Anti-DLL3 antibodies and uses thereof

Abstract

The subject matter disclosed herein provides antibodies or antigen-binding fragments thereof that bind to DLL3, and methods of using such antibodies or antigen-binding fragments thereof. In certain embodiments, the DLL3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:60, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:83, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:108, SEQ ID NO:119, SEQ ID NO:126, SEQ ID NO:131, SEQ ID NO:141, SEQ ID NO:147, SEQ ID NO:153, SEQ ID NO:157, SEQ ID NO:163, or SEQ ID NO:172.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 240,216, filed September 2, 2021, the contents of which are incorporated by reference in their entirety and priority is claimed thereto.

[0002] Sequence Listing This application contains a Sequence Listing that was submitted via EFS-Web and is incorporated herein by reference in its entirety. The Sequence Listing, created on August 30, 2022, is named 0727341388.xml and is 212,422 bytes in size.

[0003] 1.Technical Field The presently disclosed subject matter relates to antibodies that bind to DLL3 and methods of using such antibodies. [Background technology]

[0004] 2. Background technology DLL3 is selectively expressed in high-grade lung neuroendocrine tumors (LU-NETs). Lu-NETs encompass a heterogeneous tumor family classified into four histological variants: typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung cancer (SCLC). Increased DLL3 expression was observed in xenograft tumors from patients with SCLC and LCNEC and was also confirmed in primary tumors. See Saunders et al., Sci Translational Medicine (302):302ra136 (2015). Both SCLC and lung LCNEC are high-grade tumors with poor prognosis and a higher incidence in smokers. Similar to SCLC, lung LCNEC exhibits biologically aggressive behavior. The survival curves of lung LCNEC and SCLC overlap at different stages, and the survival rates are lower than those of other NSCLCs. Prognosis is poor even for patients with potentially resectable stage I lung cancer, with 5-year survival rates ranging from 27% to 67%. See Iyoda A. et al., J Thorac Cardiovasc Surg. 138:446-453 (2009). Given the important role of DLL3 in a variety of diseases or disorders, antibodies that recognize DLL3 and methods of using such agents are desirable. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Saunders et al., Sci Translational Medicine(302):302ra136(2015) [Non-patent document 2] Iyoda A. et al., J Thorac Cardiovasc Surg.138:446-453(2009) Summary of the Invention

[0006] 3. Summary of the Invention The presently disclosed subject matter provides antibodies or antigen-binding fragments thereof that specifically bind to DLL3, and methods of using the antibodies or antigen-binding fragments thereof.

[0007] In certain embodiments, the DLL3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:60, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:83, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:108, SEQ ID NO:119, SEQ ID NO:126, SEQ ID NO:131, SEQ ID NO:141, SEQ ID NO:147, SEQ ID NO:153, SEQ ID NO:157, SEQ ID NO:163, or SEQ ID NO:172.

[0008] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:61, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:84, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:109, SEQ ID NO:113, SEQ ID NO:120, SEQ ID NO:127, SEQ ID NO:132, SEQ ID NO:142, SEQ ID NO:148, SEQ ID NO:154, SEQ ID NO:158, SEQ ID NO:164, or SEQ ID NO:173.

[0009] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof (a) comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:60, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:83, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:108, SEQ ID NO:119, SEQ ID NO:126, SEQ ID NO:131, SEQ ID NO:141, SEQ ID NO:147, SEQ ID NO:153, SEQ ID NO:157, SEQ ID NO:163, or SEQ ID NO:172. and (b) a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:61, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:84, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:109, SEQ ID NO:113, SEQ ID NO:120, SEQ ID NO:127, SEQ ID NO:132, SEQ ID NO:142, SEQ ID NO:148, SEQ ID NO:154, SEQ ID NO:158, SEQ ID NO:164, or SEQ ID NO:173.

[0010] In certain embodiments, the heavy chain variable region and the light chain variable region of the anti-DLL3 antibody or antigen-binding fragment thereof are (a) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:7, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:8; (b) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 17, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 18; (c) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:24, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:25; (d) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 34, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 35; (e) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 42, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 43; (f) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 52, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 53; (g) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 60, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 61; (h) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 66, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 67; (i) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 76, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 77; (j) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 83, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 84; (k) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 92, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 93; (l) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 102, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 103; (m) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 108, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 109; (n) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 108, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 113; (o) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 119, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 120; (p) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 126, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 127; (q) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 131, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 132; (r) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 141, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 142; (s) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 147, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 148; (t) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 153, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 154; (u) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 157, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 158; (v) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 163, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 164; and (w) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 172; and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 173.

[0011] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:60, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:83, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:108, SEQ ID NO:119, SEQ ID NO:126, SEQ ID NO:131, SEQ ID NO:141, SEQ ID NO:147, SEQ ID NO:153, SEQ ID NO:157, SEQ ID NO:163, or SEQ ID NO:172.

[0012] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:61, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:84, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:109, SEQ ID NO:113, SEQ ID NO:120, SEQ ID NO:127, SEQ ID NO:132, SEQ ID NO:142, SEQ ID NO:148, SEQ ID NO:154, SEQ ID NO:158, SEQ ID NO:164, or SEQ ID NO:173.

[0013] In certain embodiments, the DLL3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:60, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:83, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:108, SEQ ID NO:119, SEQ ID NO:126, SEQ ID NO:131, SEQ ID NO:141, SEQ ID NO:147, SEQ ID NO:153, SEQ ID NO:157, SEQ ID NO:163, or SEQ ID NO:172, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:61, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:84, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:109, SEQ ID NO:113, SEQ ID NO:120, SEQ ID NO:127, SEQ ID NO:132, SEQ ID NO:142, SEQ ID NO:148, SEQ ID NO:154, SEQ ID NO:158, SEQ ID NO:164, or SEQ ID NO:173.

[0014] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region and the light chain variable region are: (a) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 8; (b) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 17, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 18; (c) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 24, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 25; (d) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 34, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 35; (e) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 42, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 43; (f) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 52, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 53; (g) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 60, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 61; (h) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 66, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 67; (i) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 76, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; (j) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 83, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 84; (k) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 92, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 93; (l) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 102, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 103; (m) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 108, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 109; (n) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 108, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 113; (o) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 119, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 120; (p) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 126, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 127; (q) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 131, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 132; (r) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 141, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 142; (s) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 147, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 148; (t) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 153, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 154; (u) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 157, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 158; (v) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 163, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 164; and (w) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 172, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 173.

[0015] In certain embodiments, (a) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:7 and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:8; or (b) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 34 and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 35; or (c) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 42, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 43.

[0016] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising a CDR1 domain, a CDR2 domain, and a CDR3 domain, and a light chain variable region comprising a CDR1 domain, a CDR2 domain, and a CDR3 domain, wherein the CDR3 domain of the heavy chain variable region and the light chain variable region is (a) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6 and conservative modifications thereof; (b) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16 and conservative modifications thereof; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 22 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 23 and conservative modifications thereof; (d) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 33 and conservative modifications thereof; (e) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 39 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 41 and conservative modifications thereof; (f) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 51 and conservative modifications thereof; (g) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 56 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59 and conservative modifications thereof; (h) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 64 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 65 and conservative modifications thereof; (i) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 75 and conservative modifications thereof; (j) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 81 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 82 and conservative modifications thereof; (k) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 89 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 91 and conservative modifications thereof; (l) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 98 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 101 and conservative modifications thereof; (m) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 107 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 82 and conservative modifications thereof; (n) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 107 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112 and conservative modifications thereof; (o) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 116 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 118 and conservative modifications thereof; (p) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 123 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 125 and conservative modifications thereof; (q) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 56 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 130 and conservative modifications thereof; (r) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 137 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 140 and conservative modifications thereof; (s) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 145 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 125 and conservative modifications thereof; (t) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 82 and conservative modifications thereof; (u) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 123 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59 and conservative modifications thereof; (v) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 161 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 162 and conservative modifications thereof; and (w) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 168 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 171 and conservative modifications thereof.

[0017] In certain embodiments, the CDR2 domains of the heavy chain variable region and the light chain variable region of the antibody or antigen-binding fragment thereof comprise: (a) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 and conservative modifications thereof; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15 and conservative modifications thereof; (c) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 29 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 32 and conservative modifications thereof; (d) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 and conservative modifications thereof; (e) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 47 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50 and conservative modifications thereof; (f) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 and conservative modifications thereof; (g) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 and conservative modifications thereof; (h) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 71 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74 and conservative modifications thereof; (i) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 80 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 and conservative modifications thereof; (j) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 88 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 216 and conservative modifications thereof; (k) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 97 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 100 and conservative modifications thereof; (l) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 and conservative modifications thereof; (m) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 and conservative modifications thereof; (n) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 115 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 100 and conservative modifications thereof; (o) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 and conservative modifications thereof; (p) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 136 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 139 and conservative modifications thereof; (q) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 146 and conservative modifications thereof; (r) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 136 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74 and conservative modifications thereof; and (s) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 167 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 170 and conservative modifications thereof.

[0018] In certain embodiments, the CDR1 domains of the anti-DLL3 heavy chain variable region and light chain variable region of the antibody or antigen-binding fragment thereof are (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4 and conservative modifications thereof; (b) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14 and conservative modifications thereof; (c) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4 and conservative modifications thereof; (d) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 28 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 31 and conservative modifications thereof; (e) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 40 and conservative modifications thereof; (f) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 46 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49 and conservative modifications thereof; (g) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57 and conservative modifications thereof; (h) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 70 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73 and conservative modifications thereof; (i) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 87 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 90 and conservative modifications thereof; (j) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 99 and conservative modifications thereof; (k) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 117 and conservative modifications thereof; (l) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124 and conservative modifications thereof; (m) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 135 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 138 and conservative modifications thereof; (n) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 151 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57 and conservative modifications thereof; (o) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73 and conservative modifications thereof; and (p) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 169 and conservative modifications thereof.

[0019] In certain embodiments, one or more of the CDR sequences have up to about 5 amino acid substitutions. In certain embodiments, one or more of the CDR sequences have up to about 3 amino acid substitutions.

[0020] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof (a) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3; (b) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13; (c) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 22; (d) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 28, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 29, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30; (e) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 39; (f) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 46, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 47, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48; (g) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 56; (h) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 64; (i) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 70, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 71, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72; (j) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 80, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 81; (k) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 87, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 88, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 89; (l) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 97, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 98; (m) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 107; (n) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 115, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 116; (o) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 123; (p) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 135, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 136, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 137; (q) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 145; (r) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 151, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152; (s) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 136, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 161; (t) A heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 167, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 168.

[0021] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof (a) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6; (b) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16; (c) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 23; (d) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 31, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 32, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 33; (e) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 40, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 41; (f) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 51; (g) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59; (h) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 65; (i) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 75; (j) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 82; (k) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 90, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 216, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 91; (l) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 99, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 100, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 101; (m) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112; (n) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 117, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 100, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 118; (o) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 125; (p) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 130; (q) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 138, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 139, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 140; (r) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 146, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 125; (s) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59; (t) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 162; (u) A light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 169, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 170, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 171.

[0022] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof (a) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6; (b) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16; (c) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 22, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 23; (d) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 28, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 29, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 31, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 32, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 33; (e) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 39, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 40, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 41; (f) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 46, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 47, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 51; (g) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 56, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59; (h) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 64, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 65; (i) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 70, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 71, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 75; (j) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 80, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 81, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 82; (k) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 87, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 88, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 89, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 90, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 216, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 91; (l) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 97, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 98, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 99, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 100, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 101; (m) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 107, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 82; (n) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 107, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112; (o) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 115, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 116, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 117, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 100, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 118; (p) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 123, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 125; (q) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 56, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 130; (r) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 135, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 136, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 137, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 138, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 139, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 140; (s) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 145, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 146, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 125; (t) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 151, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 82; (u) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 123, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59; (v) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 136, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 161, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 162; (w) A heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 96, CDR2 having the amino acid sequence set forth in SEQ ID NO: 167, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 168, and a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 169, CDR2 having the amino acid sequence set forth in SEQ ID NO: 170, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 171.

