and steric variants). Each set of variants can be independently and optionally included or excluded from any heterodimeric protein.FcyR Variants

[0131] Accordingly, there are several useful Fc substitutions that can be made to alter binding to one or more of the FcyR receptors. In certain embodiments, the subject antibody includes modifications that alter the binding to one or more FcyR receptors (i.e., “FcyR variants”). Substitutions that result in increased binding as well as decreased binding can be useful. For example, it is known that increased binding to FcyRIIIa generally results in increased ADCC (antibody dependent cell-mediated cytotoxicity; the cell-mediated reaction wherein nonspecific cytotoxic cells that express FcyRs recognize bound antibody on a target cell and subsequently cause lysis of the target cell). Similarly, decreased binding to FcyRIIb (an inhibitory receptor) can be beneficial as well in some circumstances. Amino acid substitutions that find use in the antibodies described herein include those listed in US Patent Nos. 8,188,321 (particularly Figure 41) and 8,084,582, and US Publ. App. Nos. 20060235208 and 20070148170. Particular variants that find use include, but are not limited to, 236A, 239D, 239E, 332E, 332D, 239D / 332E, 267D, 267E, 328F, 267E / 328F, 236A / 332E, 239D / 332E / 330Y, 239D / 332E / 330L, 243A, 243L, 264A, 264V and 299T.78MF - 363628584Attorney Docket No. 22419-20011.40

[0132] In addition, there are additional Fc substitutions that find use in increased binding to the FcRn receptor and increased serum half-life, as specifically disclosed in USSN 12 / 341,769 including, but not limited to, 434S, 434A, 428L, 308F, 2591, 428L / 434S, 259I308F, 436I428L, 4361, 436V / 434S, 436V / 428L and 259E308F / 428L. Such modification may be included in one or both Fc domains of the subject antibody. In certain embodiments, the anti- SEZ6L2 antibodies comprising Fc substitutions that have increased binding to the FcRn receptor and increased serum half-life have an increased half-life that is about 10,000-fold, 1,000-fold, 500-fold, 100-fold, 50-fold, 20-fold, 10-fold, 9-fold, 8-fold, 7-fold, 6-fold, 5-fold, 4.5-fold, 4-fold, 3.5-fold, 3-fold, 2.5-fold, 2-fold, 1.95-fold, 1.9-fold, 1.85-fold, 1.8-fold, 1.75-fold, 1.7-fold, 1.65-fold, 1.6-fold, 1.55-fold, 1.50-fold, 1.45-fold, 1.4-fold, 1.35-fold, 1.3-fold, 1.25-fold, 1.2-fold, 1.15-fold, 1.1-fold, or 1.05-fold longer compared to a binding protein comprising a wild-type Fc region.

[0133] In some embodiments, an anti-SEZ6L2 antibody disclosed herein, including antibody fragments, of the present disclosure comprises an Fc region that has effector function, e.g., exhibits antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and / or complement-dependent cytotoxicity (CDC). In some embodiments, the Fc region may be an Fc region engineered to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding, and / or ADCC. Accordingly, an Fc region can comprise additional mutations to increase or decrease effector functions, i.e., the ability to induce certain biological functions upon binding to an Fc receptor expressed on an immune cell. Immune cells include, but are not limited to, monocytes, macrophages, neutrophils, dendritic cells, eosinophils, mast cells, platelets, B cells, large granular lymphocytes, Langerhans’ cells, natural killer (NK) cells, and cytotoxic T cells.

[0134] In some embodiments, an Fc region described herein can include additional modifications that modulate effector function. Examples of Fc region amino acid mutations that modulate an effector function include, but are not limited to, one or more substitutions at positions 228, 233, 234, 235, 236, 237, 238, 239, 243, 265, 269, 270, 297, 298, 318, 326, 327, 329, 330, 331, 332, 333, and 334 (EU numbering scheme) of an Fc region.

[0135] Illustrative substitutions that decrease effector functions include the following: position 329 may have a mutation in which proline is substituted with a glycine or arginine or an amino acid residue large enough to destroy the Fc / Fcy receptor interface that is formed between proline 329 of the Fc and tryptophan residues Trp 87 and Trp 110 of FcyRIII.Additional illustrative substitutions that decrease effector functions include S228P, E233P,79MF - 363628584Attorney Docket No. 22419-20011.40L235E, N297A, N297D, and P331S. Multiple substitutions may also be present, e.g., L234A and L235A of a human IgGl Fc region; L234A, L235A, P329A of a human IgGl Fc region; F234A, F235A, and P329G of a human IgGl Fc region; S228P and F235E of a human IgG4 Fc region; E234A and G237A of a human IgGl Fc region; E234A, E235A, and G237A of a human IgGl Fc region; V234A and G237A of a human IgG2 Fc region; E235A, G237A, and E318A of a human IgG4 Fc region; and S228P and E236E of a human IgG4 Fc region, to decrease effectors functions. Examples of substitutions that increase effector functions include, e.g., E333A, K326W / E333S, S239D / I332E / G236A, S239D / A330E / I332E, G236A / S239D / A330E / I332E, F243E, G236A, and S298A / E333A / K334A. In some embodiments, the Fc mutations include P329G, E234A, E235A, or a combination thereof.

[0136] In some embodiments, an Fc region may have one or more amino acid substitutions that modulate ADCC, e.g., substitutions at positions 298, 333, and / or 334 of the Fc region, according to the EU numbering scheme. Specifically, S298A, E333A, and K334A can be introduced to an Fc region to increase the affinity of the Fc region to FcyRIIIa and decrease the affinity of the Fc region to FcyRIIa and FcyRIIb.

[0137] An Fc region can also comprise additional mutations to increase serum half-life. Through enhanced binding to the neonatal Fc receptor (FcRn), such mutations in an Fc region can improve the pharmacokinetics of the antibody. Examples of substitutions in an Fc region that increase the serum half-life of an antibody include, e.g., M252Y / S254T / T256E, T250Q / M428L, N434A, N434H, T307A / E380A / N434A, M428L / N434S, M252Y / M428L, D259I / V308F, N434S, V308W, V308Y, and V308F.

[0138] In some embodiments, an anti-SEZ6L2 antibody described herein comprise an Fc region having altered glycosylation that increases the ability of the antibody to recruit NK cells and / or increase ADCC. In some embodiments, the Fc region comprises glycan containing no fucose (z.e., the Fc region is afucosylated). Afucosylated antibodies can be produced using cell lines that express a heterologous enzyme that depletes the fucose pool inside the cell e.g., GlymaxX® by ProBioGen AG, Berlin, Germany).

[0139] Furthermore, in some embodiments, an antibody of the disclosure may be chemically modified (e.g., one or more chemical moieties can be attached to the antibody) or be modified, e.g., produced in cell lines and / or in cell culture conditions to alter its glycosylation (e.g., hypofucosylation, afucosylation, or increased sialylation), to alter one or more functional properties of the antibody. For example, the antibody can be linked to one of a variety of polymers, for example, polyethylene glycol. In some embodiments, an antibody80MF - 363628584Attorney Docket No. 22419-20011.40may comprise mutations to facilitate linkage to a chemical moiety and / or to alter residues that are subject to post-translational modifications, e.g., glycosylation.ACTIVITY SEZ6L2-binding activity

[0140] The activity of the anti-SEZ6L2 antibodies as described herein can be assessed for binding in binding assays. Nonlimiting examples of suitable assays include bio-layer interferometry (BLI), surface plasmon resonance analysis using a biosensor system such as a Biacore® system, plate-based immunoassays (e.g., ELISA) or a flow cytometry assay, which are further described in the EXAMPLES section.

[0141] In some embodiments, a variant anti-SEZ6L2 antibody in accordance with the present disclosure may block binding of the reference antibody in a competition assay by about 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 80% or more, or about 90% or more.

[0142] In some embodiments, binding assays to assess variant activity are performed on SEZ6L2-expressing tissues or SEZ6L2-expressing cells. Binding can be assessed by any number of means including flow cytometry and immunohistochemistry or immunofluorescence-based assays.

[0143] In some embodiments the antibody is added to a cancer cell line and the binding is analyzed by flow cytometry. In some embodiments, the binding of the antibodies to bind to SEZ6L2-expressing cells are assessed by immunofluorescence methods, as described in the EXAMPLES. The anti-SEZ6L2 antibodies preferentially bind to SEZ6L2 expressing cells.

[0144] In some embodiments, the binding activity of the antibodies is assessed by determining EC50 values, and in some embodiments additionally determining delta activity, i.e., the difference in specific activity between lower and upper plateaus of the activation curve expressed as percent of activity of a selected antibody having known in vitro activity. In typical embodiments, EC50 values are compared to a reference antibody.

[0145] In some embodiments antibodies of the present disclosure have a KD of less than about 50 nM, typically less than about 25 nM, or less than 10 nM, e.g., less than about 5 nM or than about 1 nM and often less than about 10 nM as determined by surface plasmon resonance analysis using a biosensor system such as a Biacore® system performed at 37°C. In some embodiments, an antibody of the present disclosure has a KD of less than 10’7M, less than 5 x 10’8M, less than 10’8M, less than 5 x 10’9M, less than 10’9M, less than 5 xlO10M, less than 1010M or lower as measured as a bivalent antibody. In the context of the present 81MF - 363628584Attorney Docket No. 22419-20011.40disclosure, an “improved” KD refers to a lower KD. In some embodiments, an antibody of the present disclosure has a KD of less than 10’7M, less than 5 x 10’8M, less than 10’8M, less than 5 x 10’9M, less than 10’9M, less than 5 xlO10M, less than 1010M or lower as measured as a monovalent antibody, such as a monovalent Fab. In some embodiments, the antibodies provided herein bind to human, cynomolgus, rat, and / or mouse SEZ6L2 at a high affinity. In some embodiments, an antibody of the present disclosure has a similar affinity to human, cynomolgus, rat, and / or mouse SEZ6L2. In some embodiments, an antibody of the present invention has a KD of about of less than 50 nM, such as between 0.1 nM and 50 nM, or between 1 nM and 50 nM for human, cynomolgus, rat, and / or mouse SEZ6L2. In some embodiments, an anti- SEZ6L2 antibody of the present disclosure has KD less than 100 pM, e.g., or less than 75 pM, e.g., in the range of 1 to 100 pM, when measured by surface plasmon resonance analysis using a biosensor system such as a Biacore® system performed at 37 °C. In some embodiments, an anti- SEZ6L2 antibody of the present disclosure has KD of greater than 100 pM, e.g., in the range of 100-1000 pM or 500-1000 pM when measured by bio-layer interferometry (BLI) or surface plasmon resonance (SPR) analysis using a biosensor system such as a Biacore® system performed at 37°C.

[0146] In some embodiments, the binding affinity (KD) and / or binding activity of the anti-SEZ6L2 antibodies can be evaluated under stress conditions (e.g., evaluating retention of binding response under an acidic stress condition as compared to an unstressed control).

[0147] In some embodiments, the anti-SEZ6L2 antibodies described herein bind human SEZ6L2. In some embodiments, the anti-SEZ6L2 antibodies described herein are cross-reactive with cynomolgus, mouse, and / or rat SEZ6L2. In some embodiments, the anti-SEZ6L2 antibodies described herein bind human SEZ6L2, cynomolgus SEZ6L2, mouse SEZ6L2, and rat SEZ6L2.

[0148] In some embodiments, the anti-SEZ6L2 antibodies described herein do not bind to human SEZ6. In some embodiments, the anti-SEZ6L2 antibodies described herein do not bind to human SEZ6L. In some embodiments, the anti-SEZ6L2 antibodies described herein do not bind to human SEZ6 or SEZ6L.Fc effector function

[0149] In some embodiments, an anti-SEZ6L2 antibody of the present disclosure comprises an Fc region that has effector function. Examples of effector functions include, but are not limited to, Clq binding and complement-dependent cytotoxicity (CDC), Fc receptor binding (e.g., FcyR binding), ADCC, antibody-dependent cell-mediated phagocytosis (ADCP), down- 82MF - 363628584Attorney Docket No. 22419-20011.40regulation of cell surface receptors (e.g., B cell receptor), and B-cell activation. Effector functions may vary with the antibody class. For example, native human IgGl and IgG3 antibodies can elicit ADCC and CDC activities upon binding to an appropriate Fc receptor present on an immune system cell; and native human IgGl, IgG2, IgG3, and IgG4 can elicit ADCP functions upon binding to the appropriate Fc receptor present on an immune cell.

[0150] In some embodiments, the Fc region of an anti-SEZ6L2 antibody disclosed herein may be an Fc region engineered to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding, and / or ADCC.Accordingly, an Fc region can comprise additional mutations to increase or decrease effector functions, i.e., the ability to induce certain biological functions upon binding to an Fc receptor expressed on an immune cell. Immune cells include, but are not limited to, monocytes, macrophages, neutrophils, dendritic cells, eosinophils, mast cells, platelets, B cells, large granular lymphocytes, Eangerhans’ cells, natural killer (NK) cells, and cytotoxic T cells.

[0151] The anti-SEZ6L2 antibodies of the present disclosure may be evaluated in various assays for their ability to mediate FcR-dependent activity. In one assay, the binding activity of an anti-SEZ6L2 antibody is evaluated in an Fc receptor engagement assay. For purposes of testing variants, “engagement” of an Fc receptor occurs when a variant antibody binds to both a target SEZ6L2 cell via its Fv region and an FcyR present on an immune cell via the antibody Fc region in such as manner to transduce a signal. If the Fc region is kept constant among variants that differ in their Fv regions, then the assay allows an evaluation of SEZ6L2 binding activity across such variants in the context of potential signal transduction through a particular Fc region binding a particular Fc receptor. In some embodiments, binding of the antibody Fc region can result in clustering and / or internalization of the FcR, resulting in a luminescence signal in cells harboring a NFAT-RE-Eucif erase reporter construct.ANTIBODY FORMATS

[0152] In some embodiments, an anti-SEZ6L2 antibody in accordance with the present disclosure is in a monovalent format. In some embodiments, the SEZ6L2-targeting antibody is in a fragment format, e.g., a Fv, Fab, Fab’, scFv, diabody, or F(ab’)2 fragment. In some embodiments, the SEZ6L2-targeting antibody is a nanobody (nb), minibody, small immunoprotein (SIP), or variable new antigen receptor (VNAR). In some embodiments, of the disclosure, an anti-SEZ6L2 antibody in accordance with the disclosure may be an antibody fragment, e.g., a Fv, Fab, Fab’, scFv, VHH, diabody, or F(ab’)2 fragment. In 83MF - 363628584Attorney Docket No. 22419-20011.40another embodiment, the antibody is a substantially full-length antibody, e.g., an IgG antibody or other antibody class or isotype as defined herein. For a review of certain antibody fragments, see Hudson et al. Nat. Med. 9: 129-134 (2003). Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells.

[0153] In some embodiments, an anti-SEZ6L2 antibody according to the present disclosure that is administered to a patient is an IgG of the IgGl subclass. In some embodiments, such an antibody is an IgG of the IgG2, IgG3, or IgG4 subclass. In some embodiments, such an antibody is an IgM. In some embodiments, such an antibody has a lambda light chain constant region. In some embodiments, such an antibody has a kappa light chain constant region.

[0154] In some embodiments, an anti-SEZ6L2 antibody of the present disclosure is employed in a bispecific or multi-specific format, e.g., a tri-specific format. For example, in some embodiments, the antibody may be incorporated into a bispecific or multi- specific antibody that comprises a further binding domain that binds to the same or a different antigen.