[0023] In certain embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6; (b) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 28, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 29, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 31, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 32, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 33; or (c) A heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 21, CDR2 having the amino acid sequence set forth in SEQ ID NO: 38, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 39, and a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 40, CDR2 having the amino acid sequence set forth in SEQ ID NO: 5, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 41.

[0024] In certain embodiments, the antibody sequences are in a light-heavy variable chain orientation (V L -V H ) In certain embodiments, the antibody or antigen-binding fragment thereof comprises human variable region framework regions.

[0025] In certain embodiments, the antibody or antigen-binding fragment thereof is fully human or an antigen-binding fragment thereof. In certain embodiments, the antibody or antigen-binding fragment thereof is a chimeric antibody or an antigen-binding fragment thereof. In certain embodiments, the antibody or antigen-binding fragment thereof is a humanized antibody or an antigen-binding fragment thereof. In certain embodiments, the antigen-binding fragment of an antibody is a Fab, Fab', F(ab')2, variable fragment (Fv), or single-chain variable region (scFv).

[0026] In certain embodiments, the antigen-binding fragment of the antibody or antigen-binding fragment thereof is an scFv.

[0027] Additionally, the presently disclosed subject matter provides antibodies or antigen-binding fragments thereof that cross-compete with any of the above-described antibodies or antigen-binding fragments thereof for binding to DLL3.

[0028] The presently disclosed subject matter further provides antibodies or antigen-binding fragments thereof that bind to the same epitope region on DLL3 as any of the above-described antibodies or antigen-binding fragments thereof.

[0029] The presently disclosed subject matter also provides immunoconjugates comprising an antibody or antigen-binding fragment thereof disclosed herein linked to a therapeutic agent. In certain embodiments, the therapeutic agent is a drug, a cytotoxin, or a radioisotope. In certain embodiments, the immunoconjugate further comprises a chelating agent. In certain embodiments, the chelating agent is selected from the group consisting of AAZTA, BAT, BARAC, BPCA, TE2A, CB-TE2A, CBOTEA1P, CB-TE2P, MM-TE2A, DM TE-2A, CP356, DATA, DBCO, DiAmSar, DIBO, DIMA, DFO, DGO, DOTA, DOTMA, DTPA, EDTA, EGTA, EHPG, H2dedpa, H4octapa, H2azapa, H5decapa, H6phospa, HBED, SHBED, HEHA, HYNIC, LICAM, MECAM, NODASA, NODAGA, NOPO, NOTA, NETA, PEPA, PCTA, PDTA, TACN-TM, TCMC, TETA, TETMA, TRAP (PRP9), TRITA, TTHA, and derivatives thereof. In certain embodiments, the chelating agent is DFO. In certain embodiments, the radioisotope is 47 Sc, 67 Cu, 90 Y, 131 I, 149 Tb, 161 Tb, 177 Lu, 225 Ac, 213 Bi,223 Ra, 89 Zr, and 227 In certain embodiments, the radioisotope is selected from the group consisting of: 177 In certain embodiments, the radioisotope is 89 It is Zr.

[0030] The presently disclosed subject matter further provides multispecific molecules comprising an antibody or antigen-binding fragment thereof disclosed herein linked to one or more functional moieties, in certain embodiments, the one or more functional moieties have a different binding specificity than the antibody or antigen-binding fragment thereof.

[0031] Additionally, the presently disclosed subject matter provides a composition comprising a disclosed antibody or antigen-binding fragment thereof, a disclosed immunoconjugate, or a disclosed multispecific molecule. In certain embodiments, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

[0032] Additionally, the presently disclosed subject matter provides nucleic acids encoding the antibodies or antigen-binding fragments thereof disclosed herein, vectors comprising such nucleic acid molecules, and host cells comprising such vectors.

[0033] The presently disclosed subject matter provides methods for detecting DLL3 in a cell, tissue, or blood sample. In certain embodiments, the method includes contacting the cell, tissue, or blood sample with an antibody or antigen-binding fragment thereof disclosed herein, where the antibody or antigen-binding fragment thereof comprises a detectable label, and determining the amount of the labeled antibody or antigen-binding fragment thereof bound to the cell, tissue, or blood sample by measuring the amount of detectable label associated with the cell, tissue, or blood sample, where the amount of bound antibody or antigen-binding fragment thereof indicates the amount of DLL3 in the cell, tissue, or blood sample.

[0034] The presently disclosed subject matter further provides methods of treating or ameliorating a disease or disorder in a subject. In certain embodiments, the method comprises administering to the subject an antibody or antigen-binding fragment thereof, immunoconjugate thereof, multispecific molecule, or composition disclosed herein. In certain embodiments, the disease or disorder expresses DLL3. In certain embodiments, the disease or disorder is associated with overexpression of DLL3. In certain embodiments, the disease or disorder is a tumor. In certain embodiments, the tumor is cancer. In certain embodiments, the disease or disorder is selected from the group consisting of neuroendocrine tumors of the lung, extrapulmonary neuroendocrine carcinoma, melanoma, neuroendocrine prostate cancer, breast cancer, neuroendocrine tumors of the gastrointestinal tract, pancreatic cancer, medullary thyroid carcinoma, small cell bladder cancer, small cell ovarian carcinoma, low-grade glioma, glioblastoma, and neuroblastoma. In certain embodiments, the neuroendocrine tumor of the lung is selected from the group consisting of lung neuroendocrine carcinoma (including typical carcinoid tumors and atypical carcinoid tumors), large cell neuroendocrine carcinoma, and small cell lung cancer.

[0035] Additionally, the presently disclosed subject matter provides kits for treating or ameliorating a disease or disorder in a subject, the kit comprising an antibody or antigen-binding fragment thereof, immunoconjugate thereof, multispecific molecule thereof, or composition disclosed herein. In certain embodiments, the kit further comprises written instructions for using the antibody or antigen-binding fragment thereof, immunoconjugate thereof, multispecific molecule thereof, or composition disclosed herein to treat or ameliorate a disease or disorder in a subject.

[0036] The presently disclosed subject matter further provides an antibody or antigen-binding fragment thereof, immunoconjugate, multispecific molecule, or composition disclosed herein for use in treating or ameliorating a disease or disorder associated with DLL3 in a subject. In certain embodiments, the disease or disorder is a tumor. In certain embodiments, the tumor is cancer. In certain embodiments, the disease or disorder is selected from the group consisting of neuroendocrine tumors of the lung, extrapulmonary neuroendocrine carcinoma, melanoma, neuroendocrine prostate cancer, breast cancer, neuroendocrine tumors of the gastrointestinal tract, pancreatic cancer, medullary thyroid carcinoma, small cell bladder cancer, small cell ovarian carcinoma, low-grade glioma, glioblastoma, and neuroblastoma. In certain embodiments, the neuroendocrine tumor of the lung is selected from the group consisting of lung neuroendocrine carcinoma, large cell neuroendocrine carcinoma, and small cell lung carcinoma. In certain embodiments, the subject is a human.

[0037] The presently disclosed subject matter provides an immunoconjugate comprising an anti-DLL3 antibody or antigen-binding fragment thereof linked to a therapeutic agent. In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 187, SEQ ID NO: 197, SEQ ID NO: 204, or SEQ ID NO: 212. In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 188, SEQ ID NO: 198, SEQ ID NO: 205, or SEQ ID NO: 213.

[0038] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof a) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 187, SEQ ID NO: 197, SEQ ID NO: 204, or SEQ ID NO: 212; and b) An immunoconjugate comprising a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 188, SEQ ID NO: 198, SEQ ID NO: 205, or SEQ ID NO: 213.

[0039] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof a) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 187, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 188; b) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 197, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 198; c) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:204, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:205; and d) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 212; and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 213.

[0040] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 187, SEQ ID NO: 197, SEQ ID NO: 204, or SEQ ID NO: 212. In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 188, SEQ ID NO: 198, SEQ ID NO: 205, or SEQ ID NO: 213.

[0041] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof a) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 187, SEQ ID NO: 197, SEQ ID NO: 204, or SEQ ID NO: 212, and b) An immunoconjugate comprising a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 188, SEQ ID NO: 198, SEQ ID NO: 205, or SEQ ID NO: 213.

[0042] In certain embodiments, a) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 187, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 188; b) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 197, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 198; c) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 204, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 205; and d) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 212, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 213.

[0043] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising a CDR1 domain, a CDR2 domain, and a CDR3 domain, and a light chain variable region comprising a CDR1 domain, a CDR2 domain, and a CDR3 domain, wherein the CDR3 domain of the heavy chain variable region and the light chain variable region is a) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 184 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 186 and conservative modifications thereof; b) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 193 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 196 and conservative modifications thereof; c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 202 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 203 and conservative modifications thereof; and d) An immunoconjugate selected from the group consisting of a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 210 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 211 and conservative modifications thereof.

[0044] In certain embodiments, the CDR2 domains of the heavy chain variable region and the light chain variable region comprise: a) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 183 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50 and conservative modifications thereof; b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 192 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 195 and conservative modifications thereof; c) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 201 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 and conservative modifications thereof; and d) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 209 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 and conservative modifications thereof.

[0045] In certain embodiments, the CDR1 domains of the heavy chain variable region and the light chain variable region comprise: a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 185 and conservative modifications thereof; b) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 191 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 194 and conservative modifications thereof; c) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4 and conservative modifications thereof; and d) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 208 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57 and conservative modifications thereof.

[0046] In certain embodiments, one or more of the CDR sequences have up to about 5 amino acid substitutions. In certain embodiments, one or more of the CDR sequences have up to about 3 amino acid substitutions.

[0047] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof a) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 183, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 184; b) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 191, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 192, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 193; c) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 201, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 202; or d) An immunoconjugate comprising a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 208, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 209, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 210.

[0048] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof a) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 185, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 186; b) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 194, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 195, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 196; c) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 203; or d) An immunoconjugate comprising a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 211.

[0049] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof a) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 183, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 184, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 185, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 186; b) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 191, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 192, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 193, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 194, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 195, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 196; c) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 201, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 202, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 203; or d) A heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 208, CDR2 having the amino acid sequence set forth in SEQ ID NO: 209, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 210, and a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 57, CDR2 having the amino acid sequence set forth in SEQ ID NO: 58, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 211.

[0050] In certain embodiments, the antibody or antigen-binding fragment thereof binds to DLL3 comprising the amino acid sequence set forth in SEQ ID NO: 215 or a fragment thereof. In certain embodiments, the antibody comprises a human variable region framework region. In certain embodiments, the antibody or antigen-binding fragment thereof is fully human or an antigen-binding fragment thereof. In certain embodiments, the antibody or antigen-binding fragment thereof is a chimeric antibody or antigen-binding fragment thereof. In certain embodiments, the antibody or antigen-binding fragment thereof is a humanized antibody or antigen-binding fragment thereof. In certain embodiments, the antigen-binding fragment is a Fab, Fab', F(ab')2, variable fragment (Fv), or single-chain variable region (scFv). In certain embodiments, the antigen-binding fragment of the antigen is an scFv. In certain embodiments, the therapeutic agent is a radioisotope.

[0051] In certain embodiments, the immunoconjugate further comprises a chelating agent. In certain embodiments, the chelating agent is selected from the group consisting of AAZTA, BAT, BARAC, BPCA, TE2A, CB-TE2A, CBOTEA1P, CB-TE2P, MM-TE2A, DM TE-2A, CP356, DATA, DBCO, DiAmSar, DIBO, DIMA, DFO, DGO, DOTA, DOTMA, DTPA, EDTA, EGTA, EHPG, H2dedpa, H4octapa, H2azapa, H5decapa, H6phospa, HBED, SHBED, HEHA, HYNIC, LICAM, MECAM, NODASA, NODAGA, NOPO, NOTA, NETA, PEPA, PCTA, PDTA, TACN-TM, TCMC, TETA, TETMA, TRAP (PRP9), TRITA, TTHA, and derivatives thereof. In certain embodiments, the chelating agent is DFO. In certain embodiments, the radioisotope is 47 Sc, 67 Cu, 90 Y, 131 I, 149 Tb, 161 Tb, 177 Lu, 225 Ac, 213 Bi, 223 Ra, 89 Zr, and 227 In certain embodiments, the radioisotope is selected from the group consisting of: 177 In certain embodiments, the radioisotope is 89 It is Zr.

[0052] The presently disclosed subject matter also provides compositions comprising the immunoconjugates disclosed herein. In certain embodiments, the compositions are pharmaceutical compositions further comprising a pharmaceutically acceptable carrier.

[0053] The presently disclosed subject matter further provides a method for detecting DLL3 in a whole cell, tissue, or blood sample, comprising: a) contacting the cell, tissue, or blood sample with an immunoconjugate disclosed herein; and b) determining the amount of immunoconjugate bound to the cell, tissue, or blood sample by measuring the amount of detectable label associated with the cell or tissue, wherein the amount of bound immunoconjugate indicates the amount of DLL3 in the cell, tissue, or blood sample.

[0054] The presently disclosed subject matter further provides methods for treating or ameliorating a disease or disorder associated with DLL3 in a subject, the method comprising administering to the subject an immunoconjugate or composition disclosed herein. In certain embodiments, the disease or disorder is a tumor. In certain embodiments, the tumor is cancer. In certain embodiments, the disease or disorder is selected from the group consisting of neuroendocrine tumors of the lung, extrapulmonary neuroendocrine carcinoma, melanoma, neuroendocrine prostate cancer, breast cancer, neuroendocrine tumors of the gastrointestinal tract, pancreatic cancer, medullary thyroid carcinoma, small cell bladder cancer, small cell ovarian carcinoma, low-grade glioma, glioblastoma, and neuroblastoma. In certain embodiments, the neuroendocrine tumor of the lung is selected from the group consisting of lung neuroendocrine carcinoma, large cell neuroendocrine carcinoma, and small cell lung carcinoma. In certain embodiments, the subject is a human.

[0055] The presently disclosed subject matter further provides kits for treating or ameliorating a disease or disorder in a subject, the kit comprising an immunoconjugate or composition disclosed herein. In certain embodiments, the kit further comprises written instructions for using the antibody or antigen-binding fragment thereof, immunoconjugate, multispecific molecule, or composition to treat or ameliorate a disease or disorder in a subject.

[0056] Finally, the presently disclosed subject matter further provides an immunoconjugate or composition disclosed herein for use in treating or ameliorating a disease or disorder associated with DLL3 in a subject. In certain embodiments, the disease or disorder is a tumor. In certain embodiments, the tumor is cancer. In certain embodiments, the disease or disorder is selected from the group consisting of neuroendocrine tumors of the lung, extrapulmonary neuroendocrine carcinoma, melanoma, neuroendocrine prostate cancer, breast cancer, neuroendocrine tumors of the gastrointestinal tract, pancreatic cancer, medullary thyroid carcinoma, small cell bladder cancer, small cell ovarian carcinoma, low-grade glioma, glioblastoma, and neuroblastoma. In certain embodiments, the neuroendocrine tumor of the lung is selected from the group consisting of lung neuroendocrine carcinoma, large cell neuroendocrine carcinoma, and small cell lung carcinoma. In certain embodiments, the subject is a human.

[0057] 4. Brief description of the drawings The following detailed description, given by way of example and not intended to limit the invention to the particular embodiments described, may be understood in conjunction with the accompanying drawings, in which: [Brief explanation of the drawings]

[0058] [Figure 1A] Figure 1 shows the role of DLL3 in SCLC. Figure 2 shows a schematic diagram of the molecular mechanism involving DLL3. [Figure 1B] Figure 1 shows the role of DLL3 in SCLC. DLL3 expression levels on the cell membrane of SCLC cells are shown. [Figure 2A] Figure 1 shows that DLL3 is selectively expressed on the cell membrane in SCLC.Figure 2 shows the expression of DLL3 in different tissues. [Figure 2B] DLL3 is selectively expressed on the cell membrane in SCLC. Membrane H-scores are shown. LCNEC = large cell neuroendocrine carcinoma, lung cancer. [Figure 3] FIG. 1 shows a schematic diagram of the immunoconjugates disclosed herein. [Figure 4] Results of the Fab-Zap internalization assay are shown. RLU = relative light units. [Figure 5]FIG. 1 shows a schematic diagram of the immunoconjugates disclosed herein. [Figure 6A] Figure 1 shows the effect of 89Zr-DFO-BivE23. Figure 2 shows a schematic diagram of the bioconjugation of E23 clones. [Figure 6B] 1 shows the effect of 89Zr-DFO-BivE23. A schematic diagram of the in vivo experimental setup is shown. [Figure 6C] Effect of 89Zr-DFO-BivE23. Maximum intensity projection of representative images from Zr-89 immunoPET imaging of E23biv 120 hours after injection in an H82 SCLC model (300 μCi, 30 μg, via tail vein, n = 3–4 per cohort). [Figure 6D] Figure 1 shows the effect of 89Zr-DFO-BivE23. Figure 2 shows the biodistribution of 89Zr-DFO-BivE23 in mice using PET / CT. [Figure 7] FIG. 1 shows a schematic diagram of a dosimetry study performed to analyze the presently disclosed subject matter. [Figure 8] 1 shows the biodistribution of 89Zr-DFO-BivE23 in H660 male nude mice using PET / CT. [Figure 9A] Figure 1 shows E23 analysis of dosimetry studies. Figure 2 shows extrapolation of human absorbed dose (AD) from biodistribution experiments of 89Zr-DFO-BivE23. [Figure 9B] Figure 1 shows E23 analysis of dosimetry studies. Figure 2 shows Lu177-DTPA-BivE23 H660 tumor model mouse dosimetry. [Figure 10] 1 shows a full-course biodistribution study for H82 in female nude mice. [Figure 11A] Figure 1 shows the quality control after radiolabeling of the cell binding assay for the C8 clone. Figure 2 shows the results for the C8 IgG1 clone. [Figure 11B] Figure 1 shows the quality control after radiolabeling of the cell binding assay for the C8 clone. Figure 2 shows the results for the C8 IgG4 clone. [Figure 12A]Figure 1 shows the effects of 89Zr-DFO-C8 IgG1 and 89Zr-DFO-C8 IgG4. Figure 2 shows a schematic diagram of the bioconjugation of C8 clones and the in vivo experimental setup. [Figure 12B] Effect of 89Zr-DFO-C8 IgG1 and 89Zr-DFO-C8 IgG4. Maximum intensity projection of representative images from Zr-89 immunoPET imaging of C8 IgG1 120 hours after injection in an H82 SCLC model (120 μCi, 30 μg, via tail vein, n=3-4 per cohort). [Figure 12C] Effect of 89Zr-DFO-C8 IgG1 and 89Zr-DFO-C8 IgG4. Maximum intensity projection of representative images from Zr-89 immunoPET imaging of C8 IgG4 120 hours after injection in an H82 SCLC model (120 μCi, 30 μg, via tail vein, n=3-4 per cohort). [Figure 12D] Figure 1 shows the effects of 89Zr-DFO-C8 IgG1 and 89Zr-DFO-C8 IgG4. Figure 2 shows the results of a biodistribution study of C8 IgG1 120 hours after injection. [Figure 12E] Figure 1 shows the effects of 89Zr-DFO-C8 IgG1 and 89Zr-DFO-C8 IgG4. Figure 2 shows the results of a biodistribution study of C8 IgG4 120 hours after injection. [Figure 13] FIG. 1 shows a schematic diagram of the dosimetry studies performed to analyze C8 IgG1 and C8 IgG4. [Figure 14A] 1 shows quality control data for the C8 clone. 2 shows the radiochemical yield of the C8 IgG1 clone. [Figure 14B] 1 shows quality control data for the C8 clone. 2 shows the radiochemical yield of the C8 IgG4 clone. [Figure 15A] A and B show the biodistribution of C8 clones in H82 female nude mice using PET / CT. B shows the biodistribution of 89Zr-DFO-C8 IgG1. [Figure 15B]Figure 1 shows the biodistribution of C8 clones in H82 female nude mice using PET / CT. Figure 2 shows the biodistribution of 89Zr-DFO-C8 IgG4. [Figure 16A] 1 shows a blocking study of C8 clones in H82 female nude mice using PET / CT. 1 shows blocking of 89Zr-DFO-C8 IgG1. [Figure 16B] 1 shows a blocking study of C8 clones in H82 female nude mice using PET / CT. 89Zr-DFO-C8 IgG4 blocking is shown. [Figure 17] 1 shows the biodistribution of control SC16 in H82 female nude mice using PET / CT at 72 hours. [Figure 18A] 1 shows the extrapolation of human absorbed dose (AD) from biodistribution experiments of 89Zr-DFO-C8 IgG1 and 89Zr-DFO-C8 IgG4. [Figure 18B] Figure 1 shows C8 analysis of dosimetry studies. Figure 1 shows Lu177-DTPA-C8 IgG1 and Lu177-DTPA-C8 IgG4 in H82 tumor model mice dosimetry. DETAILED DESCRIPTION OF THE INVENTION

[0059] 5. MODE FOR CARRYING OUT THE INVENTION The presently disclosed subject matter provides anti-DLL3 antibodies. Non-limiting embodiments of the disclosure are illustrated herein and by the Examples.

[0060] For clarity of disclosure, and not by way of limitation, this detailed description is divided into the following subsections. 5.1. Definition, 5.2.DLL3, 5.3. Anti-DLL3 antibody, 5.4. Nucleic Acids Encoding Antibodies or Antigen-Binding Fragments 5.5. Pharmaceutical compositions and methods of treatment 5.6. Diagnostic and prognostic methods; 5.7. Kits, and 5.8. Exemplary Embodiments.

[0061] 5.1 Definition In the following description, certain rules regarding the use of terminology are followed: In general, the terms used herein are intended to be interpreted consistently with the meaning of those terms as they are known to those skilled in the art.

[0062] The terms "antibody" and "antibody" as known in the art refer to an antigen-binding protein of the immune system. The term "antibody" referred to herein includes a full-length antibody having an antigen-binding region, and an "antigen-binding fragment" or any fragment thereof in which the "antigen-binding region" is retained, or a single chain thereof, for example, a single-chain variable fragment (scFv). A naturally occurring "antibody" is a glycoprotein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain comprises a heavy chain variable region (herein referred to as V H Each light chain consists of a light chain variable region (abbreviated herein as V) and a heavy chain constant region (CH). The heavy chain constant region is composed of three domains: CH1, CH2, and CH3. L ) and light chain constant C L The light chain constant region consists of one domain, C L It consists of V H Area and V L The regions can be further subdivided into regions of hypervariability, called complementarity-determining regions (CDRs), interspersed with more conserved regions, called framework regions (FRs). H and V L is composed of three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The constant region of the antibody may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system.

[0063] The term "human antibody," as used herein, is intended to include antibodies having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region also is derived from human germline immunoglobulin sequences. The human antibodies of the presently disclosed subject matter may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo).