[0155] There are a variety of possible formats that can be used in bispecific or multi- specific antibodies. The formats can vary elements such as the number of binding arms, the format of each binding arm e.g., Fab, scFv, scFab, or VH-only), the number of antigen binding domains present on the binding arms, the connectivity and geometry of each arm with respect to each other, the presence or absence of an Fc domain, the Ig class (e.g., IgG or IgM), the Fc subclass (e.g., hlgGl, hIgG2, or hIgG4), and any mutations to the Fc (e.g., mutations to reduce or increase effector function or extend serum half-life).. Also see Speiss, et al., Alternative Molecular Formats and Therapeutic Applications for Bispecific Antibodies, Mol Immunol, 67, 95-106 (2015), particularly FIG. 1, for examples of bispecific and multispecific formats.

[0156] In some embodiments of any of the above bispecific or multispecific antibody constructs, the SEZ6L2-targeting binding domain comprises all six CDRs (CDR1, CDR2, CDR3, CDR1, CDR2, and CDR3) sequences from the individual antibodies disclosed in Tables 1 and 2.

[0157] In some embodiments of any of the above bispecific or multispecific antibody constructs, the SEZ6L2-targeting binding domain comprises the VH and VL sequences from the individual antibodies disclosed in Table 3.

[0158] In some embodiments of any of the above bispecific or multispecific antibody constructs, the SEZ6L2-targeting binding domain comprises all six CDRs (CDR1, CDR2,84MF - 363628584Attorney Docket No. 22419-20011.40CDR3, CDR1, CDR2, and CDR3) sequences from any one of antibodies Antibody 1 or Antibody 2.

[0159] In some embodiments of any of the above bispecific or multispecific antibody constructs, the SEZ6L2-targeting binding domain comprises the VH and VL sequences of Antibody 1 or Antibody 2.

[0160] In some embodiments, an anti-SEZ6L2 antibody disclosed herein is constructed as a multivalent antibody. In some embodiments an anti-SEZ6L2 antibody is constructed as a tetravalent molecule, comprising four glycan-binding arms per molecule. Such constructs exhibit increased ADCC activity, as well as increased binding to SEZ6L2 cells a measured by flow cytometry.

[0161] In some embodiments, an anti-SEZ6L2 antibody of the present disclosure is employed in a bispecific or multi-specific format, e.g., a tri-specific format. For example, in some embodiments, the antibody may be incorporated into a bispecific or multi- specific antibody that comprises a further binding domain that binds to the same or a different antigen.

[0162] There are a variety of possible formats that can be used in bispecific or multi- specific antibodies. The formats can vary elements such as the number of binding arms, the format of each binding arm e.g., Fab, scFv, scFab, or VH-only), the number of antigen binding domains present on the binding arms, the connectivity and geometry of each arm with respect to each other, the presence or absence of an Fc domain, the Ig class (e.g., IgG or IgM), the Fc subclass (e.g., hlgGl, hIgG2, or hIgG4), and any mutations to the Fc (e.g., mutations to reduce or increase effector function or extend serum half-life).GENERATION OF ANTIBODIES

[0163] The anti-SEZ6L2 antibodies can be produced using vectors and recombinant methodology well known in the art. Reagents, cloning vectors, and kits for genetic manipulation are available from commercial vendors. Accordingly, in some embodiments of the disclosure, provided herein are isolated nucleic acids encoding a VH and / or VE region, or fragment thereof, of any of the SEZ6L2-targeting antibodies as described herein; vectors comprising such nucleic acids and host cells into which the nucleic acids are introduced that are used to replicate the antibody-encoding nucleic acids and / or to express the antibodies. Such nucleic acids may encode an amino acid sequence containing the VL and / or an amino acid sequence containing the VH of the SEZ6L2-targeting antibody (e.g., the light and / or heavy chains of the antibody). In some embodiments, the host cell contains (1) a vector containing a polynucleotide that encodes the VL amino acid sequence and a polynucleotide 85MF - 363628584Attorney Docket No. 22419-20011.40that encodes the VH amino acid sequence, or (2) a first vector containing a polynucleotide that encodes the VL amino acid sequence and a second vector containing a polynucleotide that encodes the VH amino acid sequence.

[0164] In some embodiments, the disclosure provides a method of making an anti-SEZ6L2 antibody as described herein. In some embodiments, the method includes culturing a host cell as described in the preceding paragraph under conditions suitable for expression of the antibody. In some embodiments, the antibody is subsequently recovered from the host cell (or host cell culture medium).

[0165] Suitable vectors containing polynucleotides encoding antibodies of the present disclosure, or fragments thereof, include cloning vectors and expression vectors. While the cloning vector selected may vary according to the host cell intended to be used, useful cloning vectors generally can self-replicate, may possess a single target for a particular restriction endonuclease, and / or may carry genes for a marker that can be used in selecting clones containing the vector. Examples include plasmids and bacterial viruses, e.g., pUC18, pUC19, Bluescript (e.g., pBS SK+) and its derivatives, mpl8, mpl9, pBR322, pMB9, ColEl plasmids, pCRl, RP4, phage DNAs, and shuttle vectors. These and many other cloning vectors are available from commercial vendors.

[0166] Expression vectors generally are replicable polynucleotide constructs that contain a nucleic acid of the present disclosure. The expression vector can be replicable in the host cells either as episomes or as an integral part of the chromosomal DNA. Suitable expression vectors include but are not limited to plasmids and viral vectors, including adenoviruses, adeno-associated viruses, retroviruses, and any other vector.

[0167] Suitable host cells for expressing an anti-SEZ6L2 antibody as described herein include both prokaryotic and eukaryotic cells. For example, an anti-SEZ6L2 antibody may be produced in bacteria when glycosylation and Fc effector function are not needed. After expression, the antibody may be isolated from the bacterial cell paste in a soluble fraction and can be further purified. Alternatively, the host cell may be a eukaryotic host cell, including eukaryotic microorganisms, such as filamentous fungi or yeast, including fungi and yeast strains whose glycosylation pathways have been “humanized,” resulting in the production of an antibody with a partially or fully human glycosylation pattern, vertebrate, invertebrate, and plant cells. Examples of invertebrate cells include insect cells. Numerous baculoviral strains have been identified which may be used in conjunction with insect cells. Plant cell cultures can also be utilized as host cells.86MF - 363628584Attorney Docket No. 22419-20011.40

[0168] In some embodiments, vertebrate host cells are used for producing an anti-SEZ6L2 antibody of the present disclosure. For example, mammalian cell lines such as a monkey kidney CV1 line transformed by SV40 (COS-7); human embryonic kidney line (293 or 293 cells as described, e.g., in Graham et al., J. Gen Virol. 36:59,1977; baby hamster kidney cells (BHK); mouse sertoli cells (TM4 cells as described, e.g., in Mather, Biol. Reprod. 23:243-251, 1980 monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK; buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary SEZ6L2 (MMT 060562); TRI cells, as described, e.g., in Mather et al., Annals N. Y. Acad. Sci.383:44-68, 1982; MRC 5 cells; and FS4 cells may be used to express an SEZ6L2-targeting antibodies. Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR- CHO cells (Urlaub et al., Proc. Natl. Acad. Sci. USA 7. A2A6, 1980); and myeloma cell lines such as Y0, NS0 and Sp2 / 0. Host cells of the present disclosure also include, without limitation, isolated cells, in vitro cultured cells, and ex vivo cultured cells. For a review of certain mammalian host cell lines suitable for antibody production, see, e.g., Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (B. K. C. Lo, ed., Humana Press, Totowa, NJ), pp. 255-268, 2003.

[0169] In some embodiments, an anti-SEZ6L2 antibody of the present disclosure is produced by a CHO cell line, e.g., the CHO-K1 cell line. One or more expression plasmids can be introduced that encode heavy and light chain sequences. For example, an expression plasmid encoding a heavy chain disclosed herein, and an expression plasmid encoding a light chain disclosed herein are transfected into host cells. The expression plasmids can be introduced as linearized plasmids at a ratio of 1:1 in the CHO-K1 host cell line using reagents such as Freestyle Max reagent. Fluorescence-activated cell sorting (FACS) coupled with single cell imaging can be used as a cloning method to obtain a production cell line.

[0170] A host cell transfected with an expression vector encoding an anti-SEZ6L2 antibody of the present disclosure, or fragment thereof, can be cultured under appropriate conditions to allow expression of the polypeptide to occur. The polypeptides may be secreted and isolated from a mixture of cells and medium containing the polypeptides. Alternatively, the polypeptide may be retained in the cytoplasm or in a membrane fraction and the cells harvested, lysed, and the polypeptide isolated using a desired method.

[0171] In some embodiments, an anti-SEZ6L2 antibody of the present disclosure can be produced by in vitro synthesis (see, e.g., Sutro Biopharma biochemical protein synthesis platform).87MF - 363628584Attorney Docket No. 22419-20011.40

[0172] In some embodiments, provided herein is a method of generating variants of an anti-SEZ6L2 antibody as disclosed herein. Thus, for example, a construct encoding a variant of a VH CDR3 as described herein can be modified and the VH region encoded by the modified construct can be tested for binding activity to NCI-H69 (ATCC catalog no. HTB-119) cells and / or in vivo SEZ6L2-targeting activity in the context of a VH region as described herein, that is paired with a VL region or variant region as described herein. Similarly, a construct encoding a variant of a VL CDR3 as described herein can be modified and the VL region encoded by the modified construct can be tested for binding to NCLH69 (ATCC catalog no. HTB-119) cells, or other SEZ6L2 cells, and / or in vivo SEZ6L2-targeting activity efficacy. Such an analysis can also be performed with other CDRs or framework regions and an antibody having the desired activity can then be selected.

[0173] In some embodiments, the anti-SEZ6L2 antibodies described herein can be manufactured at high concentrations and are thermally stable (e.g., the anti-SEZ6L2 antibodies are stable after multiple freeze / thaw rounds).SEZ6L2-TARGETING IMMUNOCONJUGATES

[0174] Described herein, in certain embodiments, are immunoconjugates comprising anti-SEZ6L2 antibodies described herein.

[0175] In certain embodiments, the present disclosure provides an immunoconjugate, comprising: a) an antibody or antigen-binding fragment thereof that binds to SEZ6L2, wherein the antibody comprises: a heavy chain variable region (VH) comprising (i) a complementarity determining region (CDR) 1 having an amino acid sequence according to SEQ ID NOs: 1-12; (ii) a CDR2 having an amino acid sequence according to SEQ ID NOs: 13-24; and (iii) a CDR3 having an amino acid sequence according to SEQ ID NOs: 25-36; and a light chain variable region (VL) comprising (i) a complementarity determining region (CDR) 1 having an amino acid sequence according to SEQ ID NOs: 37-48; (ii) a CDR2 having an amino acid sequence according to SEQ ID NOs: 49-60; and (iii) a CDR3 having an amino acid sequence according to SEQ ID NOs: 61-72; and b) a topoisomerase I inhibitor conjugated to the antibody or the antigen-binding fragment thereof using a linker.

[0176] In some embodiments, the topoisomerase I inhibitor is represented by Formula (ILA) having the structure:88MF - 363628584Attorney Docket No. 22419-20011.40wherein: R1and R2are each individually selected from the group consisting of hydrogen, halogen, -CN, -OR5, -NR5R6, a substituted or an unsubstituted Ci-Ce alkyl, a substituted or unsubstituted Ci-Ce haloalkyl, a substituted or unsubstituted -O-(Ci-Ce alkyl), a substituted or unsubstituted -O-(Ci-Ce haloalkyl), and -[(CY2)pO(CY2)q]tCY3, or a substituted or unsubstituted -O-(CR5R6)m-O- such that R1and R2are taken together form a ring; R3is a hydrogen or a substituted or an unsubstituted Ci-Ce alkyl, a substituted or an unsubstituted Ci-C6haloalkyl, or — [(CY2)PO(CY2)q]tCY3; R4is hydrogen, a substituted or an unsubstituted — (Ci-Cealkyl)-X2, a substituted or an unsubstituted — (Ci-Ce haloalkyl)-X2, a substituted or an unsubstituted — (Ci-Ce alkenyl)-X2, a substituted or an unsubstituted — (Ci-Ce haloalkenyl)-X2, a substituted or an unsubstituted — (Ci-Ce alkynyl)-X2, or a substituted or an unsubstituted — (Ci-C6haloalkynyl)-X2; X1is — O —, — S(O)W—, — NH —, — O — (C=O) —, — NH— (C=O)—, — NH— (C=O)— O—, — NH— (C=O)— NH—, or — NH— S(O)W—; X2is — OR9, — SR9, or — NHR9; R5and R6are each individually hydrogen, halogen, a substituted or an unsubstituted Ci-Ce alkyl, a substituted or an unsubstituted Ci-Ce haloalkyl, or — [(CY2)PO(CY2)q]tCY3; m is 1 or 2; n4and n5are each individually 0, 1 or 2, with the proviso that n4and n5are not both 0; each w is 0, 1 or 2; each Y is individually H or halogen; each p is individually 1, 2, 3, 4, 5, or 6; each q is individually 0, 1, 2, 3, 4, 5, or 6; each t is individually 1, 2, 3, 4, 5, or 6; R7is H, — COR8, — CO2R8, — (CO) — NHR8, or the point of attachment to the linker; R8is a substituted or an unsubstituted Ci-Ce alkyl-X3, a substituted or an unsubstituted Ci-Ce haloalkyl-X3, or — [(CY2)PO(CY2)q]tCY2 — X3; R9is H, — COR8, — CO2R8, — (CO) — NHR8, or the point of attachment to the linker, with the proviso that exactly one of R7and R9is the point of attachment to the linker; and each X3is individually — H, —OH, — SH, or — NH2.89MF - 363628584Attorney Docket No. 22419-20011.40

[0177] In some embodiments, the topoisomerase I inhibitor is represented by Formula (II) having the structure:wherein: R1and R2are each individually selected from the group consisting of hydrogen, halogen, -CN, -OR5, -NR5R6, a substituted or an unsubstituted Ci-Ce alkyl, a substituted or unsubstituted Ci-Ce haloalkyl, a substituted or unsubstituted -O-(Ci-Ce alkyl), a substituted or unsubstituted -O-(Ci-Ce haloalkyl), and -[(CY2)pO(CY2)q]tCY3, or a substituted or unsubstituted -O-(CR5R6)m-O- such that R1and R2are taken together form a ring; R3is a hydrogen or a substituted or an unsubstituted Ci-Ce alkyl, a substituted or an unsubstituted Ci-C6haloalkyl, or — [(CY2)PO(CY2)q]tCY3; R4is hydrogen, a substituted or an unsubstituted — (Ci-Cealkyl)-X2, a substituted or an unsubstituted — (Ci-Ce haloalkyl)-X2, a substituted or an unsubstituted — (Ci-Ce alkenyl)-X2, a substituted or an unsubstituted — (Ci-Ce haloalkenyl)-X2, a substituted or an unsubstituted — (Ci-Ce alkynyl)-X2, or a substituted or an unsubstituted — (Ci-C6haloalkynyl)-X2; X1is — O —, — S(O)W—, — NH —, — O — (C=O) —, — NH— (C=O)—, — NH— (C=O)— O—, — NH— (C=O)— NH—, or — NH— S(O)W—; X2is — OR9, — SR9, or — NHR9; R5and R6are each individually hydrogen, halogen, a substituted or an unsubstituted Ci-Ce alkyl, a substituted or an unsubstituted Ci-Ce haloalkyl, or — [(CY2)PO(CY2)q]tCY3; m is 1 or 2; n4and n5are each individually 0, 1 or 2, with the proviso that n4and n5are not both 0; each w is 0, 1 or 2; each Y is individually H or halogen; each p is individually 1, 2, 3, 4, 5, or 6; each q is individually 0, 1, 2, 3, 4, 5, or 6; each t is individually 1, 2, 3, 4, 5, or 6; R7is H, — COR8, — CO2R8, — (CO) — NHR8, or the point of attachment to the linker; R8is a substituted or an unsubstituted Ci-Ce alkyl-X3, a substituted or an unsubstituted Ci-Ce haloalkyl-X3, or — [(CY2)PO(CY2)q]tCY2 — X3; R9is H, — COR8, — CO2R8, — (CO) — NHR8, or the point of attachment to the linker, with the proviso that90MF - 363628584Attorney Docket No. 22419-20011.40exactly one of R7and R9is the point of attachment to the linker; and each X3is individually — H, —OH, — SH, or — NH2.