[0064] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and / or bind the same epitope, except for, for example, naturally occurring mutations or possible variant antibodies that arise during production of the monoclonal antibody preparation (such variants are generally present in minor amounts). Furthermore, in contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous antibody population and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the subject matter disclosed herein may be produced by a variety of techniques, including, but not limited to, hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci; such methods, as well as other exemplary methods for producing monoclonal antibodies, are described herein.

[0065] As used herein, the term "recombinant human antibody" includes all human antibodies prepared, expressed, generated, or isolated by recombinant means, such as (a) antibodies isolated from animals (e.g., mice) that are transgenic or transchromosomal for human immunoglobulin genes or hybridomas prepared therefrom (described further below); (b) antibodies isolated from host cells that have been transformed to express human antibodies, e.g., from transfectomas; (c) antibodies isolated from recombinant combinatorial human antibody libraries; and (d) antibodies prepared, expressed, generated, or isolated by any other means involving splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable regions in which the framework and CDR regions are derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies may be subjected to in vitro mutagenesis (or, when animals transgenic for human Ig sequences are used, in vivo somatic mutagenesis), thus allowing for the development of recombinant antibody Vs. H Area and V L The amino acid sequence of the region is human germline V H Sequence and V L These are sequences that, while derived from and related to a sequence, may not naturally occur in the human antibody germline repertoire in vivo.

[0066] The term "humanized antibody" is intended to refer to antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. Additional framework region modifications may be made within the human framework sequences.

[0067] The term "chimeric antibody" is intended to refer to an antibody in which the variable region sequences are derived from one species and the constant region sequences are derived from another species, e.g., an antibody in which the variable region sequences are derived from a murine antibody and the constant region sequences are derived from a human antibody.

[0068] As used herein, an antibody that "specifically binds to DLL3" is an antibody that specifically binds to DLL3 and has a binding capacity of about 1 x 10 -8M or less, about 5 x 10 -9 M or less, approximately 1×10 -9 M or less, about 5 x 10 -10 M or less, approximately 1×10 -10 M or less, about 5 x 10 -11 M or less, approximately 1×10 -11 M or less, about 5 x 10 -12 M or less, or about 1 x 10 -12 The dissociation constant (K D ), and is intended to refer to an antibody that binds to DLL3 (e.g., human DLL3).

[0069] An "antibody that competes for binding" or "antibody that cross-competes for binding" with a reference antibody for binding to an antigen, e.g., DLL3, refers to an antibody that blocks the binding of the reference antibody to the antigen (e.g., DLL3) by 50% or more in a competition assay, and conversely, the reference antibody blocks the binding of the antibody to the antigen (e.g., DLL3) by 50% or more in a competition assay. Exemplary competition assays are described in "Antibodies," Harlow and Lane (Cold Spring Harbor Press, Cold Spring Harbor, NY).

[0070] As used herein, "isotype" refers to the antibody class (e.g., IgM or IgG1) that is encoded by heavy chain constant region genes.

[0071] The phrases "antibody that recognizes an antigen" and "antibody specific for an antigen" may be used interchangeably herein with the term "antibody that specifically binds to an antigen (eg, a DLL3 polypeptide)."

[0072] As used herein, the term "antigen-binding fragment" or "antigen-binding region" of an antibody refers to a region or fragment of an antibody that binds to an antigen and confers antigen specificity to the antibody, and fragments of antigen-binding proteins, e.g., antibodies, include one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., a DLL3 polypeptide). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of antigen-binding fragments encompassed by the term "antibody fragment" of an antibody include V L Domain, V H Domain, C L a Fab fragment, which is a monovalent fragment consisting of a CH1 domain and a CH2 domain; a F(ab)2 fragment, which is a bivalent fragment containing two Fab fragments linked by a disulfide bridge at the hinge region; a V H Fd fragment consisting of the V domain and CH1 domain of a single arm of an antibody L Domain and V H Fv fragment consisting of domains, V H These include dAb fragments consisting of domains (Ward et al., Nature 1989;341:544-546), as well as isolated complementarity determining regions (CDRs).

[0073] Furthermore, the two domains V of the Fv fragment L and V H are encoded by separate genes, but these are collectively referred to as V L Area and V H These antibody fragments can be joined using recombinant methods by a synthetic linker that allows them to be produced as a single protein chain that pairs to form a monovalent molecule. These are known as single-chain Fvs (scFvs); see, e.g., Bird et al., Science (1988); 242:423-426; and Huston et al., Proc Natl Acad Sci (1998); 85:5879-5883. These antibody fragments are obtained using conventional techniques known to those of skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies.

[0074] An "antibody" or "antigen binding protein" is one that has been identified and separated and / or recovered from a component of its natural environment. A "synthetic antibody" or "recombinant antibody" is generally produced using recombinant techniques or peptide synthesis techniques known to those skilled in the art.

[0075] As used herein, the term "single-chain variable fragment" or "scFv" refers to a V H ::V L Heavy chains (V) of immunoglobulins (e.g., murine or human) covalently linked to form heterodimers H ) and light chain (V L ) is a fusion protein of the variable region of the heavy chain (V H ) and light chain (V L ) are either directly connected or connected by a linker encoding a peptide (e.g., 10, 15, 20, 25 amino acids), and V H N-terminus of V L or V H The C-terminus of V L The linker is usually rich in glycine for flexibility and rich in serine or threonine for solubility. The linker can connect the heavy chain variable region and the light chain variable region of the extracellular antigen-binding domain.

[0076] Non-limiting examples of linkers are described in Shen et al., Anal Chem (2008); 80(6): 1910-1917 and WO2014 / 087010, the contents of which are incorporated herein by reference in their entirety. In certain embodiments, the linker is a G4S linker. In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 176, provided below: GGGGSGGGGSGGGSGGGGS [SEQ ID NO: 176]

[0077] In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 177, provided below: GGGGSGGGGSGGGGS [SEQ ID NO: 177]

[0078] In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 178, provided below: GGGGSGGGGSGGGGSGGGSGGGGS [SEQ ID NO: 178]

[0079] In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 179, provided below: GGGGSGGGGSGGGGSGGGGSGGGSGGGGS [SEQ ID NO: 179]

[0080] In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 180, provided below: GGGGS [SEQ ID NO: 180]

[0081] In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 181, provided below: GGGGSGGGGS [SEQ ID NO: 181]

[0082] Despite the removal of the constant region and the introduction of the linker, the scFv protein retains the specificity of the original immunoglobulin. Single-chain Fv polypeptide antibodies are synthesized using the V, ... H and V LThe scFvs can be expressed from nucleic acids containing sequences encoding the scFvs. See also U.S. Patent Nos. 5,091,513, 5,132,405, and 4,956,778, and U.S. Patent Publication Nos. 2005 / 0196754 and 2005 / 0196754. Antagonistic scFvs with inhibitory activity have been described (see, e.g., ). Agonistic scFvs with stimulatory activity have been described (e.g., Zhao et al., Hyrbidoma (Larchmt) 2008;27(6):455-51; Peter et al., J Cachexia Sarcopenia Muscle 2012 August 12; Shieh et al., J Imunol 2009;183(4):2277-85; Giomarelli et al., Thromb Haemost 2007;97(6):955-63; Fife et al., J Clin Invst 2006;116(8):2252-61; Brocks et al., Immunotechnology 1997;3(3):173-84; Moosmayer et al., Ther Immunol 1995;2 (10:31-40). Agonistic scFvs with stimulatory activity have been described (see, e.g., Peter et al., J Bioi Chern 2003;25278(38):36740-7; Xie et al., Nat Biotech 1997;15(8):768-71; Ledbetter et al., Crit Rev Immunol 1997;17(5-6):427-55; Ho et al., BioChim Biophys Acta 2003;1638(3):257-66).

[0083] As used herein, "F(ab)" refers to the fragment of an antibody structure that binds to an antigen but is monovalent and does not have the Fc portion; for example, digestion of an antibody with the enzyme papain produces two F(ab) fragments and an Fc fragment (heavy (H) chain constant region, the Fc region that does not bind to antigen).

[0084] As used herein, "F(ab')2" refers to an antibody fragment produced by pepsin digestion of a whole IgG antibody, which fragment has two antigen-binding (ab') (bivalent) regions, each (ab') region containing two separate amino acid chains, a portion of an H chain and a light (L) chain, linked by an S-type disulfide bond to bind the antigen, with the remaining H chain portions linked together. The "F(ab')2" fragment can be separated into two individual Fab' fragments.

[0085] As used herein, the term "vector" refers to any genetic element, such as a plasmid, phage, transposon, cosmid, chromosome, virus, virion, etc., that is capable of replication and transfer of genetic sequences into a cell when associated with the appropriate control elements. Thus, the term includes cloning and expression vehicles, as well as viral and plasmid vectors.

[0086] "CDR" is defined as the complementarity-determining region amino acid sequence of an antibody, which is the hypervariable region of the immunoglobulin heavy and light chains. See, for example, Kabat et al., Sequences of Proteins of Immunological Interest, 4th USDepartment of Health and Human Services, National Institutes of Health (1987), or the IMGT numbering system (Lefranc, The Immunologist (1999); 7:132-136; Lefranc et al., Dev. Comp. Immunol. (2003); 27:55-77). As used herein, the term "hypervariable region" or "HVR" refers to each of the regions of an antibody variable domain that are hypervariable in sequence ("complementarity-determining region" or "CDR") and / or form structurally defined loops ("hypervariable loops") and / or contain antigen-contacting residues ("antigen contacts"). Generally, antibodies contain three heavy-chain and three light-chain CDRs or CDR regions in the variable region. CDRs provide the majority of contact residues for antibody binding to the antigen or epitope region. In certain embodiments, CDRs are identified according to the IMGT system. In certain embodiments, CDRs are identified using the IMGT numbering system, accessible at http: / / www.imgt.org / IMGT_vquest / input.

[0087] The term "isolated" refers to the degree of separation from the original source or surroundings.

[0088] An "isolated antibody" is one that has been separated from a component of its natural environment. In certain embodiments, the antibody is purified to greater than 95% or 99% purity, as determined, for example, by electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse-phase HPLC). For a review of methods for assessing antibody purity, see, e.g., Flatman et al., J. Chromatogr (2007); B 848:79-87.

[0089] An "isolated nucleic acid" refers to a nucleic acid molecule that has been separated from a component of its natural environment. Isolated nucleic acid includes a nucleic acid molecule contained within a cell that ordinarily contains the nucleic acid molecule, but where the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.

[0090] An "isolated nucleic acid encoding an antibody" (including reference to a specific antibody, e.g., an anti-KLB antibody) refers to one or more nucleic acid molecules encoding antibody heavy and light chains (or fragments thereof), including such nucleic acid molecules within a single vector or separate vectors, and such nucleic acid molecules are present in one or more locations within a host cell.

[0091] The term "vector," as used herein, is intended to refer to a nucleic acid molecule capable of propagating another nucleic acid to which it has been linked. This term includes vectors as self-replicating nucleic acid structures and vectors that integrate into the genome of a host cell into which they have been introduced. Certain vectors are capable of directing the expression of genes to which they are operatively linked. Such vectors are referred to herein as "expression vectors."

[0092] An "immunoconjugate" is an antibody conjugated to one or more heterologous molecules, including, but not limited to, cytotoxic agents.

[0093] As used herein, the term "derivative" refers to a compound that is derived from some other compound and maintains its general structure. For example, without any limitation, trichloromethane (chloroform) is a derivative of methane.

[0094] An "effective amount" (or "therapeutically effective amount") is an amount sufficient to produce a beneficial or desired clinical result upon treatment. An effective amount can be administered to a subject in one or more doses. From a therapeutic perspective, an effective amount is an amount sufficient to palliate, ameliorate, stabilize, reverse, or slow the progression of a disease, or otherwise reduce the pathological consequences of a disease. An effective amount is generally determined by a physician on a case-by-case basis and is within the skill of one of ordinary skill in the art. Several factors are typically considered in determining the appropriate dosage to achieve an effective amount. These factors include the age, sex, and weight of the subject, the condition being treated, the severity of the condition, and the form and effective concentration of the cells administered.

[0095] An "individual" or "subject" herein is a vertebrate, e.g., a human or a non-human animal, e.g., a mammal. Mammals include, but are not limited to, humans, primates, farm animals, sport animals, rodents, and pets. Non-limiting examples of non-human animal subjects include rodents, such as mice, rats, and hamsters, guinea pigs, rabbits, dogs, cats, sheep, pigs, goats, cows, horses, and non-human primates, such as apes and monkeys.

[0096] As used herein, "treatment" (and grammatical variations such as "treat" or "treating") refers to clinical intervention in an attempt to alter the natural course of the treated individual and can be performed either prophylactically or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing the occurrence or recurrence of disease, alleviation of symptoms, mitigation of any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. In certain embodiments, antibodies of the presently disclosed subject matter are used to delay the onset of disease or to slow the progression of a disease, e.g., a tumor, e.g., a tumor associated with DLL3.

[0097] The terms "comprises" and "comprising" are intended to have the broad meaning ascribed to them in U.S. patent law and may mean "includes," "including," etc.

[0098] As used herein, the term "about" or "approximately" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 3 or more than 3 standard deviations, in accordance with practice in the art. Alternatively, "about" can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and even more preferably up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold of a value.

[0099] As described herein, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the recited range, and fractions thereof (such as integer tenths and hundredths), where appropriate, unless otherwise indicated.

[0100] Other aspects of the presently disclosed subject matter are described in the disclosure that follows and are within the scope of the presently disclosed subject matter.

[0101] 5.2 DLL3 DLL3 is selectively expressed in high-grade lung neuroendocrine tumors (LU-NETs). Lu-NETs encompass a heterogeneous tumor family classified into four histological variants: typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung cancer (SCLC). Increased DLL3 expression was observed in xenograft tumors from patients with SCLC and LCNEC and was also confirmed in primary tumors. See Saunders et al., Sci Translational Medicine (302):302ra136 (2015). Both SCLC and lung LCNEC are high-grade tumors with poor prognosis and a higher incidence in smokers. Similar to SCLC, lung LCNEC exhibits biologically aggressive behavior. The survival curves of lung LCNEC and SCLC overlap at different stages, and the survival rates are lower than those of other NSCLCs. Prognosis is poor even for patients with potentially resectable stage I lung cancer, with 5-year survival rates ranging from 27% to 67%. See Iyoda A. et al., J Thorac Cardiovasc Surg. 138:446-453 (2009).

[0102] Delta is one of the Drosophila ligands of Notch, which activates signaling in neighboring cells. Humans have four known Notch receptors (NOTCH1-NOTCH4) and three homologs of Delta, termed Delta-like ligands: DLL1, DLL3, and DLL4. Unlike DLL1 and DLL4, DLL3 has been reported to inhibit, rather than activate, Notch signaling.

[0103] DLL3 (also known as Delta-like 3 or SCDO1) is a member of the Delta-like family of Notch DSL ligands. Aberrant DLL3 expression (genotypic and / or phenotypic) is associated with various tumor-initiating cell subpopulations, including cancer stem cells and tumor-initiating cells.

[0104] In certain embodiments, the anti-DLL3 antibodies or antigen-binding fragments thereof disclosed herein bind to human DLL3. In certain embodiments, the human DLL3 comprises or consists of an amino acid sequence having UniProt Reference Number: Q9NYJ7-1 (SEQ ID NO: 182), or a fragment thereof. SEQ ID NO: 182 is provided below. In certain embodiments, DLL3 comprises an extracellular domain, a transmembrane domain, and a cytoplasmic domain. In certain embodiments, the extracellular domain comprises or consists of amino acids 27-492 of SEQ ID NO: 182. In certain embodiments, the transmembrane domain comprises or consists of amino acids 493-513 of SEQ ID NO: 182. In certain embodiments, the cytoplasmic domain comprises or consists of amino acids 514-618 of SEQ ID NO: 182.

[0105] In certain embodiments, the extracellular domain of DLL3 comprises a DSL domain, an EGF-like 1 domain, an EGF-like 2 domain, an EGF-like 3 domain, an EGF-like 4 domain, an EGF-like 5 domain, and an EGF-like 6 domain. In certain embodiments, the DSL domain comprises or consists of amino acids 176-215 of SEQ ID NO: 182. In certain embodiments, the EGF-like 1 domain comprises or consists of amino acids 216-249 of SEQ ID NO: 182. In certain embodiments, the EGF-like 2 domain comprises or consists of amino acids 274-310 of SEQ ID NO: 182. In certain embodiments, the EGF-like 3 domain comprises or consists of amino acids 312-351 of SEQ ID NO: 182. In certain embodiments, the EGF-like 4 domain comprises or consists of amino acids 353-389 of SEQ ID NO: 182. In certain embodiments, the EGF-like 5 domain comprises or consists of amino acids 391-427 of SEQ ID NO: 182. In certain embodiments, the EGF-like 6 domain comprises or consists of amino acids 429 to 465 of SEQ ID NO:182. [SEQ ID NO: 182]

[0106] In certain embodiments, DLL3 comprises or consists of an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, or at least about 100% identical to the amino acid sequence set forth in SEQ ID NO: 182 or a fragment thereof.

[0107] In certain embodiments, the antigen recognition receptor binds to the EGF-like 3 domain of DLL3. In certain embodiments, the antigen recognition receptor binds to amino acids 312-351 of SEQ ID NO: 182. In certain embodiments, the antigen recognition receptor binds to the EGF-like 4 domain of DLL3. In certain embodiments, the antigen recognition receptor binds to amino acids 353-389 of SEQ ID NO: 182. In certain embodiments, the antigen recognition receptor binds to the EGF-like 5 domain of DLL3. In certain embodiments, the antigen recognition receptor binds to amino acids 391-427 of SEQ ID NO: 182. In certain embodiments, the antigen recognition receptor binds to the EGF-like 6 domain of DLL3. In certain embodiments, the antigen recognition receptor binds to amino acids 429-465 of SEQ ID NO: 182.

[0108] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof binds to a portion of human DLL3. In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof binds to the extracellular domain of DLL3. In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof binds to amino acids 27-492 of SEQ ID NO: 182.

[0109] 5.3 Anti-DLL3 antibody The antibodies of the presently disclosed subject matter are characterized by a particular functional feature or property of the antibody, for example, the antibody specifically binds to DLL3 (e.g., binds to human DLL3).

[0110] In certain embodiments, the antibodies or antigen-binding fragments disclosed herein have a binding affinity of, for example, about 1×10 -8 M or less, about 5 x 10 -9 M or less, approximately 1×10 -9 M or less, about 5 x 10 -10 M or less, approximately 1×10 -10 M or less, about 5 x 10 -11 M or less, or about 1 x 10 -11 M or less, about 5 x 10 -12 M or less, or about 1 x 10 -12 The dissociation constant (K DIn certain embodiments, the antibodies or antigen-binding fragments disclosed herein bind to DLL3 (e.g., human DLL3) with a binding affinity of, for example, about 5×10 -9 The dissociation constant (K D In certain embodiments, the antibodies or antigen-binding fragments disclosed herein bind to DLL3 (e.g., human DLL3) with a binding affinity of, for example, about 1×10 -9 The dissociation constant (K D In certain embodiments, the antibodies or antigen-binding fragments disclosed herein bind to DLL3 (e.g., human DLL3) with a binding affinity of, for example, about 3.5×10 -9 Dissociation constant of M (K D In certain embodiments, the antibodies or antigen-binding fragments disclosed herein bind to DLL3 (e.g., human DLL3) with a binding affinity of, for example, about 1.5×10 -9 Dissociation constant of M (K D In certain embodiments, the antibodies or antigen-binding fragments disclosed herein bind to DLL3 (e.g., human DLL3) with a binding affinity of, for example, about 1×10 -12 Dissociation constant of M (K D ) binds to DLL3 (e.g., human DLL3).

[0111] The heavy and light chains of the antibodies or antigen-binding fragments disclosed herein can be full-length (e.g., an antibody can comprise at least one (e.g., one or two) complete heavy chains and at least one (e.g., one or two) complete light chains), or can comprise an antigen-binding fragment (e.g., a Fab, F(ab'), Fv, or single-chain Fv fragment ("scFv")). In certain embodiments, the antibody heavy chain constant region is selected from, e.g., IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE, particularly, e.g., IgG1, IgG2, IgG3, and IgG4. In certain embodiments, the immunoglobulin isotype is IgG1 (e.g., human IgG1). The choice of antibody isotype can depend on the immune effector function that the antibody is designed to elicit. In certain embodiments, the antibody light chain constant region is selected from, e.g., kappa or lambda, particularly kappa.

[0112] In constructing recombinant immunoglobulins, suitable amino acid sequences for the constant regions of various immunoglobulin isotypes and methods for producing a broad range of antibodies are known to those skilled in the art.

[0113] 5.3.1 Single-chain variable fragments (scFv) In certain embodiments, the presently disclosed subject matter includes antibodies or antigen-binding fragments thereof in which an scFv sequence is fused to one or more constant domains to form an antibody with the Fc region of a human immunoglobulin, producing a bivalent protein and increasing the overall affinity and stability of the antibody. Additionally, the Fc portion allows for other molecules to be directly conjugated to the antibody, including, but not limited to, fluorescent dyes, cytotoxins, radioisotopes, etc., for use in, for example, antigen quantitation studies, to immobilize the antibody for affinity measurements, for targeted delivery of therapeutic agents, to test Fc-mediated cytotoxicity using immune effector cells, and many other applications.

[0114] The results presented herein highlight the specificity, sensitivity, and utility of the antibodies or antigen-binding fragments disclosed herein that target DLL3 polypeptides (eg, human DLL3 polypeptides).

[0115] In certain embodiments, the anti-DLL3 scFv is an scFv-Fc fusion protein or a VFv selected from Table 1. H Area and V L In certain embodiments, the anti-DLL3 scFv is a full-length human IgG having a V region or CDR. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO:7 is set forth in SEQ ID NO:9. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO:8. L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 8 is set forth in SEQ ID NO: 10. SEQ ID NOs: 7-10 are provided in Table 1. In certain embodiments, the scFv is designated "J8."

[0116] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO:7. H and V comprising the amino acid sequence set forth in SEQ ID NO:8 L In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3 or a conservative modification thereof. SEQ ID NOs: 1-3 are provided in Table 1.

[0117] In certain embodiments, the anti-DLL3 scFv comprises a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6 or a conservative modification thereof. SEQ ID NOs: 4-6 are provided in Table 1.

[0118] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3 or a conservative modification thereof, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6 or a conservative modification thereof.

[0119] In certain embodiments, the anti-DLL3 scFv comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a V comprising the amino acid sequence set forth in SEQ ID NO: 3, and a V H It includes a VH having a CDR3, and a VL having a CDR1 having the amino acid sequence set forth in SEQ ID NO:4, a CDR2 having the amino acid sequence set forth in SEQ ID NO:5, and a CDR3 having the amino acid sequence set forth in SEQ ID NO:6.

[0120] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO:7. H and V comprising the amino acid sequence set forth in SEQ ID NO:8 L In certain embodiments, V H and V L are linked via a linker. In certain embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 177.