[0178] In some embodiments, the topoisomerase I inhibitor is represented by Formula (II) having the structure:wherein: R1and R2are each individually selected from the group consisting of hydrogen, halogen, -OR5, an unsubstituted Ci-Ce alkyl, an unsubstituted Ci-Ce haloalkyl and an unsubstituted -O-(Ci-Ce alkyl), or an unsubstituted -O-(CR5R6)m-O- such that R1and R2are taken together form a ring; R3is a hydrogen or an unsubstituted Ci-Ce alkyl; R4is a substituted or an unsubstituted -(Ci-Ce alkyl)-X2; X1is — O —; X2is — OR9; R5and R6are each individually hydrogen; m is 1; n4is 1 or 2; n5is 0; R7is H; and R9is the point of attachment to the linker. In some embodiments, n4is 1. In some embodiments, n4is 2.

[0179] In some embodiments, the topoisomerase I inhibitor comprises Formula (II) having the structure:wherein: R1is methyl; R2is fluoro; R3is hydrogen; R4is a substituted or an unsubstituted -(C2alkyl)-X2; and n4is 2, and wherein the remaining variables are as described herein. In some embodiments, L2is absent; n1is the integer 2 or 5; L4is gly-gly-phe-gly; L5is - 91MF - 363628584Attorney Docket No. 22419-20011.40[NH(CH2)n2]n3-; n2is the integer 1; n3is the integer 1; and L7is absent, and wherein the remaining variables are as described herein.

[0180] In some embodiments, the topoisomerase I inhibitor comprises Formula (II) having the structure:wherein: R1is methyl; R2is fluoro; R3is hydrogen; R4is a substituted or an unsubstituted -(C2 alkyl)-X2; and n4is 2, and wherein the remaining variables are as described herein.

[0181] In some embodiments, the topoisomerase I inhibitor is represented by:wherein R9is the point of attachment to the linker.

[0182] In some embodiments, the topoisomerase I inhibitor is represented by:wherein R9is the point of attachment to the linker.

[0183] In some embodiments, the topoisomerase I inhibitor is represented by:92MF - 363628584Attorney Docket No. 22419-20011.40wherein R9is the point of attachment to the linker.

[0184] In some embodiments, the topoisomerase I inhibitor and the linker, taken together, are represented by:

[0185] In some embodiments, the topoisomerase I inhibitor and the linker, taken together, are represented by:

[0186] In some embodiments, the topoisomerase I inhibitor and the linker, taken together, are represented by:93MF - 363628584Attorney Docket No. 22419-20011.40

[0187] In some embodiments, the topoisomerase I inhibitor and the linker, taken together, are

[0188] In some embodiments, the topoisomerase I inhibitor and the linker, taken together, are represented by:

[0189] In some embodiments, the topoisomerase I inhibitor and the linker, taken together, are represented by:94MF - 363628584Attorney Docket No. 22419-20011.40

[0190] In some embodiments, the topoisomerase I inhibitor and the linker, taken together, are represented by:

[0191] In some embodiments, the topoisomerase I inhibitor and the linker, taken together, are represented by:95MF - 363628584Attorney Docket No. 22419-20011.40

[0192] In some embodiments, the topoisomerase I inhibitor and the linker, taken together, are represented by:F orF

[0193] In some embodiments, the topoisomerase I inhibitor and the linker, taken together, are represented by:96MF - 363628584Attorney Docket No. 22419-20011.40

[0194] In some embodiments, the topoisomerase I inhibitor is exatecan. In some embodiments the topoisomerase I inhibitor is an exatecan derivative. In some embodiments the topoisomerase I inhibitor is selected from the group consisting of exatecan, deruxtecan, SN-38, belotecan, topotecan, adizutecan, YL0014, tirumotecan, rezetecan, and A- 1743332. In some embodiments, the topoisomerase I inhibitor is deruxtecan. In some embodiments, the topoisomerase I inhibitor is SN-38. In some embodiments, the topoisomerase I inhibitor is belotecan. In some embodiments, the topoisomerase I inhibitor is topotecan. In some embodiments, the topoisomerase I inhibitor is adizutecan. In some embodiments, the topoisomerase I inhibitor is YL0014. In some embodiments, the topoisomerase I inhibitor is tirumotecan. In some embodiments, the topoisomerase I inhibitor is rezetecan. In some embodiments, the topoisomerase I inhibitor is A- 1743332.

[0195] In some embodiments, the VH comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NOs: 73-84. In some embodiments, the VL comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NOs: 85-96. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NOs: 73-84. In some embodiments, the VL comprises an amino acid sequence according to SEQ ID NOs: 85-96. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 73 and the VL comprises an amino acid sequence according to SEQ ID NO: 85. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 74 and the VL comprises an amino acid sequence according to SEQ ID NO: 86. In some97MF - 363628584Attorney Docket No. 22419-20011.40embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 75 and the VL comprises an amino acid sequence according to SEQ ID NO: 87. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 76 and the VL comprises an amino acid sequence according to SEQ ID NO: 88. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 77 and the VL comprises an amino acid sequence according to SEQ ID NO: 89. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 78 and the VL comprises an amino acid sequence according to SEQ ID NO: 90. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 79 and the VL comprises an amino acid sequence according to SEQ ID NO: 91. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 80 and the VL comprises an amino acid sequence according to SEQ ID NO: 92. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 81 and the VL comprises an amino acid sequence according to SEQ ID NO: 93. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 82 and the VL comprises an amino acid sequence according to SEQ ID NO: 94. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 83 and the VL comprises an amino acid sequence according to SEQ ID NO: 95. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 84 and the VL comprises an amino acid sequence according to SEQ ID NO: 96. In some embodiments, the antibody comprises a Fc domain comprising one or more modifications that reduces binding to an Fc receptor, reduces binding to complement component Cl q, or both binding to an Fc receptor and reduces binding to complement component Clq. In some embodiments, the antibody comprises a Fc domain comprising the amino acid modifications L234A / L235A (LALA), L234A / L235A / P329A (LALAPA) or L234A / L235A / P329G (LALAPG). In some embodiments, the antibody or antibody fragment binds to human SEZ6L2 with an affinity of 10’7M to 1010M.

[0196] In certain embodiments, provided herein is an immunoconjugate having Formula (I),Ab-[S-L1-L2-L3-L4-L5-L6-L7-D]n(I)wherein: Ab is an antibody or an antigen-binding fragment thereof that binds SEZ6L2, comprising: a heavy chain variable region (VH) comprising (i) a complementarity determining region (CDR) 1 having an amino acid sequence according to SEQ ID NOs: 1-12;98MF - 363628584Attorney Docket No. 22419-20011.40(ii) a CDR2 having an amino acid sequence according to SEQ ID NOs: 13-24; and (iii) a CDR3 having an amino acid sequence according to SEQ ID NOs: 25-36; and a light chain variable region (VL) comprising (i) a complementarity determining region (CDR) 1 having an amino acid sequence according to SEQ ID NOs: 37-48; (ii) a CDR2 having an amino acid sequence according to SEQ ID NOs: 49-60; and (iii) a CDR3 having an amino acid sequence according to SEQ ID NOs: 61-72;L2is absent,z- Z1and Z2are each individually hydrogen, halogen, NO2, -O-(Ci-Ce alkyl), or Ci-Ce alkyl; L3is -(CH2)n1-C(=O)- or-(CH2CH20)n1-(CH2)n1C(=0)-; each n1is individually an integer from 0 to 10; L4is a tetrapeptide residue; L5is absent or -[NH(CH2)n2]n3-; n2is an integer from 0 to 6; n3is an integer from 0 to 2;L6is absent,eNx^\ P— £HN, wherein G is a beta-glucuronic acid moiety;L7is absent,D is a drug moiety; and n is an integer from 1 to 10.99MF - 363628584Attorney Docket No. 22419-20011.40

[0197] In certain embodiments, provided herein is an immunoconjugate having Formula (I),Ab-[S-L1-L2-L3-L4-L5-L6-L7-D]n(I)wherein: Ab is an antibody or an antigen-binding fragment thereof that binds SEZ6L2, comprising: a heavy chain variable region (VH) comprising (i) a complementarity determining region (CDR) 1 having an amino acid sequence according to SEQ ID NOs: 1-12; (ii) a CDR2 having an amino acid sequence according to SEQ ID NOs: 13-24; and (iii) a CDR3 having an amino acid sequence according to SEQ ID NOs: 25-36; and a light chain variable region (VL) comprising (i) a complementarity determining region (CDR) 1 having an amino acid sequence according to SEQ ID NOs: 37-48; (ii) a CDR2 having an amino acid sequence according to SEQ ID NOs: 49-60; and (iii) a CDR3 having an amino acid sequence according to SEQ ID NOs: 61-72;L1isL2is absent,Z1and Z2are each individually hydrogen, halogen, NO2, -O-(Ci-Ce alkyl), or Ci-Ce alkyl; L3is -(CH2)n1-C(=O)- or-(CH2CH20)n1-(CH2)n1C(=0)-; each n1is individually an integer from 0 to 10; L4is a tetrapeptide residue; L5is absent or -[NH(CH2)n2]n3-; n2is an integer from 0 to 6; n3is an integer from 0 to 2;L6is absent orL7is absent,100MF - 363628584Attorney Docket No. 22419-20011.40D is a drug moiety; and n is an integer from 1 to 10.

[0198] In some embodiments, D in Formula (I) is a drug moiety of Formula (II- A) having the structure:wherein: R1and R2are each individually selected from the group consisting of hydrogen, halogen, -CN, -OR5, -NR5R6, a substituted or an unsubstituted Ci-Ce alkyl, a substituted or unsubstituted Ci-Ce haloalkyl, a substituted or unsubstituted -O-(Ci-Ce alkyl), a substituted or unsubstituted -O-(Ci-Ce haloalkyl), and -[(CY2)pO(CY2)q]tCY3, or a substituted or unsubstituted -O-(CR5R6)m-O- such that R1and R2are taken together form a ring; R3is a hydrogen or a substituted or an unsubstituted Ci-Ce alkyl, a substituted or an unsubstituted Ci-C6haloalkyl, or — [(CY2)PO(CY2)q]tCY3; R4is hydrogen, a substituted or an unsubstituted — (Ci-Cealkyl)-X2, a substituted or an unsubstituted — (Ci-Ce haloalkyl)-X2, a substituted or an unsubstituted — (Ci-Ce alkenyl)-X2, a substituted or an unsubstituted — (Ci-Ce haloalkenyl)-X2, a substituted or an unsubstituted — (Ci-Ce alkynyl)-X2, or a substituted or an unsubstituted — (Ci-C6haloalkynyl)-X2; X1is — O —, — S(O)W—, — NH —, — O — (C=O) —, — NH— (C=O)—, — NH— (C=O)— O—, — NH— (C=O)— NH—, or — NH— S(O)W—; X2is — OR9, — SR9, or — NHR9; R5and R6are each individually hydrogen, halogen, a substituted or an unsubstituted Ci-Ce alkyl, a substituted or an unsubstituted Ci-Ce haloalkyl, or — [(CY2)PO(CY2)q]tCY3; m is 1 or 2; n4and n5are each individually 0, 1 or 2, with the proviso that n4and n5are not both 0; each w is 0, 1 or 2; each Y is individually H or halogen; each p is individually 1, 2, 3, 4, 5, or 6; each q is individually 0, 1, 2, 3, 4, 5, or 6; each t is101MF - 363628584Attorney Docket No. 22419-20011.40individually 1, 2, 3, 4, 5, or 6; R7is H, — COR8, — CO2R8, — (CO) — NHR8, or the point of attachment to the linker; R8is a substituted or an unsubstituted Ci-Ce alkyl-X3, a substituted or an unsubstituted Ci-Ce haloalkyl-X3, or — [(CY2)pO(CY2)q]tCY2 — X3; R9is H, — COR8, — CO2R8, — (CO) — NHR8, or the point of attachment to the linker, with the proviso that exactly one of R7and R9is the point of attachment to the linker; and each X3is individually — H, —OH, — SH, or — NH2.

[0199] In some embodiments, D in Formula (I) is a drug moiety of Formula (II) having the structure:(II)wherein: R1and R2are each individually selected from the group consisting of hydrogen, halogen, -CN, -OR5, -NR5R6, a substituted or an unsubstituted Ci-Ce alkyl, a substituted or unsubstituted Ci-Ce haloalkyl, a substituted or unsubstituted -O-(Ci-Ce alkyl), a substituted or unsubstituted -O-(Ci-Ce haloalkyl), and -[(CY2)PO(CY2)q]tCY3, or a substituted or unsubstituted -O-(CR5R6)m-O- such that R1and R2are taken together form a ring; R3is a hydrogen or a substituted or an unsubstituted Ci-Ce alkyl, a substituted or an unsubstituted Ci-Ce haloalkyl, or — [(CY2)PO(CY2)q]tCY3; R4is hydrogen, a substituted or an unsubstituted — (Ci-Cealkyl)-X2, a substituted or an unsubstituted — (Ci-Ce haloalkyl)-X2, a substituted or an unsubstituted — (Ci-Ce alkenyl)-X2, a substituted or an unsubstituted — (Ci-Ce haloalkenyl)-X2, a substituted or an unsubstituted — (Ci-Ce alkynyl)-X2, or a substituted or an unsubstituted — (Ci-C6haloalkynyl)-X2; X1is — O —, — S(O)W—, — NH —, — O — (C=O) —, — NH— (C=O)—, — NH— (C=O)— O—, — NH— (C=O)— NH—, or — NH— S(O)W—; X2is — OR9, — SR9, or — NHR9; R5and R6are each individually hydrogen, halogen, a substituted or an unsubstituted Ci-Ce alkyl, a substituted or an unsubstituted Ci-Ce haloalkyl, or —[(CY2)PO(CY2)q]tCY3; m is 1 or 2; n4and n5are each individually 0, 1 or 2, with the proviso 102MF - 363628584Attorney Docket No. 22419-20011.40that n4and n5are not both 0; each w is 0, 1 or 2; each Y is individually H or halogen; each p is individually 1, 2, 3, 4, 5, or 6; each q is individually 0, 1, 2, 3, 4, 5, or 6; each t is individually 1, 2, 3, 4, 5, or 6; R7is H, —COR8, — CO2R8, — (CO)— NHR8, L4, L5, L6, or L7; R8is a substituted or an unsubstituted Ci-Ce alkyl-X3, a substituted or an unsubstituted Ci-Ce haloalkyl-X3, or — [(CY2)pO(CY2)q]tCY2— X3; R9is H, —COR8, — CO2R8, —(CO)— NHR8, L4, L5, L6, or L7, with the proviso that exactly one of R7and R9is L4, L5, L6, or L7; and each X3is individually — H, — OH, — SH, or — NH2.