[0121] In certain embodiments, the variable region is a heavy chain variable region (V H ) are located at the N-terminus. In certain embodiments, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L In certain embodiments, the light chain variable region (V L ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V L -V H . [Table 1]

[0122] In certain embodiments, the anti-DLL3 scFv is an scFv-Fc fusion protein or a VFv selected from Table 2. H Area and V L In certain embodiments, the anti-DLL3 scFv is a full-length human IgG having a V domain or CDR. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 17 is set forth in SEQ ID NO: 19. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 18. L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 18 is set forth in SEQ ID NO: 20. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 17. H and V comprising the amino acid sequence set forth in SEQ ID NO: 18 L SEQ ID NOs: 17-20 are provided in Table 2. In certain embodiments, the scFv is designated "L22."

[0123] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13 or a conservative modification thereof. SEQ ID NOs: 11-13 are provided in Table 2.

[0124] In certain embodiments, the anti-DLL3 scFv comprises a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16 or a conservative modification thereof. SEQ ID NOs: 14-16 are provided in Table 2.

[0125] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13 or a conservative modification thereof, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16 or a conservative modification thereof.

[0126] In certain embodiments, the anti-DLL3 scFv comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, a V comprising the amino acid sequence set forth in SEQ ID NO: 13, and a V H It includes a VH having a CDR3, and a VL having a CDR1 having the amino acid sequence set forth in SEQ ID NO: 14, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 15, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 16.

[0127] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO: 17. H and V comprising the amino acid sequence set forth in SEQ ID NO: 18 L In certain embodiments, V H and V L are linked via a linker. In certain embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 177.

[0128] In certain embodiments, the heavy chain variable region (V H ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V H -V L In certain embodiments, the light chain variable region (V L ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V L -V H . [Table 2]

[0129] In certain embodiments, the anti-DLL3 scFv is an scFv-Fc fusion protein or a VFv selected from Table 3. H Area and V L In certain embodiments, the anti-DLL3 scFv is a full-length human IgG having a V domain or CDR, as shown in Table 3, comprising the amino acid sequence set forth in SEQ ID NO: 24. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO:24 is set forth in SEQ ID NO:26. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO:25. L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 25 is set forth in SEQ ID NO: 27. SEQ ID NOs: 24-27 are provided in Table 3. In certain embodiments, the scFv is designated "B2."

[0130] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO:24. H and V comprising the amino acid sequence set forth in SEQ ID NO: 25 L Includes:

[0131] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 22 or a conservative modification thereof. SEQ ID NOs: 2, 21, and 22 are provided in Table 3.

[0132] In certain embodiments, the anti-DLL3 scFv comprises a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 23 or a conservative modification thereof. SEQ ID NOs: 4, 5, and 23 are provided in Table 3.

[0133] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 22 or a conservative modification thereof, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 23 or a conservative modification thereof.

[0134] In certain embodiments, the anti-DLL3 scFv comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a V comprising the amino acid sequence set forth in SEQ ID NO: 22, and a V H It includes a VH having a CDR3, and a VL having a CDR1 having the amino acid sequence set forth in SEQ ID NO: 4, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 23.

[0135] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO:24. H and V comprising the amino acid sequence set forth in SEQ ID NO: 25 L In certain embodiments, V H and V L are linked via a linker. In certain embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 177.

[0136] In certain embodiments, the heavy chain variable region (V H) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V H -V L In certain embodiments, the light chain variable region (V L ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V L -V H [Table 3]

[0137] In certain embodiments, the anti-DLL3 scFv is an scFv-Fc fusion protein or a VFv selected from Table 4. H Area and V L In certain embodiments, the anti-DLL3 scFv is a full-length human IgG having a V domain or CDR, as shown in Table 4, comprising the amino acid sequence set forth in SEQ ID NO: 34. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 34 is set forth in SEQ ID NO: 36. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 35. L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 35 is set forth in SEQ ID NO: 37. SEQ ID NOs: 34-37 are provided in Table 4. In certain embodiments, the scFv is designated "A18"

[0138] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO: 34. H and V comprising the amino acid sequence set forth in SEQ ID NO: 35 L SEQ ID NOs: 34 and 35 are provided in Table 4.

[0139] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 28 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 29 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30 or a conservative modification thereof. SEQ ID NOs: 28, 29, and 30 are provided in Table 4.

[0140] In certain embodiments, the anti-DLL3 scFv comprises a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 31 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 32 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 33 or a conservative modification thereof. SEQ ID NOs: 31, 32, and 33 are provided in Table 4.

[0141] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 28 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 29 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30 or a conservative modification thereof, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 31 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 32 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 33 or a conservative modification thereof.

[0142] In certain embodiments, the anti-DLL3 scFv comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 28, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 29, a V comprising the amino acid sequence set forth in SEQ ID NO: 30, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 31. H It includes a VH having a CDR3, and a VL having a CDR1 having the amino acid sequence set forth in SEQ ID NO: 31, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 32, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 33.

[0143] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO: 34. H and V comprising the amino acid sequence set forth in SEQ ID NO: 35L In certain embodiments, V H and V L are linked via a linker. In certain embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 177.

[0144] In certain embodiments, the heavy chain variable region (V H ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V H -V L In certain embodiments, the light chain variable region (V L ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V L -V H . [Table 4]

[0145] In certain embodiments, the anti-DLL3 scFv is an scFv-Fc fusion protein or a VFv selected from Table 5. H Area and V L In certain embodiments, the anti-DLL3 scFv is a full-length human IgG having a V domain or CDR, as shown in Table 5, comprising the amino acid sequence set forth in SEQ ID NO: 42. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 42 is set forth in SEQ ID NO: 44. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 43. L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 43 is set forth in SEQ ID NO: 45. SEQ ID NOs: 42-45 are provided in Table 5. In certain embodiments, the scFv is designated "E9."

[0146] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO:42. Hand V comprising the amino acid sequence set forth in SEQ ID NO: 43 L Includes:

[0147] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 39 or a conservative modification thereof. SEQ ID NOs: 21, 38 and -39 are provided in Table 5.

[0148] In certain embodiments, the anti-DLL3 scFv comprises a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 40 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 41 or a conservative modification thereof. SEQ ID NOs: 40, 5, and 41 are provided in Table 5.

[0149] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 39 or a conservative modification thereof, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 40 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 41 or a conservative modification thereof.

[0150] In certain embodiments, the anti-DLL3 scFv comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, a V comprising the amino acid sequence set forth in SEQ ID NO: 39, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40. H It includes a VH having a CDR3, and a VL having a CDR1 having the amino acid sequence set forth in SEQ ID NO: 40, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 41.

[0151] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO:42. H and V comprising the amino acid sequence set forth in SEQ ID NO: 43 L In certain embodiments, V H and V L are linked via a linker. In certain embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 177.

[0152] In certain embodiments, the heavy chain variable region (V H ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V H -V L In certain embodiments, the light chain variable region (V L ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V L -V H . [Table 5]

[0153] In certain embodiments, the anti-DLL scFv is an scFv-Fc fusion protein or a VFv selected from Table 6. H Area and V L In certain embodiments, the anti-DLL3 scFv is a full-length human IgG having a V domain or CDR. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 52 is set forth in SEQ ID NO: 54. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 53. L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 53 is set forth in SEQ ID NO: 55. SEQ ID NOs: 52-55 are provided in Table 6. In certain embodiments, the scFv is designated "G3."

[0154] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO: 52. H and V comprising the amino acid sequence set forth in SEQ ID NO: 53 L Includes:

[0155] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 47 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48 or a conservative modification thereof. SEQ ID NOs: 46-48 are provided in Table 6.

[0156] In certain embodiments, the anti-DLL3 scFv comprises a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 51 or a conservative modification thereof. SEQ ID NOs: 49, 50, and 51 are provided in Table 6.

[0157] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 47 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48 or a conservative modification thereof, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 51 or a conservative modification thereof.

[0158] In certain embodiments, the anti-DLL3 scFv comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 46, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 47, a V comprising the amino acid sequence set forth in SEQ ID NO: 48, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 49. HIt includes a VH having a CDR3, and a VL having a CDR1 having the amino acid sequence set forth in SEQ ID NO: 49, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 50, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 51.

[0159] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO: 52. H and V comprising the amino acid sequence set forth in SEQ ID NO: 53 L In certain embodiments, V H and V L are linked via a linker. In certain embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 177.

[0160] In certain embodiments, the heavy chain variable region (V H ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V H -V L In certain embodiments, the light chain variable region (V L ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V L -V H [Table 6]

[0161] In certain embodiments, the anti-DLL3 scFv is an scFv-Fc fusion protein or a VFv selected from Table 7. H Area and V L In certain embodiments, the anti-DLL3 scFv is a full-length human IgG having a V domain or CDR. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 60 is set forth in SEQ ID NO: 62. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 61.L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 61 is set forth in SEQ ID NO: 63. SEQ ID NOs: 60-63 are provided in Table 7. In certain embodiments, the scFv is designated "M11."

[0162] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO: 60. H and V comprising the amino acid sequence set forth in SEQ ID NO: 61. L Includes:

[0163] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 56 or a conservative modification thereof. SEQ ID NOs: 2, 21, and 56 are provided in Table 7.

[0164] In certain embodiments, the anti-DLL3 scFv comprises a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59 or a conservative modification thereof. SEQ ID NOs: 57-59 are provided in Table 7.

[0165] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 56 or a conservative modification thereof, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59 or a conservative modification thereof.

[0166] In certain embodiments, the anti-DLL3 scFv comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:21, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, a V comprising the amino acid sequence set forth in SEQ ID NO:56, and a V H It includes a VH having a CDR3, and a VL having a CDR1 having the amino acid sequence set forth in SEQ ID NO: 57, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 58, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 59.

[0167] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO: 60. H and V comprising the amino acid sequence set forth in SEQ ID NO: 61. L In certain embodiments, V H and V L are linked via a linker. In certain embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 177.

[0168] In certain embodiments, the heavy chain variable region (V H ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V H -V L In certain embodiments, the light chain variable region (V L ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V L -V H . [Table 7]

[0169] In certain embodiments, the anti-DLL3 scFv is an scFv-Fc fusion protein or a VFv selected from Table 8. H Area and V L In certain embodiments, the anti-DLL3 scFv is a full-length human IgG having a V domain or CDR.H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 66 is set forth in SEQ ID NO: 68. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 67. L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 67 is set forth in SEQ ID NO: 69. SEQ ID NOs: 66-69 are provided in Table 8. In certain embodiments, the scFv is designated "O24."

[0170] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO: 66. H and V comprising the amino acid sequence set forth in SEQ ID NO: 67 L Includes:

[0171] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 64 or a conservative modification thereof. SEQ ID NOs: 21, 2, and 64 are provided in Table 8.

[0172] In certain embodiments, the anti-DLL3 scFv comprises a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 65 or a conservative modification thereof. SEQ ID NOs: 4, 5, and 65 are provided in Table 8.

[0173] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 64 or a conservative modification thereof, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 65 or a conservative modification thereof.

[0174] In certain embodiments, the anti-DLL3 scFv comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:21, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, a V comprising the amino acid sequence set forth in SEQ ID NO:64, and a V H It includes a VH having a CDR3, and a VL having a CDR1 having the amino acid sequence set forth in SEQ ID NO: 4, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 65.

[0175] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO: 66. H and V comprising the amino acid sequence set forth in SEQ ID NO: 67 L In certain embodiments, V H and V L are linked via a linker. In certain embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 177.

[0176] In certain embodiments, the heavy chain variable region (V H ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V H -V L In certain embodiments, the light chain variable region (V L ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V L -V H . [Table 8]

[0177] In certain embodiments, the anti-DLL3 scFv is an scFv-Fc fusion protein or a VFv selected from Table 9. H Area and V L In certain embodiments, the anti-DLL3 scFv is a full-length human IgG having a V domain or CDR. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 76 is set forth in SEQ ID NO: 78. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 77. L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 77 is set forth in SEQ ID NO: 79. SEQ ID NOs: 76-79 are provided in Table 9. In certain embodiments, the scFv is designated "P4."

[0178] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO: 76. H and V comprising the amino acid sequence set forth in SEQ ID NO: 77 L Includes:

[0179] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 70 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 71 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72 or a conservative modification thereof. SEQ ID NOs: 70-72 are provided in Table 9.

[0180] In certain embodiments, the anti-DLL3 scFv comprises a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 75 or a conservative modification thereof. SEQ ID NOs: 73-75 are provided in Table 9.

[0181] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 70 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 71 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72 or a conservative modification thereof, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 75 or a conservative modification thereof.

[0182] In certain embodiments, the anti-DLL3 scFv comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 70, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 71, a V comprising the amino acid sequence set forth in SEQ ID NO: 72, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 73. H It includes a VH having a CDR3, and a VL having a CDR1 having the amino acid sequence set forth in SEQ ID NO: 73, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 74, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 75.

[0183] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO:78. H and V comprising the amino acid sequence set forth in SEQ ID NO: 79 L In certain embodiments, V H and V L are linked via a linker. In certain embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 177.

[0184] In certain embodiments, the heavy chain variable region (V H) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V H -V L In certain embodiments, the light chain variable region (V L ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V L -V H . [Table 9]

[0185] In certain embodiments, the anti-DLL3 scFv is an scFv-Fc fusion protein or a VFv selected from Table 10. H Area and V L In certain embodiments, the anti-DLL3 scFv is a full-length human IgG having a V domain or CDR. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 83 is set forth in SEQ ID NO: 85. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 84. L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 84 is set forth in SEQ ID NO: 86. SEQ ID NOs: 83-86 are provided in Table 10. In certain embodiments, the scFv is designated "J23."

[0186] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO: 83. H and V comprising the amino acid sequence set forth in SEQ ID NO: 84. L Includes:

[0187] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 80 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 81 or a conservative modification thereof. SEQ ID NOs: 21, 80, and 81 are provided in Table 10.

[0188] In certain embodiments, the anti-DLL3 scFv comprises a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 82 or a conservative modification thereof. SEQ ID NOs: 57, 58, and 82 are provided in Table 10.

[0189] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 80 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 81 or a conservative modification thereof, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 82 or a conservative modification thereof.

[0190] In certain embodiments, the anti-DLL3 scFv comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 80, a V comprising the amino acid sequence set forth in SEQ ID NO: 81, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 82. H It includes a VH having a CDR3, and a VL having a CDR1 having the amino acid sequence set forth in SEQ ID NO: 57, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 58, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 82.

[0191] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO: 83. H and V comprising the amino acid sequence set forth in SEQ ID NO: 84.L In certain embodiments, V H and V L are linked via a linker. In certain embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 177.

[0192] In certain embodiments, the heavy chain variable region (V H ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V H -V L In certain embodiments, the light chain variable region (V L ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V L -V H . [Table 10]

[0193] In certain embodiments, the anti-DLL3 scFv is an scFv-Fc fusion protein or a VFv selected from Table 11. H Area and V L In certain embodiments, the anti-DLL3 scFv is a full-length human IgG having a V domain or CDR, as shown in Table 1, comprising the amino acid sequence set forth in SEQ ID NO: 92. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 92 is set forth in SEQ ID NO: 94. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 93. L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 93 is set forth in SEQ ID NO: 95. SEQ ID NOs: 92-95 are provided in Table 11. In certain embodiments, the scFv is designated "K19."

[0194] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO: 92. Hand V comprising the amino acid sequence set forth in SEQ ID NO: 93 L Includes:

[0195] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 87 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 88 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 89 or a conservative modification thereof. SEQ ID NOs: 87-89 are provided in Table 11.

[0196] In certain embodiments, the anti-DDL3 scFv comprises a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 90 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 216 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 91 or a conservative modification thereof. SEQ ID NOs: 90, 32, and 91 are provided in Table 11.

[0197] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 87 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 88 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 89 or a conservative modification thereof, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 90 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 216 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 91 or a conservative modification thereof.

[0198] In certain embodiments, the anti-DLL3 scFv comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 87, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 88, a V comprising the amino acid sequence set forth in SEQ ID NO: 89, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 90. H It comprises a VH comprising a CDR3, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 216, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 32, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 91.

[0199] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO: 92. H and V comprising the amino acid sequence set forth in SEQ ID NO: 93 L In certain embodiments, V H and V L are linked via a linker. In certain embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 177.

[0200] In certain embodiments, the heavy chain variable region (V H ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V H -V L In certain embodiments, the light chain variable region (V L ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V L -V H . [Table 11]

[0201] In certain embodiments, the anti-DLL3 scFv is an scFv-Fc fusion protein or a VFv selected from Table 12. H Area and V L In certain embodiments, the anti-DLL3 scFv is a full-length human IgG having a V domain or CDR. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 102 is set forth in SEQ ID NO: 104. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 103. L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 103 is set forth in SEQ ID NO: 105. SEQ ID NOs: 102-105 are provided in Table 12. In certain embodiments, the scFv is designated "N10."

[0202] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO: 102. H and V comprising the amino acid sequence set forth in SEQ ID NO: 103. L Includes:

[0203] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 97 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 98 or a conservative modification thereof. SEQ ID NOs: 96-98 are provided in Table 12.

[0204] In certain embodiments, the anti-DLL3 scFv comprises a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 99 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 100 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 101 or a conservative modification thereof. SEQ ID NOs: 99-101 are provided in Table 12.

[0205] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 97 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 98 or a conservative modification thereof, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 99 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 100 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 101 or a conservative modification thereof.

[0206] In certain embodiments, the anti-DLL3 scFv comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 97, a V comprising the amino acid sequence set forth in SEQ ID NO: 98, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 99. HIt includes a VH having a CDR3, and a VL having a CDR1 having the amino acid sequence set forth in SEQ ID NO: 99, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 100, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 101.

[0207] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO: 103. H and V comprising the amino acid sequence set forth in SEQ ID NO: 103. L In certain embodiments, V H and V L are linked via a linker. In certain embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 177.

[0208] In certain embodiments, the heavy chain variable region (V H ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V H -V L In certain embodiments, the light chain variable region (V L ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V L -V H . [Table 12]

[0209] In certain embodiments, the anti-DLL3 scFv is an scFv-Fc fusion protein or a VFv selected from Table 13. H Area and V L In certain embodiments, the anti-DLL3 scFv is a full-length human IgG having a V domain or CDR. HAn exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 108 is set forth in SEQ ID NO: 110. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 109. L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 109 is set forth in SEQ ID NO: 111. SEQ ID NOs: 108-111 are provided in Table 13. In certain embodiments, the scFv is designated "B16-v1."

[0210] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO: 108. H and V comprising the amino acid sequence set forth in SEQ ID NO: 109 L Includes:

[0211] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 107 or a conservative modification thereof. SEQ ID NOs: 105-107 are provided in Table 13.

[0212] In certain embodiments, the anti-DLL3 scFv comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof, a V comprising the amino acid sequence set forth in SEQ ID NO: 82 or a conservative modification thereof, and a V comprising the amino acid sequence set forth in SEQ ID NO: 83 or a conservative modification thereof. L SEQ ID NOs: 57, 58 and 82 are provided in Table 13.

[0213] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 107 or a conservative modification thereof, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 82 or a conservative modification thereof.

[0214] In certain embodiments, the anti-DLL3 scFv comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106, a V comprising the amino acid sequence set forth in SEQ ID NO: 107, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 109. H It includes a VH having a CDR3, and a VL having a CDR1 having the amino acid sequence set forth in SEQ ID NO: 57, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 58, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 82.

[0215] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO: 108. H and V comprising the amino acid sequence set forth in SEQ ID NO: 109 L In certain embodiments, V H and V L are linked via a linker. In certain embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 177.

[0216] In certain embodiments, the heavy chain variable region (V H ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V H -V L In certain embodiments, the light chain variable region (V L ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V L -V H . [Table 13]

[0217] In certain embodiments, the anti-DLL3 scFv is an scFv-Fc fusion protein or a VFv selected from Table 14. H Area and V L In certain embodiments, the anti-DLL3 scFv is a full-length human IgG having a V domain or CDR. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 108 is set forth in SEQ ID NO: 110. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 113. L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 113 is set forth in SEQ ID NO: 114. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 108. H and V comprising the amino acid sequence set forth in SEQ ID NO: 113. L SEQ ID NOs: 108, 113, 110, and 114 are provided in Table 14. In certain embodiments, the scFv is designated "B16-v2."

[0218] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 107 or a conservative modification thereof. SEQ ID NOs: 21, 106 and 107 are provided in Table 14.

[0219] In certain embodiments, the anti-DLL3 scFv comprises a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112 or a conservative modification thereof. SEQ ID NOs: 4, 5, and 112 are provided in Table 14.

[0220] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 107 or a conservative modification thereof, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112 or a conservative modification thereof.

[0221] In certain embodiments, the anti-DLL3 scFv comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106, a V comprising the amino acid sequence set forth in SEQ ID NO: 107, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 109. H It comprises a VH comprising a CDR3, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112.

[0222] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO: 108. H and V comprising the amino acid sequence set forth in SEQ ID NO: 113. L In certain embodiments, V H and V L are linked via a linker. In certain embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 177.

[0223] In certain embodiments, the heavy chain variable region (V H) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V H -V L In certain embodiments, the light chain variable region (V L ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V L -V H . [Table 14]

[0224] In certain embodiments, the anti-DLL3 scFv is an scFv-Fc fusion protein or a VFv selected from Table 15. H Area and V L In certain embodiments, the anti-DLL3 scFv is a full-length human IgG having a V domain or CDR. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 119 is set forth in SEQ ID NO: 121. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 120. L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 120 is set forth in SEQ ID NO: 122. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 119. H and V comprising the amino acid sequence set forth in SEQ ID NO: 120. L SEQ ID NOs: 119-122 are provided in Table 15. In certain embodiments, the scFv is designated "E23."

[0225] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 115 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 116 or a conservative modification thereof. SEQ ID NOs: 96, 115, and 116 are provided in Table 15.

[0226] In certain embodiments, the anti-DLL3 scFv comprises a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 117 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 100 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 118 or a conservative modification thereof. SEQ ID NOs: 117, 100, and 118 are provided in Table 15.

[0227] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 115 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 116 or a conservative modification thereof, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 117 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 100 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 118 or a conservative modification thereof.

[0228] In certain embodiments, the anti-DLL3 scFv comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 115, a V comprising the amino acid sequence set forth in SEQ ID NO: 116, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 117. H It comprises a VH comprising a CDR3, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 117, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 100, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 118.

[0229] In certain embodiments, the anti-DLL3 scFv comprises a V sequence comprising the amino acid sequence set forth in SEQ ID NO: 119. Hand V comprising the amino acid sequence set forth in SEQ ID NO: 112. L In certain embodiments, V H and V L are linked via a linker. In certain embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 177.

[0230] In certain embodiments, the heavy chain variable region (V H ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V H -V L In certain embodiments, the light chain variable region (V L ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V L -V H . [Table 15]

[0231] In certain embodiments, the anti-DLL3 scFv is an scFv-Fc fusion protein or a VFv selected from Table 16. H Area and V L In certain embodiments, the anti-DLL3 scFv is a full-length human IgG having a V domain or CDR. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 126 is set forth in SEQ ID NO: 128. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 127. L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 127 is set forth in SEQ ID NO: 129. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 126. H and V comprising the amino acid sequence set forth in SEQ ID NO: 127 LSEQ ID NOs: 126-129 are provided in Table 16. In certain embodiments, the scFv is designated "F9."