[0200] In some embodiments, D in Formula (I) is a drug moiety of Formula (II) having the structure:wherein: R1and R2are each individually selected from the group consisting of hydrogen, halogen, -OR5, an unsubstituted Ci-Ce alkyl, an unsubstituted Ci-Ce haloalkyl and an unsubstituted -O-(Ci-Ce alkyl), or an unsubstituted -O-(CR5R6)m-O- such that R1and R2are taken together form a ring; R3is a hydrogen or an unsubstituted Ci-Ce alkyl; R4is a substituted or an unsubstituted -(Ci-Ce alkyl)-X2; X1is — O —; X2is — OR9; R5and R6are each individually hydrogen; m is 1; n4is 1 or 2; n5is 0; R7is H; and R9is L4, L5, L6, or L7.

[0201] In some embodiments, n4is 1. In some embodiments, n4is 2.

[0202] In some embodiments, D in Formula (I) is a drug moiety of Formula (II) having the structure:103MF - 363628584Attorney Docket No. 22419-20011.40wherein: R1is methyl; R2is fluoro; R3is hydrogen; R4is a substituted or an unsubstituted - (C2 alkyl)-X2; and n4is 2, and wherein the remaining variables are as described herein.

[0203] In some embodiments, L2is absent; nl is the integer 2 or 5; L4is gly-gly-phe-gly; L5is -[NH(CH2)n2]n3-; n2is the integer 1; n3is the integer 1; and L7is absent, and wherein the remaining variables are as described herein.

[0204] In some embodiments, L6isIn some embodiments, L6isIn some embodiments, L6is104MF - 363628584Attorney Docket No. 22419-20011.40In some embodiments, L6is

[0205] In some embodiments, L7is absent. In some embodiments,L7is

[0206] In some embodiments, L7is I. In some embodiments, L7is

[0207] In some embodiments, D in Formula (I) is a drug moiety of Formula (II) having the structure:wherein: R1is methyl; R2is fluoro; R3is hydrogen; R4is a substituted or an unsubstituted -(C2 alkyl)-X2; and n4is 2.

[0208] In some embodiments, D in Formula (I) is represented by:105MF - 363628584Attorney Docket No. 22419-20011.40

[0209] In some embodiments, D in Formula (I) is represented by:wherein R9is L4, L5, L6, or L7.

[0210] In some embodiments, D in Formula (I) is represented by:wherein R9is L4, L5, L6, or L7.

[0211] In some embodiments, D in Formula (I) is represented by:106MF - 363628584Attorney Docket No. 22419-20011.40

[0212] In some embodiments, Formula (I) is:wherein n is as described herein.

[0213] In some embodiments, Formula (I) is:wherein n is as described herein.

[0214] In some embodiments, Formula (I) is:107MF - 363628584Attorney Docket No. 22419-20011.40wherein n is as described herein.

[0215] In some embodiments, Formula (I) is represented by:wherein n is as described herein.

[0216] In some embodiments, Formula (I) is represented by:wherein n is as described herein.

[0217] In some embodiments, Formula (I) is:108MF - 363628584Attorney Docket No. 22419-20011.40n is as described herein.

[0218] In some embodiments, Formula (I) is:wherein n is as described herein.

[0219] In some embodiments, Formula (I) is:109MF - 363628584Attorney Docket No. 22419-20011.40wherein n is as described herein.

[0220] In some embodiments, Formula (I) is represented by:110MF - 363628584Attorney Docket No. 22419-20011.40wherein n is as described herein.

[0221] In some embodiments, Formula (I) is represented by:is as described herein.

[0222] The immunoconjugate of Formula (I) described herein comprises an antibody conjugated to a payload-linker, wherein the payload is a topoisomerase I inhibitor as described herein, and n is an is an integer from 1 to 10 and represents the number of topoisomerase I-inhibiting payload-linkers conjugated to an individual antibody in the immunoconjugate.

[0223] In some embodiments, n is an integer from 4 to 8. In some embodiments, n is an integer up to 8. In some embodiments, n is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, n is an integer of 2. In some embodiments, n is an integer of 4. In some embodiments, n is an integer of 8.111MF - 363628584Attorney Docket No. 22419-20011.40

[0224] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10.

[0225] In some aspects, provided herein is a composition comprising a plurality of any of the immunoconjugates provided herein. In some embodiments, the average n within a composition comprising the immunoconjugates of Formula (I) is a number from 1 to 10. In some embodiments, the average n within a composition comprising the immunoconjugates of Formula (I) is a number from 1 to 10. In some embodiments, the average n is about 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0.

[0226] For example, in some embodiments, each immunoconjugate of a plurality of immunoconjugates comprises Formula (I), wherein n is a different integer and n is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (i.e., plurality of immunoconjugates comprising heterogenous DAR or mixed DAR). In some embodiments, at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85% 90%, 95%, or more) of the plurality of immunoconjugates comprise Formula (I), wherein n is 4 and the remaining immunoconjugates comprise Formula (I), wherein n is a different integer and n is an integer of 1, 2, 3, 5, 6, 7, 8, 9, or 10. In some embodiments, at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85% 90%, 95%, or more) of the plurality of immunoconjugates comprise Formula (I), wherein n is 6 and the remaining immunoconjugates comprise Formula (I), wherein n is a different integer and n is an integer of 1, 2, 3, 4, 5, 7, 8, 9, or 10. In some embodiments, at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85% 90%, 95%, or more) of the plurality of immunoconjugates comprise Formula (I), wherein n is 8 and the remaining immunoconjugates comprise Formula (I), wherein n is a different integer and n is an integer of 1, 2, 3, 4, 5, 6, 7, 9, or 10.

[0227] In some embodiments, the average n within a pharmaceutical composition comprising the immunoconjugates of Formula (I) is about 1. In some embodiments, the average n within a pharmaceutical composition comprising the immunoconjugates of Formula (I) is about 2. In some embodiments, the average n within a pharmaceutical composition comprising the immunoconjugates of Formula (I) is about 3. In some embodiments, the average n within a pharmaceutical composition comprising the immunoconjugates of Formula (I) is about 4. In 112MF - 363628584Attorney Docket No. 22419-20011.40some embodiments, the average n within a pharmaceutical composition comprising the immunoconjugates of Formula (I) is about 5. In some embodiments, the average n within a pharmaceutical composition comprising the immunoconjugates of Formula (I) is about 6. In some embodiments, the average n within a pharmaceutical composition comprising the immunoconjugates of Formula (I) is about 7. In some embodiments, the average n within a pharmaceutical composition comprising the immunoconjugates of Formula (I) is about 8. In some embodiments, the average n within a pharmaceutical composition comprising the immunoconjugates of Formula (I) is about 9. In some embodiments, the average n within a pharmaceutical composition comprising the immunoconjugates of Formula (I) is about 10.

[0228] In some embodiments, the VH comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NOs: 73-84. In some embodiments, the VL comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NOs: 85-96. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NOs: 73-84. In some embodiments, the VL comprises an amino acid sequence according to SEQ ID NOs: 85-96. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 73 and the VL comprises an amino acid sequence according to SEQ ID NO: 85. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 74 and the VL comprises an amino acid sequence according to SEQ ID NO: 86. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 75 and the VL comprises an amino acid sequence according to SEQ ID NO: 87. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 76 and the VL comprises an amino acid sequence according to SEQ ID NO: 88. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 77 and the VL comprises an amino acid sequence according to SEQ ID NO: 89. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 78 and the VL comprises an amino acid sequence according to SEQ ID NO: 90. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 79 and the VL comprises an amino acid sequence according to SEQ ID NO: 91. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 80 and the VL comprises an amino acid sequence according to SEQ ID NO: 92. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 81 and the VL comprises an amino acid sequence according to SEQ ID NO: 93. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 82 and the VL comprises an amino acid sequence according to SEQ ID NO: 94. In some113MF - 363628584Attorney Docket No. 22419-20011.40embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 83 and the VL comprises an amino acid sequence according to SEQ ID NO: 95. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 84 and the VL comprises an amino acid sequence according to SEQ ID NO: 96. In some embodiments, the antibody comprises a Fc domain comprising one or more modifications that reduces binding to an Fc receptor, reduces binding to complement component Cl q, or both binding to an Fc receptor and reduces binding to complement component Cl q. In some embodiments, the antibody comprises a Fc domain comprising the amino acid modifications L234A / L235A (LALA), L234A / L235A / P329A (LALAPA), or L234A / L235A / P329G (LALAPG). In some embodiments, the antibody or antibody fragment binds to human SEZ6L2 with an affinity of 10’7M to IO10M.

[0229] In certain embodiments, also provided herein is an immunoconjugate having Formula (I),Ab-[S-L1-L2-L3-L4-L5-L6-L7-D]n(I)wherein: Ab is an antibody or an antigen-binding fragment thereof that binds SEZ6L2, comprising: a heavy chain variable region (VH) comprising (i) a complementarity determining region (CDR) 1 having an amino acid sequence according to SEQ ID NOs: 1-12; (ii) a CDR2 having an amino acid sequence according to SEQ ID NOs: 13-24; and (iii) a CDR3 having an amino acid sequence according to SEQ ID NOs: 25-36; and a light chain variable region (VL) comprising (i) a complementarity determining region (CDR) 1 having an amino acid sequence according to SEQ ID NOs: 37-48; (ii) a CDR2 having an amino acid sequence according to SEQ ID NOs: 49-60; and (iii) a CDR3 having an amino acid sequence according to SEQ ID NOs: 61-72;S is a sulfur atom of a cysteine of the antibody or the antigen-binding fragment thereof;L1isL2is absent,114MF - 363628584Attorney Docket No. 22419-20011.40Z1and Z2are each individually hydrogen, halogen, NO2, -O-(Ci-Ce alkyl), or Ci-Ce alkyl; L3is -(CH2)n1-C(=O)- or-(CH2CH20)n1-(CH2)n1C(=0)-; each n1is individually an integer from 0 to 10; L4is a tetrapeptide residue; L5is absent or -[NH(CH2)n2]n3-; n2is an integer from 0 to 6; n3is an integer from 0 to 2;L6is absent,, wherein G is a beta- glucuronic acidL7is absent,wherein D has the structure:and n is an integer from 1 to 10.

[0230] In certain embodiments, also provided herein is an immunoconjugate having Formula (I),Ab-[S-L1-L2-L3-L4-L5-L6-L7-D]n115MF - 363628584Attorney Docket No. 22419-20011.40(I)wherein: Ab is an antibody or an antigen-binding fragment thereof that binds SEZ6L2, comprising: a heavy chain variable region (VH) comprising (i) a complementarity determining region (CDR) 1 having an amino acid sequence according to SEQ ID NOs: 1-12; (ii) a CDR2 having an amino acid sequence according to SEQ ID NOs: 13-24; and (iii) a CDR3 having an amino acid sequence according to SEQ ID NOs: 25-36; and a light chain variable region (VL) comprising (i) a complementarity determining region (CDR) 1 having an amino acid sequence according to SEQ ID NOs: 37-48; (ii) a CDR2 having an amino acid sequence according to SEQ ID NOs: 49-60; and (iii) a CDR3 having an amino acid sequence according to SEQ ID NOs: 61-72;S is a sulfur atom of a cysteine of the antibody or the antigen-binding fragment thereof;L1isL2is absent,Z1and Z2are each individually hydrogen, halogen, NO2, -O-(Ci-Ce alkyl), or Ci-Ce alkyl; L3is -(CH2)n1-C(=O)- or-(CH2CH20)n1-(CH2)n1C(=0)-; each n1is individually an integer from 0 to 10; L4is a tetrapeptide residue; L5is absent or -[NH(CH2)n2]n3-; n2is an integer from 0 to 6; n3is an integer from 0 to 2;L6is absent orL7is absent,116MF - 363628584Attorney Docket No. 22419-20011.40In some embodiments, L6is117MF - 363628584Attorney Docket No. 22419-20011.40In some embodiments, L6iss / w 'vw 077

[0232] In some embodiments, L7is absent. In some embodiments,L7is. InHlV O JVUV iWW ° 11 \ ly "some embodiments, L7is'. In some embodiments, L7is

[0233] In some embodiments, n is an integer from 4 to 8. In some embodiments, n is an integer up to 8. In some embodiments, n is an integer of 2. In some embodiments, n is an integer of 4. In some embodiments, n is an integer of 8.

[0234] In some embodiments, the VH comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NOs: 73-84. In some embodiments, the VL comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 85-96. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 73-84. In some embodiments, the VL comprises an amino acid sequence according to SEQ ID NO: 85-96. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 73 and the VL comprises an amino acid sequence according to SEQ ID NO: 85. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 74 and the VL comprises an amino acid sequence according to SEQ ID NO: 86. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 75 and the VL comprises an amino acid sequence according to SEQ ID NO: 87. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 76 and 118MF - 363628584Attorney Docket No. 22419-20011.40the VL comprises an amino acid sequence according to SEQ ID NO: 88. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 77 and the VL comprises an amino acid sequence according to SEQ ID NO: 89. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 78 and the VL comprises an amino acid sequence according to SEQ ID NO: 90. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 79 and the VL comprises an amino acid sequence according to SEQ ID NO: 91. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 80 and the VL comprises an amino acid sequence according to SEQ ID NO: 92. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 81 and the VL comprises an amino acid sequence according to SEQ ID NO: 93. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 82 and the VL comprises an amino acid sequence according to SEQ ID NO: 94. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 83 and the VL comprises an amino acid sequence according to SEQ ID NO: 95. In some embodiments, the VH comprises an amino acid sequence according to SEQ ID NO: 84 and the VL comprises an amino acid sequence according to SEQ ID NO: 96.

[0235] In some embodiments, provided herein is an immunoconjugate having Formula (I), Ab-[S-L1-L2-L3-L4-L5-L6-L7-D]n(I)wherein:Ab is an antibody or an antigen-binding fragment thereof that binds Seizure Related 6 Homolog Like 2 (SEZ6L2), comprising:a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO: 73; anda light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO: 85;S is a sulfur atom of a cysteine of the antibody or the antigen-binding fragment thereof;L1is O;L2is absent;L3is -(CH2)n1-C(=O)-;119MF - 363628584Attorney Docket No. 22419-20011.40n1is the integer 2;L4is gly-gly-phe-gly;L5is -[NH(CH2)n2]n3-;n2is the integer 1;n3is the integer 1; andL6is absent;L7is absent;D has the structure:and n is 8.

[0236] In some embodiments, provided herein is an immunoconjugate having Formula (I), Ab-[S-L1-L2-L3-L4-L5-L6-L7-D]n(I)wherein:Ab is an antibody or an antigen-binding fragment thereof that binds Seizure Related 6 Homolog Like 2 (SEZ6L2), comprising:a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO: 73; anda light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO: 85;S is a sulfur atom of a cysteine of the antibody or the antigen-binding fragment thereof;L1is OL2is absent;120MF - 363628584Attorney Docket No. 22419-20011.40L3is -(CH2)n1-C(=O)-;n1is the integer 5;L4is gly-gly-phe-gly;L5is -[NH(CH2)n2]n3-;n2is the integer 1;n3is the integer 1; andL6is absent;L7is absent;D has the structure:and n is 8.

[0237] In some embodiments, the antibody comprises a Fc domain comprising one or more modifications that reduces binding to an Fc receptor, reduces binding to complement component Cl q, or both binding to an Fc receptor and reduces binding to complement component Clq. In some embodiments, the antibody comprises a Fc domain comprising the amino acid modifications L234A / L235A (LALA), L234A / L235A / P329A (LALAPA), L234A / L235A / P329G (LALAPG), or L234A / L235A / P329S (LALAPS).

[0238] In some embodiments, the payload4inkers described herein may be conjugated to the anti-SEZ6L2 antibodies via cysteine modifications to allow for site-specific conjugation. In some embodiments, the anti-SEZ6L2 antibodies described herein comprise one or more cysteine modifications in the HC and / or LC to allow for one or more site-specific conjugations. In some embodiments, the LC comprises one or more mutations, including but not limited to S114C, S121C, S127C, A153C, N158C, and V205C, wherein the positions are based on EU numbering. In some embodiments, the HC comprises one or more mutations, including but not limited to S239C, V282C, S324C, and S375C, wherein the positions are based on EU numbering.121MF - 363628584Attorney Docket No. 22419-20011.40

[0239] In some embodiments, the immunoconjugates comprising anti-SEZ6L2 antibodies described herein comprise humanized anti-SEZ6L2 antibodies or antigen-binding fragments thereof.

[0240] In some embodiments, the antibody or antibody fragment binds to human SEZ6L2 with an affinity of 10’7M to 1010M.

[0241] In some embodiments, a linker described herein is an enzymatically cleavable linker. In some embodiments, the enzymatically cleavable linker is a B-glucuronic acid-based linker. Facile release of the drug may be realized through cleavage of the B-glucuronide glycosidic bond by the lysosomal enzyme B-glucuronidase. This enzyme is present abundantly within lysosomes and is overexpressed in some tumor types, while the enzyme activity outside cells is low. B-Glucuronic acid-based linkers may be used to circumvent the tendency of an ADC to undergo aggregation due to the hydrophilic nature of B-glucuronides. In some embodiments, B-glucuronic acid-based linkers are linkers for ADCs linked to hydrophobic drugs.

[0242] In some embodiments, the immunoconjugates (e.g., the ADCs) described herein comprising payloads with Formula (II) exhibit high membrane permeability. In some embodiments, the immunoconjugates (e.g., the ADCs) described herein comprising payloads with Formula (II) have greater cytotoxicity, improved bystander activity and / or improved efficacy in tumors with heterogeneous target expression as compared to immunoconjugates with a different payload.TREATMENT OF CANCER

[0243] Described herein, in certain embodiments, are methods of treating a cancer in a patient in need thereof, the method comprising administering to the patient an effective amount of an anti-SEZ6E2 immunoconjugate (e.g., an antibody-drug conjugate).

[0244] In some embodiments, the disclosure additionally provides methods of identifying subjects who are candidates for treatment with an immunoconjugates having SEZ6E2-targeting effects. Thus, in some embodiments, the disclosure provides a method of identifying a patient who can benefit from treatment with an anti-SEZ6E2 immunoconjugate disclosed herein. In some embodiments, the patient has a tumor. In some embodiments, the tumor is a solid tumor. In some embodiments, the tumor sample is from a primary tumor. In alternative embodiments, the tumor sample is a metastatic lesion. In some embodiments, the patient has a tumor that expresses SEZ6E2. Binding of the immunoconjugate to SEZ6E2-expressing tumor cells through a binding interaction SEZ6E2 can be measured using any assay, such as 122MF - 363628584Attorney Docket No. 22419-20011.40immunohistochemistry or flow cytometry. In some embodiments, binding of antibody to at least 0.2%, at least 0.5%, at least 1%, at least 5%, at least 10%, at least 20%, at least 30%, or at least 50%, of the SEZ6L2-expressing tumor cells in a sample may be used as a selection criterion for determining a patient to be treated with an anti-SEZ6L2 immunoconjugate as described herein.

[0245] An anti-SEZ6L2 antibody immunoconjugate disclosed herein can be used to treat several different cancers. In some embodiments, a cancer patient who can benefit from the treatment of the anti-SEZ6L2 antibody immunoconjugate (e.g., an anti-SEZ6L2 antibodydrug conjugate) has a cancer expressing SEZ6L2.

[0246] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a non- squamous carcinoma. In some embodiments, the cancer is selected from the group consisting of: multiple myeloma, acute myeloid leukemia, diffuse large B-cell lymphoma, hepatocellular carcinoma, small cell lung cancer, non- small cell lung cancer, head and neck squamous cell carcinoma, sarcoma, bladder cancer, cervical cancer, esophageal squamous cell carcinoma, lung squamous cell carcinoma, triple negative breast cancer, skin cutaneous melanoma, colorectal cancer, glioblastoma, ovarian cancer, kidney renal clear cell carcinoma, breast cancer, stomach adenocarcinoma, uterine corpus endometrial carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, esophageal adenocarcinoma, low-grade glioma, prostate adenocarcinoma, neuroblastoma, pancreatic cancer, neuroendocrine cancer (NET), colon adenocarcinoma, non-small cell lung cancer adenocarcinoma, gastroesophageal junction cancer (GEJ), non-small cell lung cancer squamous cell carcinoma, and renal cell carcinoma. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is acute myeloid leukemia. In some embodiments, the cancer is diffuse large B-cell lymphoma. In some embodiments, the cancer is the cancer is hepatocellular carcinoma. In some embodiments, the cancer is small cell lung cancer. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is head and neck squamous cell carcinoma. In some embodiments, the cancer is sarcoma. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is esophageal squamous cell carcinoma. In some embodiments, the cancer is lung squamous cell carcinoma. In some embodiments, the cancer is triple negative breast cancer. In some embodiments, the breast cancer is a HER2 positive, ER positive, and / or PR+ breast cancer. In some embodiments, the breast cancer is a HER2 positive breast cancer. In some embodiments, the breast cancer is a ER positive cancer. In some embodiments, the breast cancer is a PR+ breast cancer. In some embodiments, the breast cancer is a ER positive and 123MF - 363628584Attorney Docket No. 22419-20011.40PR+ breast cancer. In some embodiments, the breast cancer is a HER2 positive, ER positive, and PR+ breast cancer. In some embodiments, the cancer is skin cutaneous melanoma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is kidney renal clear cell carcinoma. In some embodiments, the cancer is stomach adenocarcinoma. In some embodiments, the cancer is uterine corpus endometrial carcinoma. In some embodiments, the cancer is lung adenocarcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is esophageal adenocarcinoma. In some embodiments, the cancer is low-grade glioma. In some embodiments, the cancer is prostate adenocarcinoma. In some embodiments, the cancer is and neuroblastoma. In some embodiments, the cancer is renal cell carcinoma. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is neuroendocrine cancer (NET). In some embodiments, the cancer is colon adenocarcinoma. In some embodiments, the cancer is non-small cell lung cancer adenocarcinoma. In some embodiments, the cancer is gastroesophageal junction (GEJ) cancer. In some embodiments, the cancer is non-small cell lung cancer squamous cell carcinoma.

[0247] In some embodiments, methods of the disclosure comprise administering an anti-SEZ6L2 immunoconjugate disclosed herein, or a variant thereof, as a pharmaceutical composition to a cancer patient in a therapeutically effective amount using a dosing regimen suitable for treatment of the cancer. The composition can be formulated for use in a variety of drug delivery systems. One or more physiologically acceptable excipients or carriers can also be included in the compositions for proper formulation.

[0248] The anti-SEZ6L2 immunoconjugate is provided in a solution suitable for administration to the patient, such as a sterile isotonic aqueous solution for injection. The antibody is dissolved or suspended at a suitable concentration in an acceptable carrier. In some embodiments the carrier is aqueous, e.g., water, saline, phosphate buffered saline, and the like. The compositions may contain auxiliary pharmaceutical substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, and the like.ADMINISTRATION

[0249] The pharmaceutical compositions are administered to a patient in an amount sufficient to cure or at least partially arrest the disease or symptoms of the disease and its124MF - 363628584Attorney Docket No. 22419-20011.40complications. An amount adequate to accomplish this is defined as a “therapeutically effective dose.” A therapeutically effective dose is determined by monitoring a patient’s response to therapy. Typical benchmarks indicative of a therapeutically effective dose includes the amelioration of symptoms of the disease in the patient. Amounts effective for this use will depend upon the severity of the disease and the general state of the patient’s health, including other factors such as age, weight, gender, administration route, and the like Single or multiple administrations of the immunoconjugate may be administered depending on the dosage and frequency as required and tolerated by the patient. In any event, the methods provide a sufficient quantity of SEZ6L2-targeting immunoconjugate to effectively treat the patient.

[0250] An anti-SEZ6L2 immunoconjugate can be administered by any suitable means, including, for example, parenteral, intrapulmonary, and intranasal, administration, as well as local administration, such as intratumor administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0251] The dose of immunoconjugate is chosen to provide effective therapy for the subject.PHARMACEUTICAL COMPOSITIONS

[0252] The present disclosure also features pharmaceutical compositions that contain a therapeutically effective amount of the anti-SEZ6L2 immunoconjugate described herein. The composition can be formulated for use in a variety of drug delivery systems. One or more physiologically acceptable excipients or carriers can also be included in the composition for proper formulation. Suitable formulations for use in the present disclosure are found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa., 17th ed., 1985. For a brief review of methods for drug delivery, see, e.g., Langer (Science 249:1527-1533, 1990).

[0253] In some embodiments, a pharmaceutical composition may contain formulation materials for modifying, maintaining or preserving, for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition. In such embodiments, suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine or lysine); antimicrobials; antioxidants (such as ascorbic acid, sodium sulfite or sodium hydrogen-sulfite); buffers (such as borate, bicarbonate, Tris-HCl, citrates, phosphates or other organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediamine tetraacetic acid (EDTA)); complexing agents (such as caffeine,125MF - 363628584Attorney Docket No. 22419-20011.40polyvinylpyrrolidone, beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin); fdlers; monosaccharides; disaccharides; and other carbohydrates (such as glucose, mannose or dextrins); proteins (such as serum albumin, gelatin or immunoglobulins); coloring, flavoring and diluting agents; emulsifying agents; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight polypeptides; salt-forming counterions (such as sodium); preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid or hydrogen peroxide); solvents (such as glycerin, propylene glycol or polyethylene glycol); sugar alcohols (such as mannitol or sorbitol); suspending agents; surfactants or wetting agents (such as pluronics, PEG, sorbitan esters, polysorbates such as polysorbate 20, polysorbate, triton, tromethamine, lecithin, cholesterol, tyloxapal); stability enhancing agents (such as sucrose or sorbitol); tonicity enhancing agents (such as alkali metal halides, preferably sodium or potassium chloride, mannitol sorbitol); delivery vehicles; diluents; excipients and / or pharmaceutical adjuvants (see, Remington’s Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990)).

[0254] In some embodiments, a pharmaceutical composition may contain nanoparticles, e.g., polymeric nanoparticles, liposomes, or micelles.

[0255] In some embodiments, a pharmaceutical composition may contain a sustained- or controlled-delivery formulation. Techniques for formulating sustained- or controlled-delivery means, such as liposome carriers, bio-erodible microparticles or porous beads and depot injections, are also known to those skilled in the art. Sustained-release preparations may include, e.g., porous polymeric microparticles or semipermeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules. Sustained release matrices may include polyesters, hydrogels, polylactides, copolymers of L-glutamic acid and gamma ethyl-L-glutamate, poly (2-hydroxyethyl-methacrylate), ethylene vinyl acetate, or poly-D(-)-3-hydroxybutyric acid. Sustained release compositions may also include liposomes that can be prepared by any of several methods known in the art.

[0256] Pharmaceutical compositions containing an anti-SEZ6L2 immunoconjugate disclosed herein can be presented in a dosage unit form and can be prepared by any suitable method. A pharmaceutical composition should be formulated to be compatible with its intended route of administration. Examples of routes of administration are intravenous (IV), intradermal, inhalation, transdermal, topical, transmucosal, intrathecal and rectal administration.

[0257] Useful formulations can be prepared by methods known in the pharmaceutical art. For example, see Remington’s Pharmaceutical Sciences, 18th ed. (Mack Publishing Company,126MF - 363628584Attorney Docket No. 22419-20011.401990). Formulation components suitable for parenteral administration include a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ED TA; buffers such as acetates, citrates or phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose.

[0258] For intravenous or subcutaneous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). The carrier should be stable under the conditions of manufacture and storage, and should be preserved against microorganisms. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol), and suitable mixtures thereof.

[0259] An intravenous or subcutaneous drug delivery formulation may be contained in a syringe, pen, or bag. In some embodiments, the bag is connected to a channel comprising a tube and / or a needle. In some embodiments, the formulation is a lyophilized formulation or a liquid formulation.

[0260] These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as-is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.

[0261] A polyol, which acts as a tonicifier and may stabilize the anti-SEZ6L2 immunoconjugate, may also be included in the formulation. The polyol is added to the formulation in an amount which may vary with respect to the desired isotonicity of the formulation. In some embodiments, the aqueous formulation is isotonic. The amount of polyol added may also be altered with respect to the molecular weight of the polyol. For example, a lower amount of a monosaccharide (e.g., mannitol) is added, compared to a disaccharide (such as trehalose). In some embodiments, the polyol which is used in the formulation as a tonicity agent is mannitol.

[0262] A detergent or surfactant may also be added to the formulation. Exemplary detergents include nonionic detergents such as polysorbates (e.g., polysorbates 20, 80 etc.) or poloxamers (e.g., poloxamer 188). The amount of detergent added is such that it reduces aggregation of the formulated antibody and / or minimizes the formation of particulates in the formulation and / or reduces adsorption. In some embodiments, the formulation may include a surfactant which is a polysorbate. In some embodiments, the formulation may contain the 127MF - 363628584Attorney Docket No. 22419-20011.40detergent polysorbate 80 or Tween 80. Tween 80 is a term used to describe polyoxyethylene (20) sorbitan monooleate (see Fiedler, Lexikon der Hifsstoffe, Editio Cantor Verlag Aulendorf, 4th edi., 1996).

[0263] In embodiments, the protein product of the present disclosure is formulated as a liquid formulation. In some embodiments, the liquid formulation is prepared in combination with a sugar at stabilizing levels. In some embodiments, the liquid formulation is prepared in an aqueous carrier. In some embodiments, a stabilizer is added in an amount no greater than that which may result in a viscosity undesirable or unsuitable for intravenous administration. In some embodiments, the sugar is disaccharides, e.g., sucrose. In some embodiments, the liquid formulation may also include one or more of a buffering agent, a surfactant, and a preservative.

[0264] In some embodiments, the pH of the liquid formulation is set by addition of a pharmaceutically acceptable acid and / or base. In some embodiments, the pharmaceutically acceptable acid is hydrochloric acid. In some embodiments, the base is sodium hydroxide.

[0265] The aqueous carrier of interest herein is one which is pharmaceutically acceptable (safe and non-toxic for administration to a human) and is useful for the preparation of a liquid formulation. Illustrative carriers include sterile water for injection (SWFI), bacteriostatic water for injection (BWFI), a pH buffered solution (e.g., phosphate-buffered saline), sterile saline solution, Ringer's solution or dextrose solution.

[0266] A preservative may be optionally added to the formulations herein to reduce bacterial action. The addition of a preservative may, for example, facilitate the production of a multiuse (multiple-dose) formulation.

[0267] The anti-SEZ6E2 immunoconjugate may be lyophilized to produce a lyophilized formulation including the proteins and a lyoprotectant. The lyoprotectant may be sugar, e.g., disaccharides. In some embodiments, the lyoprotectant is sucrose or maltose. The lyophilized formulation may also include one or more of a buffering agent, a surfactant, a bulking agent, and / or a preservative.

[0268] The amount of sucrose or maltose useful for stabilization of the lyophilized drug product may be in a weight ratio of at least 1:2 protein to sucrose or maltose. In some embodiments, the protein to sucrose or maltose weight ratio is of from 1:2 to 1:5. In some embodiments, the pH of the formulation, prior to lyophilization, is set by addition of a pharmaceutically acceptable acid and / or base. In some embodiments, the pharmaceutically acceptable acid is hydrochloric acid. In some embodiments, the pharmaceutically acceptable base is sodium hydroxide.128MF - 363628584Attorney Docket No. 22419-20011.40

[0269] A patient’s dose can be tailored to the approximate body weight or surface area of the patient. Other factors in determining the appropriate dosage can include the disease or condition to be treated or prevented, the severity of the disease, the route of administration, and the age, sex, and medical condition of the patient. Further refinement of the calculations necessary to determine the appropriate dosage for treatment is routinely made by those skilled in the art, especially in light of the dosage information and assays disclosed herein. The dosage can also be determined through the use of known assays for determining dosages used in conjunction with appropriate dose-response data. An individual patient's dosage can be adjusted as the progress of the disease is monitored. Blood levels of the targetable construct or complex in a patient can be measured to see if the dosage needs to be adjusted to reach or maintain an effective concentration. Pharmacogenomics may be used to determine which targetable constructs and / or complexes, and dosages thereof, are most likely to be effective for a given individual (Schmitz et al., Clinica Chimica Acta 308: 43-53, 2001; Steimer et al., Clinica Chimica Acta 308: 33-41, 2001).

[0270] In some embodiments, the antibody may be stored at 10 mg / ml or 20 mg / ml in a sterile isotonic aqueous solution. The solution can comprise agents such as buffering agents and stabilizing agents. For example, in some embodiments, a buffering agent such as histidine is included to maintain a formulation pH of about 5.5. Additional reagents such as sucrose or alternatives can be added to prevent aggregation and fragmentation in solution and during freezing and thawing. Agents such as polysorbate 80 or an alternative can be included to lower surface tension and stabilizes the antibody against agitation-induced denaturation and air-liquid and ice-liquid surface denaturation. In some embodiments, the solution for injection is stored at 4°C and is diluted in either 100 ml or 200 ml 0.9% sodium chloride for injection prior to administration to the patient.EXEMPLARY EMBODIMENTS

[0271] The following exemplary embodiments are provided herein:

[0272] Embodiment 1. An immunoconjugate having Formula (I),Ab-[S-L1-L2-L3-L4-L5-L6-L7-D]n(I)wherein:Ab is an antibody or an antigen-binding fragment thereof that binds Seizure Related 6 Homolog Like 2 (SEZ6L2), comprising:a heavy chain variable region (VH) comprising (i) a complementarity determining region (CDR) 1 having an amino acid sequence according to any one of SEQ ID NOs: 1-12;129MF - 363628584Attorney Docket No. 22419-20011.40(ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 13-24; and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 25-36; anda light chain variable region (VL) comprising (i) a complementarity determining region (CDR) 1 having an amino acid sequence according to any one of SEQ ID NOs: 37-48; (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 49-60; and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 61-72; L1isL2is absent,Z1and Z2are each individually hydrogen, halogen, NO2, -O-(Ci-Ce alkyl), or Ci-Ce alkyl;L3is -(CH2)n1-C(=O)- or -(CH2CH2O)n1-(CH2)n1C(=O)-;L4is a tetrapeptide residue;L5is absent or -[NH(CH2)n2]n3n2is an integer of 0 to 6;n3is an integer from 0 to 2;L6is absent,D is a drug moiety; and130MF - 363628584Attorney Docket No. 22419-20011.40n is an integer from 1 to 10.

[0273] Embodiment 2. The immunoconjugate of embodiment 1, wherein D in Formula (I) is a drug moiety of Formula (II) having the structure:(II)wherein:R1and R2are each individually selected from the group consisting of hydrogen, halogen, -CN, -OR5, -NR5R6, a substituted or an unsubstituted Ci-Ce alkyl, a substituted or unsubstituted Ci-Ce haloalkyl, a substituted or unsubstituted -O-(Ci-Ce alkyl), a substituted or unsubstituted -O-(Ci-Ce haloalkyl), and -[(CY2)pO(CY2)q]tCY3, or a substituted or unsubstituted -O-(CR5R6)m-O- such that R1and R2are taken together form a ring;R3is a hydrogen or a substituted or an unsubstituted Ci-Ce alkyl, a substituted or an unsubstituted Ci-Ce haloalkyl, or — [(CY2)PO(CY2)q]tCY3;R4is hydrogen, a substituted or an unsubstituted — (Ci-Ce alkyl)-X2, a substituted or an unsubstituted — (Ci-Ce haloalkyl)-X2, a substituted or an unsubstituted — (Ci-Ce alkenyl)-X2, a substituted or an unsubstituted — (Ci-Cehaloalkenylj-X2, a substituted or an unsubstituted — (Ci-C6alkynyl)-X2, or a substituted or an unsubstituted — (Ci-Ce haloalkynyl)-X2;X1is — O—, — S(O)W—, — NH—, — O— (C=O)—, — NH— (C=O)—, — NH— (C=O)— O—, — NH— (C=O)— NH—, or — NH— S(O)W—;X2is —OR9, —SR9, or — NHR9;R5and R6are each individually hydrogen, halogen, a substituted or an unsubstituted Ci-Ce alkyl, a substituted or an unsubstituted Ci-Ce haloalkyl, or — [(CY2)pO(CY2)q]tCY3;m is 1 or 2;n4and n5are each individually 0, 1 or 2, with the proviso that n4and n5are not both 0; each w is 0, 1 or 2;131MF - 363628584Attorney Docket No. 22419-20011.40each Y is individually H or halogen;each p is individually 1, 2, 3, 4, 5, or 6;each q is individually 0, 1, 2, 3, 4, 5, or 6;each t is individually 1, 2, 3, 4, 5, or 6;R7is H, —COR8, — CO2R8, — (CO)— NHR8, L4, L5, L6, or L7;R8is a substituted or an unsubstituted Ci-Ce alkyl-X3, a substituted or an unsubstituted Ci-Ce haloalkyl-X3, or — [(CY2)pO(CY2)q]tCY2— X3;R9is H, — COR8, — CO2R8, — (CO) — NHR8, L4, L5, L6, or L7, with the proviso that exactly one of R7and R9is L4, L5, L6, or L7; andeach X3is individually — H, — OH, — SH, or — NH2.

[0274] Embodiment 3. The immunoconjugate of embodiment 2, wherein D in Formula (I) is a drug moiety of Formula (II) having the structure:(II)wherein:R1and R2are each individually selected from the group consisting of hydrogen, halogen, -OR5, an unsubstituted Ci-Ce alkyl, an unsubstituted Ci-Ce haloalkyl and an unsubstituted -O-(Ci-Ce alkyl), or an unsubstituted -O-(CR5R6)m-O- such that R1and R2are taken together form a ring;R3is a hydrogen or an unsubstituted Ci-Ce alkyl;R4is (Ci-C6alkyl)-X2;X1is — O—;X2is —OR9;R5and R6are each individually hydrogen;m is 1;132MF - 363628584Attorney Docket No. 22419-20011.40n4is 1 or 2;n5is 0;R7is H; andR9is L4, L5, L6, or L7;

[0275] Embodiment 4. The immunoconjugate of embodiment 2, wherein n4is 1.

[0276] Embodiment 5. The immunoconjugate of embodiment 2, wherein n4is 2.

[0277] Embodiment 6. The immunoconjugate of embodiment 1, wherein D in Formula (I) is a drug moiety of Formula (II) having the structure:wherein:R1is methyl;R2is fluoro;R3is hydrogen;R4is an unsubstituted -(C2 alkyl)-X2; andn4is 2.

[0278] Embodiment 7. The immunoconjugate of embodiment 1, wherein:L2is absent;n1is the integer 5;L4is gly-gly-phe-gly;L5is -[NH(CH2)n2]n3-;n2is the integer 1;n3is the integer 1; andL7is absent.

[0279] Embodiment 8. The immunoconjugate of embodiment 2, wherein D in Formula (I) is a drug moiety of Formula (II) having the structure:133MF - 363628584Attorney Docket No. 22419-20011.40R1is methyl;R2is fluoro;R3is hydrogen;R4is an unsubstituted -(C2 alkyl)-X2; andn4is 2.

[0280] Embodiment 9. The immunoconjugate of embodiment 2, wherein D in Formula (I) is represented by:wherein R9is L4, L5, L6, or L7.

[0281] Embodiment 10. The immunoconjugate of embodiment 2, wherein D in Formula (I) is represented by:134MF - 363628584Attorney Docket No. 22419-20011.40wherein R9is L4, L5, L6, or L7.

[0282] Embodiment 11. The immunoconjugate of embodiment 2, wherein D in Formula (I) is represented by:OH Owherein R9is L4, L5, L6, or L7.

[0283] Embodiment 12. The immunoconjugate of embodiment 1, wherein Formula (I) is:

[0284] Embodiment 13. The immunoconjugate of embodiment 1, wherein Formula (I) is:135MF - 363628584Attorney Docket No. 22419-20011.40

[0285] Embodiment 14. The immunoconjugate of embodiment 1, wherein Formula (I) is:136MF - 363628584Attorney Docket No. 22419-20011.40

[0286] Embodiment 15. The immunoconjugate of embodiment 1, wherein Formula (I) is represented by:

[0287] Embodiment 16. The immunoconjugate of embodiment 1, wherein Formula (I) is represented by:137MF - 363628584Attorney Docket No. 22419-20011.40

[0288] Embodiment 17. An immunoconjugate having Formula (I),Ab-[S-L1-L2-L3-L4-L5-L6-L7-D]n(I)wherein:Ab is an antibody or an antigen-binding fragment thereof that binds SEZ6E2, comprising: a heavy chain variable region (VH) comprising (i) a complementarity determining region (CDR) 1 having an amino acid sequence according to any one of SEQ ID NOs: 1-12; (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 13-24; and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 25-36; anda light chain variable region (VL) comprising (i) a complementarity determining region (CDR) 1 having an amino acid sequence according to any one of SEQ ID NOs: 37-48; (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 49-60; and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 61-72; L1isL2is absent,138MF - 363628584Attorney Docket No. 22419-20011.40Z1and Z2are each individually hydrogen, halogen, NO2, -O-(Ci-Ce alkyl), or Ci-Ce alkyl;L3is -(CH2)n1-C(=O)- or -(CH2CH2O)n1-(CH2)n1C(=O)-;L4is a tetrapeptide residue;L5is absent or -[NH(CH2)n2]n3n2is an integer of 0 to 6;n3is an integer from 0 to 2;L6is absent,n is an integer from 1 to 10.

[0289] Embodiment 18. The immunoconjugate of any one of embodiments 1-17, wherein n is an integer from 4 to 8.139MF - 363628584Attorney Docket No. 22419-20011.40

[0290] Embodiment 19. The immunoconjugate of any one of embodiments 1-18, wherein the VH comprises an amino acid sequence having at least 80% sequence identity to any one of SEQ ID NOs: 73-84.

[0291] Embodiment 20. The immunoconjugate of any one of embodiments 1-19, wherein the VL comprises an amino acid sequence having at least 80% sequence identity to any one of SEQ ID NOs: 85-96.

[0292] Embodiment 21. The immunoconjugate of any one of embodiments 1-20, wherein the VH comprises an amino acid sequence having at least 80% sequence identity to any one of SEQ ID NOs: 73-84 and the VL comprises an amino acid sequence having at least 80% sequence identity to any one of SEQ ID NOs: 85-96.

[0293] Embodiment 22. The immunoconjugate of any one of embodiments 1-21, wherein the antibody or antibody fragment comprises:i) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 1, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 13, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 25; and a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 37, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 49, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 61; ii) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 2, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 14, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 26; and a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 38, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 50, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 62; iii) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 3, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 15, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 27; and a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 39, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 51, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 63;iv) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 4, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 16, and (iii) a CDR3 having an amino acid sequence according to SEQ ID 140MF - 363628584Attorney Docket No. 22419-20011.40NO: 28; and a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 40, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 52, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 64;v) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 5, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 17, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 29; and a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 41, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 53, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 65; vi) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 6, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 18, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 30; and a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 42, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 54, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 66;vii) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 7, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 19, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 31; and a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 43, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 55, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 67;viii) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 8, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 20, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 32; and a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 44, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 56, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 68;ix) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 9, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 21, and (iii) a CDR3 having an amino acid sequence according to SEQ ID 141MF - 363628584Attorney Docket No. 22419-20011.40NO: 33; and a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 45, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 57, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 69;x) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 10, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 22, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 34; and a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 46, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 58, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 70; xi) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 11, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 23, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 35; and a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 47, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 59, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 71; orxii) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 12, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 24, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 36; and a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 48, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 60, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 72.

[0294] Embodiment 23. The immunoconjugate of any one of embodiments 1-22, wherein the antibody comprises a Fc domain comprising one or more modifications that reduces binding to an Fc receptor, reduces binding to complement component Cl q, or both binding to an Fc receptor and reduces binding to complement component Clq.

[0295] Embodiment 24. The immunoconjugate of any one of embodiments 1-23, wherein the antibody comprises a Fc domain comprising amino acid modifications L234A / L235A / P329A (LALAPA), L234A / L235A / P329S (LALAPS), or L234A / L235A / P329G (LALAPG).

[0296] Embodiment 25. The immunoconjugate of any one of embodiments 1-24, wherein the antibody or antibody fragment binds to human SEZ6L2 with an affinity of 10’7M to 1010M.142MF - 363628584Attorney Docket No. 22419-20011.40

[0297] Embodiment 26. The immunoconjugate of any one of embodiments 1-25, wherein the antibody or antigen-binding fragment thereof does not bind to SEZ6 or SEZ6L.

[0298] Embodiment 27. A polynucleotide encoding the antibody or antigen-binding fragment thereof of any one of embodiments 1-26.

[0299] Embodiment 28. An expression vector comprising the polynucleotide of embodiment 27.

[0300] Embodiment 29. A cell comprising the expression vector of embodiment 28.

[0301] Embodiment 30. A cell capable of producing the immunoconjugate of any one of embodiments 1-26.

[0302] Embodiment 31. A pharmaceutical composition comprising an immunoconjugate of any one of embodiments 1-26, and a pharmaceutically acceptable excipient, salt, carrier, or diluent.

[0303] Embodiment 32. The pharmaceutical composition of embodiment 31 for use in treating cancer in a subject.

[0304] Embodiment 33. A method of treating cancer compromising administering to a subject in need thereof, a therapeutically effective amount of the immunoconjugate of any one of embodiments 1-26.

[0305] Embodiment 34. The method of embodiment 33, further comprising administering an additional anti-cancer therapy selected from surgery, chemotherapy, radiotherapy, and immunotherapy.

[0306] Embodiment 35. The method of embodiment 33, further comprising administering to the subject an immune modulator, activated lymphocyte cell, kinase inhibitor, or a chemotherapeutic agent.

[0307] Embodiment 36. The method of embodiment 33, wherein the cancer is multiple myeloma, acute myeloid leukemia, diffuse large B-cell lymphoma, hepatocellular carcinoma, small cell lung cancer, non- small cell lung cancer, head and neck squamous cell carcinoma, sarcoma, bladder cancer, cervical cancer, esophageal squamous cell carcinoma, lung squamous cell carcinoma, triple negative breast cancer, skin cutaneous melanoma, colorectal cancer, glioblastoma, ovarian cancer, kidney renal clear cell carcinoma, breast cancer, stomach adenocarcinoma, uterine corpus endometrial carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, esophageal adenocarcinoma, low-grade glioma, prostate adenocarcinoma, pancreatic cancer, neuroendocrine cancer, colon adenocarcinoma, non- small cell lung cancer adenocarcinoma, gastroesophageal junction cancer, non-small cell lung cancer squamous cell carcinoma, and neuroblastoma.143MF - 363628584Attorney Docket No. 22419-20011.40

[0308] Embodiment 37. A method of diagnosing or prognosing cancer in a subject, the method comprises determining the expression level of SEZ6L2 in a biological sample using the immunoconjugate of any one of embodiments 1-26.

[0309] Embodiment 38. The use of an effective amount of the immunoconjugate of any one of embodiments 1-26 for treating cancer in a subject in need thereof.

[0310] Embodiment 39. The use of embodiment 36, wherein the cancer is multiple myeloma, acute myeloid leukemia, diffuse large B-cell lymphoma, hepatocellular carcinoma, small cell lung cancer, non- small cell lung cancer, head and neck squamous cell carcinoma, sarcoma, bladder cancer, cervical cancer, esophageal squamous cell carcinoma, lung squamous cell carcinoma, triple negative breast cancer, skin cutaneous melanoma, colorectal cancer, glioblastoma, ovarian cancer, kidney renal clear cell carcinoma, breast cancer, stomach adenocarcinoma, uterine corpus endometrial carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, esophageal adenocarcinoma, low-grade glioma, prostate adenocarcinoma, pancreatic cancer, neuroendocrine cancer, colon adenocarcinoma, non-small cell lung cancer adenocarcinoma, gastroesophageal junction cancer, non-small cell lung cancer squamous cell carcinoma, and neuroblastoma.

[0311] Embodiment 40. A kit comprising the immunoconjugate of any one of embodiments 1-26 and instructions for use.EXAMPLES

[0312] The disclosure now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiment of the present disclosure, and is not intended to limit the disclosure.EXAMPLE 1. Generation of anti-SEZ6L2 antibodies

[0313] This Example describes the process for generating and characterizing anti-SEZ6L2 antibodies as described herein.

[0314] Human anti-SEZ6L2 antibodies were generated in a CHO expression system.Transiently transfected cell supernatants were harvested on day 7 via centrifugation and filtration. Expression titer was measured by bio-layer interferometry (BLI) using proA sensors. Antibodies were purified on MabSelect Sure resin using typical protein A wash and elution conditions. Purified antibodies were further polished by size-exclusion chromatography (SEC) over Superdex 200 resin at <2g scale, and by cation exchange (CEX) over Poros XS resin at >2g scale. Protein quality and mass accuracy were ensured by144MF - 363628584Attorney Docket No. 22419-20011.40analytical SEC-HPLC and mass spectrometry (MS), where final purity was >98% by analytical SEC-HPLC.

[0315] The panel of 12 antibodies was produced in hlgGlk-LALAPG (L234A / L235A / P329G) backbone. Expression titers ranged from 939.88 mg / Lto 2601.94 mg / mL, demonstrating that the antibodies could be efficiently produced in CHO cells.Additionally, Antibody 1, Antibody 2, and Antibody 3 were produced in hlgGlk-LALAPA (L234A / L235A / P329A) backbone, with expression titers ranging from 2191.29 mg / L to 2252.15 mg / L. After first step protein A purification, most antibodies had low aggregation, with %monomer ranging from 66.74% to 100%. After preparative SEC or CEX, the final %monomer for all antibodies was >99%, demonstrating that the antibodies could be purified to high purity for subsequent assays. Titers and SEC %monomer are summarized in Table El.Table El. Titers and SEC %monomerMolecule name Titer (mg / L) % monomer (proA) % monomer (final) Antibody 1 -hlgGlk-LALAPG 2410.72 98.07 100.00Antibody 10-hIgGlk-LALAPG 939.88 89.44 100.00Antibody 11 -hlgGlk-LALAPG 1944.27 86.96 100.00Antibody 12-hIgGlk-LALAPG 1708.55 93.92 100.00Antibody 2-hIgGlk-LALAPG 2214.74 98.79 99.85Antibody 4-hIgGlk-LALAPG 1217.79 66.74 99.56Antibody 8-hIgGlk-LALAPG 1247.13 81.32 99.84Antibody 9-hIgGlk-LALAPG 2601.94 89.61 100.00Antibody 7-hIgGlk-LALAPG 1988.68 100.00 100.00Antibody 6-hIgGlk-LALAPG 2342.63 91.64 100.00Antibody 3-hIgGlk-LALAPG 1973.11 96.46 100.00Antibody 5 -hlgGlk-LALAPG 2528.33 96.32 100.00Antibody 1 -hlgGlk-LALAPA 2195.14 99.69 99.72Antibody 2-hIgGlk-LALAPA 2191.29 98.73 99.21Antibody 3-hIgGlk-LALAPA 2252.15 95.54 99.56EXAMPLE 2. Specificity and binding affinity of anti-SEZ6L2 antibodies

[0316] The kinetic association constant (ka), kinetic dissociation constant (kdis), and binding affinity (KD) for each antibody were determined using bio-layer interferometry (BLI) (Table E2) on an Octet RED 384 instrument. All BLI steps were performed in assay buffer containing phosphate-buffered saline (PBS) pH 7.4 with 1% BSA and 0.05% Tween 20. Antibodies were loaded to AHC sensors for 150 seconds at 50 nM followed by a 30-second baseline step. 1:2 serial dilutions of antigen protein (starting from 200 nM) were associated for 180 seconds followed by a 600-second dissociation step. Regeneration was achieved with five rounds of 10 mM glycine pH 1.5. Fitting was performed on the Octet Analysis software 145MF - 363628584Attorney Docket No. 22419-20011.40using global fitting to a 1: 1 binding model. Purified recombinant antigen was purchased from Kactus (human SEZ6L2, SEZ-HM1L2; mouse SEZ6L2, SEZ-MM1L2; human SEZ6, SEZ-HM106) or R& D Biosystems (human SEZ6L, 5598-S6-050).Table E2. Specificity and binding affinityAntibody human SEZ6L2 mouse S EZ6L2Loading Response KD ka kdis Loading Response KD (M) ka kdis (1 / s)(M) (1 / Ms) (1 / s) (1 / Ms) Antibody 1.44 0.3895 6.780 2.302 1.561 1.11 0.3352 6.278E- 2.221E05 1.394E- 1 E-09 E05 E-03 09 03 Antibody 1.34 0.1491 5.464 1.599 8.739 1.10 0.1262 6.669E- 1.438E05 9.588E- 11 E-08 E05 E-03 08 03 Antibody 1.29 0.1496 2.873 2.595 7.455 1.08 0.1357 3.191E- 3.112E05 9.933E- 12 E-08 E05 E-03 08 03 Antibody 1.41 0.5093 1.023 1.508 1.542 1.08 0.4140 1.419E- 1.770E05 2.512E-2 E-09 E05 E-04 09 04 Antibody 1.56 0.4754 8.628 1.994 1.721 1.23 0.3996 5.278E- 2.305E05 1.217E-4 E-09 E05 E-03 09 03 Antibody 1.23 0.1688 4.615 2.655 1.225 1.03 0.1510 4.080E- 3.019E05 1.232E-8 E-08 E05 E-02 08 02 Antibody 1.18 0.2591 4.800 3.991 1.916 0.98 0.2209 4.838E- 3.987E05 1.929E-9 E-08 E05 E-02 08 02 Antibody 1.15 0.4339 5.240 1.546 8.103 0.85 0.3685 4.426E- 1.973E05 8.733E-7 E-09 E05 E-04 09 04 Antibody 1.63 0.3912 2.588 1.941 5.024 1.23 0.0856 n.d. n.d. n.d. 6 E-08 E05 E-03Antibody 1.32 0.5841 1.719 3.153 5.420 0.99 0.4589 1.435E- 3.738E05 5.363E-3 E-08 E05 E-03 08 03 Antibody 1.22 0.4590 8.986 1.115 1.002 0.90 0.3804 7.177E- 1.302E05 9.347E-5 E-09 E05 E-03 09 04 Antibody human SEZ6 human SEZ6LLoading Response KD ka kdis Loading Response KD (M) ka kdis (1 / s)(M) (1 / Ms) (1 / s) (1 / Ms) Antibody 0.99 0.0125 n.d. n.d. n.d. 0.89 0.0086 n.d. n.d. n.d. 1Antibody 0.98 0.0198 n.d. n.d. n.d. 0.89 0.0206 n.d. n.d. n.d. 11Antibody 0.96 0.0205 n.d. n.d. n.d. 0.88 0.0271 n.d. n.d. n.d. 12Antibody 0.95 0.0192 n.d. n.d. n.d. 0.86 0.0184 n.d. n.d. n.d. 2Antibody 1.10 0.0209 n.d. n.d. n.d. 0.98 0.0240 n.d. n.d. n.d. 4Antibody 0.93 0.0079 n.d. n.d. n.d. 0.84 0.0241 n.d. n.d. n.d. 8Antibody 0.88 0.0144 n.d. n.d. n.d. 0.80 0.0218 n.d. n.d. n.d. 9Antibody 0.76 0.0253 n.d. n.d. n.d. 0.70 0.0360 n.d. n.d. n.d. 7Antibody 1.06 0.0238 n.d. n.d. n.d. 0.94 0.0287 n.d. n.d. n.d.6146MF - 363628584Attorney Docket No. 22419-20011.40Antibody 0.86 0.0180 n.d. n.d. n.d. 0.76 0.0165 n.d. n.d. n.d.3Antibody 0.79 0.0184 n.d. n.d. n.d. 0.70 0.0209 n.d. n.d. n.d.5

[0317] The affinity of Antibody 1 for human SEZ6L2, cynomolgus SEZ6L2, mouse SEZ6L2, and rat SEZ6L2 was tested. As shown in Table E3, Antibody 1 had comparable affinity for human SEZ6L2, cynomolgus SEZ6L2, mouse SEZ6L2, and rat SEZ6L2.Table E3: Antibody 1 AffinityAntigen KD (nM)Human SEZ6L2 7.6Cynomolgus SEZ6L2 7.6Mouse SEZ6L2 6.4Rat SEZ6L2 7.3

[0318] The results of the BLI assay demonstrate that all of the antibodies bound human SEZ6L2, but not human SEZ6 or human SEZ6L. Thus, the antibodies are highly specific for SEZ6L2 with no binding to related proteins. The affinities for human SEZ6L2 ranged from 1.0 nM for Antibody 2 to 55 nM for Antibody 11. Most of the antibodies bound to mouse SEZ6L2 with similar affinity as human SEZ6L2, but Antibody 6 had low binding to mouse SEZ6L2 which was not quantifiable.

[0319] In addition to BLI, some antibodies were evaluated in the Retrogenix Cell Microarray Technology specificity assay. Purified antibodies were sent to Charles River Laboratory for evaluation using the Retrogenix platform technology which includes a library of 6111 proteins expressed in HEK293 cells. Antibody 1, Antibody 2, and Antibody 3 bound specifically to SEZ6L2 (both after fixation and in absence of fixation) with no other specific interactions identified. Thus, these antibodies are highly specific for the targeted SEZ6L2 with no off-target binding identified.EXAMPLE 3: Stability of anti-SEZ6L2 antibodies and corresponding anti-SEZ6L2 ADCs

[0320] To evaluate the stability of anti-SEZ6L2 antibodies at high concentrations which could be used during manufacturing, anti-SEZ6L2 antibodies were concentrated to 20 mg / mL (Concentration 1) and 50 mg / mL (Concentration 2) and analyzed by SEC. Antibody 1-147MF - 363628584Attorney Docket No. 22419-20011.40hlgGlk-LALAPA, Antibody 2-hIgGlk-LALAPA, and Antibody 3-hIgGlk-LALAPA showed good purity at these high concentrations (Table E4), demonstrating that these antibodies are manufacturable.Table E4. Stability dataConcentration ConcentrationAntibody % monomer 1 % monomer 21 (mg / ml) 2 (mg / ml)Antibody 1- hlgGlk- 24.34 53.75 99.93 99.92 LALAPAAntibody 2- hlgGlk- 23.37 53.54 99.59 99.58 LALAPAAntibody 3- hlgGlk- 23.48 53.23 97.82 97.03LALAPA

[0321] Anti-SEZ6L2 ADCs comprising Antibody 1 -hlgGlk-LALAPA (an anti-SEZ6L2 antibody comprising a VH comprising an amino acid sequence according to SEQ ID NO: 73, and a VL comprising an amino acid sequence according to SEQ ID NO: 85, and an IgGl Fc with LALAPA substitutions) and Antibody 2-hIgGlk-LALAPA (an anti-SEZ6L2 antibody comprising a VH comprising an amino acid sequence according to SEQ ID NO: 74, and a VL comprising an amino acid sequence according to SEQ ID NO: 86, and an IgGl Fc with LALAPA substitutions) and a payload-linker comprising Formula (II) were generated (DAR 8), which are referred to herein as “ADC 1” and “ADC 2,” respectively. It should be appreciated that ADC 1 and ADC 2 are exemplary anti-SEZ6L2 ADCs, and that other anti-SEZ6L2 ADCs comprising different anti-SEZ6L2 antibodies (such as those provided herein), different linkers (such as those provided herein), and payloads (such as those provided herein), also fall within the scope of the present disclosure. The structure of the payloadlinker portion of ADC 1 and ADC 2 is provided below, wherein the payload-linker is conjugated to the antibody via a cysteine of the anti-SEZL62 antibody:F148MF - 363628584Attorney Docket No. 22419-20011.40

[0322] Thermal stability of anti-SEZ6L2 antibodies (Antibody 1-hIgGlk-LALAPA and Antibody 2-hIgGlk-LALAPA) and corresponding anti-SEZ6L2 ADCs (ADC 1 and ADC 2) was assessed by differential scanning calorimetry on a MicroCai DSC (FIG. 1).

[0323] Anti-SEZ6L2 antibodies were heated to 100 °C, and the observed peaks in specific heat capacity (Cp) report on protein unfolding. All anti-SEZ6L2 antibodies had an onset unfolding temperature around 60 °C, demonstrating that they should be stable at manufacturing and biological conditions below this temperature. Antibody 1-hIgGlk-LALAPA and Antibody 2-hIgGlk-LALAPA were deconvoluted to have three melting temperatures (Tms), while Antibody 3-hIgGlk-LALAPA (an anti-SEZ6L2 antibody comprising a VH comprising an amino acid sequence according to SEQ ID NO: 75, and a VL comprising an amino acid sequence according to SEQ ID NO: 87, and an IgGl Fc with LALAPA substitutions) had four Tms (Table E5). The observed Tms are in line with those of other clinical antibodies as described in Jain T. et al., “Biophysical properties of the clinical-stage antibody landscape,” PNAS 114(5): 2017 and measured by differential scanning fluorimetry (DSF).Table E5. Tm of antibodiesAntibody Tonset (°C) Tml (°C) Tm2 (°C) Tm3 (°C) Tm4 (°C) Antibody 1-hIgGlk-LALAPA 60.7 67.5 80.4 86.5 n / a Antibody 2-hIgGlk-LALAPA 59.9 67.8 76.9 84.7 n / a Antibody 3-hIgGlk-LALAPA 60.2 67.8 73.2 79.0 85.0

[0324] To test the stability of the anti-SEZ6L2 antibodies (Antibody 1-hIgGlk-LALAPA, Antibody 2-hIgG Ik- LALAPA, and Antibody 3-hIgG Ik- LALAPA)...

Claims

Attorney Docket No. 22419-20011.40CLAIMS1. An immunoconjugate having Formula (I),Ab-[S-L1-L2-L3-L4-L5-L6-L7-D]n(I)wherein:Ab is an antibody or an antigen-binding fragment thereof that binds Seizure Related 6 Homolog Like 2 (SEZ6L2), comprising:a heavy chain variable region (VH) comprising (i) a complementarity determining region (CDR) 1 having an amino acid sequence according to any one of SEQ ID NOs: 1-12; (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 13-24; and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 25-36; anda light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 37-48; (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 49-60; and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 61-72;S is a sulfur atom of a cysteine of the antibody or the antigen-binding fragment thereof;L1isL2is absent,Z1and Z2are each individually hydrogen, halogen, NO2, -O-(Ci-Ce alkyl), or Ci-Ce alkyl;L3is -(CH2)n1-C(=O)- or -(CH2CH2O)n1-(CH2)n1C(=O)-;154MF - 363628584Attorney Docket No. 22419-20011.40each n1is individually an integer from 0 to 10;L4is a tetrapeptide residue;L5is absent or -[NH(CH2)n2]n3- n2is an integer from 0 to 6;n3is an integer from 0 to 2;L6is absent,, wherein G is a beta- glucuronic acid moiety;L7is absent,D is a drug moiety; andn is an integer from 1 to 10.

2. The immunoconjugate of claim 0, wherein the drug moiety is represented by Formula (II) having the structure:155MF - 363628584Attorney Docket No. 22419-20011.40(II)wherein:R1and R2are each individually selected from the group consisting of hydrogen, halogen, -CN, -OR5, -NR5R6, a substituted or an unsubstituted Ci-Ce alkyl, a substituted or unsubstituted Ci-Ce haloalkyl, a substituted or unsubstituted -O-(Ci-Ce alkyl), a substituted or unsubstituted -O-(Ci-Ce haloalkyl), and -[(CY2)pO(CY2)q]tCY3, or a substituted or unsubstituted -O-(CR5R6)m-O- such that R1and R2are taken together form a ring;R3is a hydrogen or a substituted or an unsubstituted Ci-Ce alkyl, a substituted or an unsubstituted Ci-Ce haloalkyl, or — [(CY2)PO(CY2)q]tCY3;R4is hydrogen, a substituted or an unsubstituted — (Ci-Ce alkyl)-X2, a substituted or an unsubstituted — (Ci-Ce haloalkyl)-X2, a substituted or an unsubstituted — (Ci-Ce alkenyl)-X2, a substituted or an unsubstituted — (Ci-C6haloalkenyl)-X2, a substituted or an unsubstituted — (Ci-Ce alkynyl)-X2, or a substituted or an unsubstituted — (Ci-Ce haloalkynyl)-X2;X1is — O—, — S(O)W—, — NH—, — O— (C=O)—, — NH— (C=O)—, — NH— (C=O)— O—, — NH— (C=O)— NH—, or — NH— S(O)W—;X2is —OR9, —SR9, or — NHR9;R5and R6are each individually hydrogen, halogen, a substituted or an unsubstituted Ci-Ce alkyl, a substituted or an unsubstituted Ci-Ce haloalkyl, or — [(CY2)PO(CY2)q]tCY3;m is 1 or 2;156MF - 363628584Attorney Docket No. 22419-20011.40n4and n5are each individually 0, 1 or 2, with the proviso that n4and n5are not both 0; each w is 0, 1 or 2;each Y is individually hydrogen or halogen;each p is individually 1, 2, 3, 4, 5, or 6;each q is individually 0, 1, 2, 3, 4, 5, or 6;each t is individually 1, 2, 3, 4, 5, or 6;R7is hydrogen, —COR8, — CO2R8, — (CO)— NHR8, L4, L5, L6, or L7;R8is a substituted or an unsubstituted Ci-Ce alkyl-X3, a substituted or an unsubstituted Ci-Ce haloalkyl-X3, or — [(CY2)pO(CY2)q]tCY2 — X3;R9is hydrogen, — COR8, — CO2R8, — (CO) — NHR8, L4, L5, L6, or L7, with the proviso that exactly one of R7and R9is L4, L5, L6, or L7; andeach X3is individually — H, — OH, — SH, or — NH2.

3. The immunoconjugate of claim 2, wherein the drug moiety of Formula (II) is represented by:(II)wherein:R1and R2are each individually selected from the group consisting of hydrogen, halogen, -OR5, unsubstituted Ci-Ce alkyl, unsubstituted Ci-Ce haloalkyl and unsubstituted -O-(Ci-Ce alkyl), or unsubstituted -O-(CR5R6)m-O- such that R1and R2are taken together form a ring;157MF - 363628584Attorney Docket No. 22419-20011.40R3is hydrogen or unsubstituted Ci-Ce alkyl;R4is a substituted or an unsubstituted -(Ci-Ce alkyl)-X2;X1is — O—;X2is —OR9;R5and R6are each individually hydrogen;m is 1;n4is 1 or 2;n5is 0;R7is H; andR9is L4, L5, L6, or L7.

4. The immunoconjugate of claim 2 or 3, wherein n4is 1.

5. The immunoconjugate of claim 2 or 3, wherein n4is 2.

6. The immunoconjugate of claim 2 or 3, wherein the drug moiety of Formula (II) is represented by:wherein:R1is methyl;R2is fluoro;R3is hydrogen;R4is a substituted or an unsubstituted -(C2 alkyl)-X2; andn4is 2.158MF - 363628584Attorney Docket No. 22419-20011.

407. The immunoconjugate of any one of claims 1-6, wherein:L2is absent;n1is the integer 2 or 5;L4is gly-gly-phe-gly;L5is -[NH(CH2)n2]n3-;n2is the integer 1;n3is the integer 1; andL7is absent.

8. The immunoconjugate of claim 2, wherein the drug moiety of Formula (II) is represented by:wherein R9is L4, L5, L6, or L7.

9. The immunoconjugate of claim 2, wherein the drug moiety of Formula (II) is represented by:wherein R9is L4, L5, L6, or L7.159MF - 363628584Attorney Docket No. 22419-20011.4010. The immunoconjugate of claim 2, wherein the drug moiety of Formula (II) is represented by:

11. The immunoconjugate of claim 1, wherein Formula (I) is:

12. The immunoconjugate of claim 1, wherein Formula (I) is:160MF - 363628584Attorney Docket No. 22419-20011.40161MF - 363628584Attorney Docket No. 22419-20011.4014. The immunoconjugate of claim 1, wherein Formula (I) is represented by:

15. The immunoconjugate of claim 1, wherein Formula (I) is represented by:162MF - 363628584Attorney Docket No. 22419-20011.4016. An immunoconjugate having Formula (I),Ab-[S-L1-L2-L3-L4-L5-L6-L7-D]n(I)wherein:Ab is an antibody or an antigen-binding fragment thereof that binds Seizure Related 6 Homolog Like 2 (SEZ6L2), comprising:a heavy chain variable region (VH) comprising (i) a complementarity determining region (CDR) 1 having an amino acid sequence according to any one of SEQ ID NOs: 1-12; (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 13-24; and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 25-36; anda light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 37-48; (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 49-60; and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 61-72;163MF - 363628584Attorney Docket No. 22419-20011.40S is a sulfur atom of a cysteine of the antibody or the antigen-binding fragment thereof;L1isL2is absent,z- Z1and Z2are each individually hydrogen, halogen, NO2, -O-(Ci-Ce alkyl), or Ci-Ce alkyl;L3is -(CH2)n1-C(=O)- or -(CH2CH2O)n1-(CH2)n1C(=O)-;each n1is individually an integer from 0 to 10;L4is a tetrapeptide residue;L5is absent or -[NH(CH2)n2]n3- n2is an integer from 0 to 6;n3is an integer from 0 to 2;L6is absent,HN, wherein G is a beta- glucuronic acid moiety;L7is absent,164MF - 363628584Attorney Docket No. 22419-20011.40wherein D has the structure:andn is an integer from 1 to 10.

17. The immunoconjugate of any one of claims 1-16, wherein n is an integer from 4 to 8.

18. The immunoconjugate of any one of claims 1-17, wherein the VH comprises an amino acid sequence having at least about 80% sequence identity to any one of SEQ ID NOs: 73-84.

19. The immunoconjugate of any one of claims 1-18, wherein the VL comprises an amino acid sequence having at least about 80% sequence identity to any one of SEQ ID NOs: 85-96.

20. The immunoconjugate of any one of claims 1-19, wherein the VH comprises an amino acid sequence having at least about 80% sequence identity to any one of SEQ ID NOs: 73-84 and the VL comprises an amino acid sequence having at least about 80% sequence identity to any one of SEQ ID NOs: 85-96.

21. The immunoconjugate of any one of claims 1-20, wherein the antibody or the antigenbinding fragment thereof comprises:165MF - 363628584Attorney Docket No. 22419-20011.40i) a VH comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 1, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 13, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 25; and a VL comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 37, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 49, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 61;ii) a VH comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 2, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 14, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 26; and a VL comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 38, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 50, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 62;iii) a VH comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 3, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 15, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 27; and a VL comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 39, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 51, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 63;iv) a VH comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 4, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 16, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 28; and a VL comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 40, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 52, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 64;v) a VH comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 5, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 17, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 29; and a VL comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 41, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 53, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 65;vi) a VH comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 6, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 18, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 30; and a VL comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 42, (ii) a CDR2 having an 166MF - 363628584Attorney Docket No. 22419-20011.40amino acid sequence according to SEQ ID NO: 54, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 66;vii)a VH comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 7, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 19, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 31; and a VL comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 43, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 55, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 67;viii) a VH comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 8, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 20, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 32; and a VL comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 44, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 56, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 68;ix) a VH comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 9, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 21, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 33; and a VL comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 45, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 57, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 69;x) a VH comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 10, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 22, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 34; and a VL comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 46, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 58, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 70;xi) a VH comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 11, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 23, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 35; and a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 47, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 59, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 71; orxii)a VH comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 12, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 24, and (iii) a 167MF - 363628584Attorney Docket No. 22419-20011.40CDR3 having an amino acid sequence according to SEQ ID NO: 36; and a VL comprising (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 48, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 60, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 72.

22. The immunoconjugate of any one of claims 1-21, wherein the antibody comprises a Fc domain comprising one or more modifications that reduces binding to an Fc receptor, reduces binding to complement component C1q, or reduces binding to an Fc receptor and reduces binding to complement component C1q.

23. The immunoconjugate of any one of claims 1-22, wherein the antibody comprises a Fc domain comprising the amino acid modifications L234A / L235A (LALA), L234A / L235A / P329A (LALAPA), L234A / L235A / P329S (LALAPS), or L234A / L235A / P329G (LALAPG).

24. The immunoconjugate of any one of claims 1-23, wherein the antibody or the antigenbinding fragment thereof binds to human SEZ6L2 with an affinity of 10’7M to 1010M.

25. The immunoconjugate of any one of claims 1-24, wherein the antibody or the antigenbinding fragment thereof does not bind to SEZ6 or SEZ6L.

26. An immunoconjugate having Formula (I),Ab-[S-L1-L2-L3-L4-L5-L6-L7-D]n(I)wherein:Ab is an antibody or an antigen-binding fragment thereof that binds Seizure Related 6 Homolog Like 2 (SEZ6L2), comprising:a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO: 73; anda light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO: 85;S is a sulfur atom of a cysteine of the antibody or the antigen-binding fragment thereof;168MF - 363628584Attorney Docket No. 22419-20011.40L1iS O;L2is absent;L3is -(CH2)n1-C(=O)-;n1is the integer 2;L4is gly-gly-phe-gly;L5is -[NH(CH2)n2]n3-;n2is the integer 1;n3is the integer 1;L6is absent;L7is absent;D has the structure:and n is 8.

27. An immunoconjugate having Formula (I),Ab-[S-L1-L2-L3-L4-L5-L6-L7-D]n(I)wherein:Ab is an antibody or an antigen-binding fragment thereof that binds Seizure Related 6 Homolog Like 2 (SEZ6L2), comprising:a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO: 73; and169MF - 363628584Attorney Docket No. 22419-20011.40a light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO: 85;S is a sulfur atom of a cysteine of the antibody or the antigen-binding fragment thereof;L2is absent;L3is -(CH2)n1-C(=O)-;n1is the integer 5;L4is gly-gly-phe-gly;L5is -[NH(CH2)n2]n3-;n2is the integer 1;n3is the integer 1;L6is absent;L7is absent;D has the structure:and n is 8.

28. A pharmaceutical composition comprising the immunoconjugate of any one of claims 1-27, and a pharmaceutically acceptable excipient, salt, carrier, or diluent.

29. The pharmaceutical composition of claim 28 for use in treating cancer in a subject.170MF - 363628584Attorney Docket No. 22419-20011.4030. A method of treating cancer comprising administering a therapeutically effective amount of the immunoconjugate of any one of claims 1-27 or the pharmaceutical composition of claim 28 to a subject in need thereof.

31. The method of claim 30, further comprising administering an additional anti-cancer therapy selected from the group consisting of surgery, chemotherapy, radiotherapy, and immunotherapy.

32. The method of claim 30 or 31, further comprising administering to the subject an immune-modulator, activated lymphocyte cell, kinase inhibitor, or a chemotherapeutic agent.

33. The method of any one of claims 30-32, wherein the cancer is selected from the group consisting of multiple myeloma, acute myeloid leukemia, diffuse large B-cell lymphoma, hepatocellular carcinoma, small cell lung cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, sarcoma, bladder cancer, cervical cancer, esophageal squamous cell carcinoma, lung squamous cell carcinoma, triple negative breast cancer, skin cutaneous melanoma, colorectal cancer, glioblastoma, ovarian cancer, kidney renal clear cell carcinoma, breast cancer, stomach adenocarcinoma, uterine corpus endometrial carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, esophageal adenocarcinoma, low-grade glioma, prostate adenocarcinoma, pancreatic cancer, neuroendocrine cancer, colon adenocarcinoma, non-small cell lung cancer adenocarcinoma, gastroesophageal junction cancer, non-small cell lung cancer squamous cell carcinoma, and neuroblastoma.

34. A method of diagnosing or prognosing cancer in a subject, the method comprising determining the expression level of SEZ6L2 in a biological sample using the immunoconjugate of any one of claims 1-27.

35. Use of an effective amount of the immunoconjugate of any one of claims 1-27 for treating cancer in a subject in need thereof.

36. The use of claim 35, wherein the cancer is selected from the group consisting of multiple myeloma, acute myeloid leukemia, diffuse large B-cell lymphoma, hepatocellular carcinoma, small cell lung cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, sarcoma, bladder cancer, cervical cancer, esophageal squamous cell carcinoma,171MF - 363628584Attorney Docket No. 22419-20011.40lung squamous cell carcinoma, triple negative breast cancer, skin cutaneous melanoma, colorectal cancer, glioblastoma, ovarian cancer, kidney renal clear cell carcinoma, breast cancer, stomach adenocarcinoma, uterine corpus endometrial carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, esophageal adenocarcinoma, low-grade glioma, prostate adenocarcinoma, pancreatic cancer, neuroendocrine cancer, colon adenocarcinoma, non-small cell lung cancer adenocarcinoma, gastroesophageal junction cancer, non-small cell lung cancer squamous cell carcinoma, and neuroblastoma.

37. A kit comprising the immunoconjugate of any one of claims 1-27 and instructions for use.

38. A composition comprising a plurality of the immunoconjugates of any one of claims 1-27, wherein the average n of the plurality of the immunoconjugates is a number from 1 to 10.172MF - 363628584

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