[0232] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 123 or a conservative modification thereof. SEQ ID NOs: 21, 2, and 123 are provided in Table 16.

[0233] In certain embodiments, the anti-DLL3 scFv comprises a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 125 or a conservative modification thereof. SEQ ID NOs: 124, 58 and 125 are provided in Table 16.

[0234] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 123 or a conservative modification thereof, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 125 or a conservative modification thereof.

[0235] In certain embodiments, the anti-DLL3 scFv comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:21, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, a V comprising the amino acid sequence set forth in SEQ ID NO:123, and a V H It comprises a VH comprising a CDR3, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 125.

[0236] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO: 126. H and V comprising the amino acid sequence set forth in SEQ ID NO: 127 L In certain embodiments, V H and V L are linked via a linker. In certain embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 177.

[0237] In certain embodiments, the heavy chain variable region (V H ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V H -V L In certain embodiments, the light chain variable region (V L ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V L -V H . [Table 16]

[0238] In certain embodiments, the anti-DLL3 scFv is an scFv-Fc fusion protein or a VFv selected from Table 17. H Area and V L In certain embodiments, the anti-DLL3 scFv is a full-length human IgG having a V region or CDR. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 131 is set forth in SEQ ID NO: 133. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 132. L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 132 is set forth in SEQ ID NO: 134. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 131.H and V comprising the amino acid sequence set forth in SEQ ID NO: 132. L SEQ ID NOs: 131-134 are provided in Table 17. In certain embodiments, the scFv is designated "L12."

[0239] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 56 or a conservative modification thereof. SEQ ID NOs: 21, 2, and 56 are provided in Table 17.

[0240] In certain embodiments, the anti-DLL3 scFv comprises a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 130 or a conservative modification thereof. SEQ ID NOs: 57, 58, and 130 are provided in Table 17.

[0241] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 56 or a conservative modification thereof, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 130 or a conservative modification thereof.

[0242] In certain embodiments, the anti-DLL3 scFv comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:21, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, a V comprising the amino acid sequence set forth in SEQ ID NO:56, and a V HIt includes a VH having a CDR3, and a VL having a CDR1 having the amino acid sequence set forth in SEQ ID NO: 57, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 58, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 130.

[0243] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO: 131. H and V comprising the amino acid sequence set forth in SEQ ID NO: 132. L In certain embodiments, V H and V L are linked via a linker. In certain embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 177.

[0244] In certain embodiments, the heavy chain variable region (V H ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V H -V L In certain embodiments, the light chain variable region (V L ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V L -V H . [Table 17]

[0245] In certain embodiments, the anti-DLL3 scFv is an scFv-Fc fusion protein or a VFv selected from Table 18. H Area and V L In certain embodiments, the anti-DLL3 scFv is a full-length human IgG having a V region or CDR. HAn exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 141 is set forth in SEQ ID NO: 143. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 142. L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 142 is set forth in SEQ ID NO: 144. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 141. H and V comprising the amino acid sequence set forth in SEQ ID NO: 142 L SEQ ID NOs: 141-144 are provided in Table 18. In certain embodiments, the scFv is designated "B22."

[0246] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 135 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 136 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 137 or a conservative modification thereof. SEQ ID NOs: 135-137 are provided in Table 18.

[0247] In certain embodiments, the anti-DLL3 scFv comprises a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 138 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 139 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 140 or a conservative modification thereof. SEQ ID NOs: 138-140 are provided in Table 18.

[0248] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 135 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 136 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 137 or a conservative modification thereof, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 138 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 139 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 140 or a conservative modification thereof.

[0249] In certain embodiments, the anti-DLL3 scFv comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 135, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 136, a V comprising the amino acid sequence set forth in SEQ ID NO: 137, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 138. H It comprises a VH comprising a CDR3, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 138, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 139, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 140.

[0250] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO: 141. H and V comprising the amino acid sequence set forth in SEQ ID NO: 142 L In certain embodiments, V H and V L are linked via a linker. In certain embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 177.

[0251] In certain embodiments, the heavy chain variable region (V H ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V H -V L In certain embodiments, the light chain variable region (V L ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V L -V H . [Table 18]

[0252] In certain embodiments, the anti-DLL3 scFv is an scFv-Fc fusion protein or a VFv selected from Table 19. H Area and V LIn certain embodiments, the anti-DLL3 scFv is a full-length human IgG having a V domain or CDR. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 147 is set forth in SEQ ID NO: 149. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 148. L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 148 is set forth in SEQ ID NO: 150. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 147. H and V comprising the amino acid sequence set forth in SEQ ID NO: 148 L SEQ ID NOs: 147-150 are provided in Table 19. In certain embodiments, the scFv is designated "C22."

[0253] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 145 or a conservative modification thereof. SEQ ID NOs: 21, 2 and 145 are provided in Table 19.

[0254] In certain embodiments, the anti-DLL3 scFv comprises a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 146 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 125 or a conservative modification thereof. SEQ ID NOs: 57, 146, and 125 are provided in Table 19.

[0255] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 145 or a conservative modification thereof, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 146 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 125 or a conservative modification thereof.

[0256] In certain embodiments, the anti-DLL3 scFv comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:21, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, a V comprising the amino acid sequence set forth in SEQ ID NO:145, and a V H It comprises a VH comprising a CDR3, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 146, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 125.

[0257] In certain embodiments, the anti-DLL3 scFv comprises a V sequence comprising the amino acid sequence set forth in SEQ ID NO: 147. H and V comprising the amino acid sequence set forth in SEQ ID NO: 148 L In certain embodiments, V H and V L are linked via a linker. In certain embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 177.

[0258] In certain embodiments, the heavy chain variable region (V H ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V H -V L In certain embodiments, the light chain variable region (V L ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V L -V H . [Table 19]

[0259] In certain embodiments, the anti-DLL3 scFv is an scFv-Fc fusion protein or a VFv selected from Table 20. H Area and V L In certain embodiments, the anti-DLL3 scFv is a full-length human IgG having a V domain or CDR. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 153 is set forth in SEQ ID NO: 155. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 154. L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 154 is set forth in SEQ ID NO: 156. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 153. H and V comprising the amino acid sequence set forth in SEQ ID NO: 154. L SEQ ID NOs: 153-156 are provided in Table 20. In certain embodiments, the scFv is designated "D8."

[0260] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 151 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152 or a conservative modification thereof. SEQ ID NOs: 151, 2 and 152 are provided in Table 20.

[0261] In certain embodiments, the anti-DLL3 scFv comprises a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 82 or a conservative modification thereof. SEQ ID NOs: 57, 58, and 82 are provided in Table 20.

[0262] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 151 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152 or a conservative modification thereof, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 82 or a conservative modification thereof.

[0263] In certain embodiments, the anti-DLL3 scFv comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 151, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a V comprising the amino acid sequence set forth in SEQ ID NO: 152, and a V H It includes a VH having a CDR3, and a VL having a CDR1 having the amino acid sequence set forth in SEQ ID NO: 57, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 58, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 82.

[0264] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO: 153. H and V comprising the amino acid sequence set forth in SEQ ID NO: 154. L In certain embodiments, V H and V L are linked via a linker. In certain embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 177.

[0265] In certain embodiments, the heavy chain variable region (V H) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V H -V L In certain embodiments, the light chain variable region (V L ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V L -V H . [Table 20]

[0266] In certain embodiments, the anti-DLL3 scFv is an scFv-Fc fusion protein or a VFv selected from Table 21. H Area and V L In certain embodiments, the anti-DLL3 scFv is a full-length human IgG having a V domain or CDR. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 157 is set forth in SEQ ID NO: 159. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 158. L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 158 is set forth in SEQ ID NO: 160. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 157. H and V comprising the amino acid sequence set forth in SEQ ID NO: 158 L SEQ ID NOs: 157-160 are provided in Table 21. In certain embodiments, the scFv is designated "G16."

[0267] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 123 or a conservative modification thereof. SEQ ID NOs: 21, 2 and 123 are provided in Table 21.

[0268] In certain embodiments, the anti-DLL3 scFv comprises a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59 or a conservative modification thereof. SEQ ID NOs: 124, 58 and 59 are provided in Table 21.

[0269] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 123 or a conservative modification thereof, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59 or a conservative modification thereof.

[0270] In certain embodiments, the anti-DLL3 scFv comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:21, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, a V comprising the amino acid sequence set forth in SEQ ID NO:123, and a V H It comprises a VH comprising a CDR3, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59.

[0271] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO: 157. H and V comprising the amino acid sequence set forth in SEQ ID NO: 158L In certain embodiments, V H and V L are linked via a linker. In certain embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 177.

[0272] In certain embodiments, the heavy chain variable region (V H ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V H -V L In certain embodiments, the light chain variable region (V L ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V L -V H . [Table 21]

[0273] In certain embodiments, the anti-DLL3 scFv is an scFv-Fc fusion protein or a VFv selected from Table 22. H Area and V L In certain embodiments, the anti-DLL3 scFv is a full-length human IgG having a V domain or CDR. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 163 is set forth in SEQ ID NO: 165. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 164. L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 164 is set forth in SEQ ID NO: 166. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 163. H and V comprising the amino acid sequence set forth in SEQ ID NO: 164. LSEQ ID NOs: 163-166 are provided in Table 22. In certain embodiments, the scFv is designated "F21."

[0274] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 136 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 161 or a conservative modification thereof. SEQ ID NOs: 11, 136, and 161 are provided in Table 22.

[0275] In certain embodiments, the anti-DLL3 scFv comprises a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 162 or a conservative modification thereof. SEQ ID NOs: 73, 74, and 162 are provided in Table 22.

[0276] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 136 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 161 or a conservative modification thereof, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 162 or a conservative modification thereof.

[0277] In certain embodiments, the anti-DLL3 scFv comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 136, a V comprising the amino acid sequence set forth in SEQ ID NO: 161, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 172. H It includes a VH having a CDR3, and a VL having a CDR1 having the amino acid sequence set forth in SEQ ID NO: 73, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 74, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 162.

[0278] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO: 163. H and V comprising the amino acid sequence set forth in SEQ ID NO: 164. L In certain embodiments, V H and V L are linked via a linker. In certain embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 177.

[0279] In certain embodiments, the heavy chain variable region (V H ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V H -V L In certain embodiments, the light chain variable region (V L ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V L -V H . [Table 22]

[0280] In certain embodiments, the anti-DLL3 scFv is an scFv-Fc fusion protein or a VFv selected from Table 23. H Area and V L In certain embodiments, the anti-DLL3 scFv is a full-length human IgG having a V domain or CDR. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 172 is set forth in SEQ ID NO: 174. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 173. L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 173 is set forth in SEQ ID NO: 175. In certain embodiments, the anti-DLL3 scFv comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 172.H and V comprising the amino acid sequence set forth in SEQ ID NO: 173 L SEQ ID NOs: 172-175 are provided in Table 23. In certain embodiments, the scFv is designated "N12."

[0281] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 167 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 168 or a conservative modification thereof. SEQ ID NOs: 96, 167 and 168 are provided in Table 23.

[0282] In certain embodiments, the anti-DLL3 scFv comprises a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 169 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 170 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 171 or a conservative modification thereof. SEQ ID NOs: 169-171 are provided in Table 23.

[0283] In certain embodiments, the anti-DLL3 scFv comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 167 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 168 or a conservative modification thereof, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 169 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 170 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 171 or a conservative modification thereof.

[0284] In certain embodiments, the anti-DLL3 scFv comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 167, a V comprising the amino acid sequence set forth in SEQ ID NO: 168, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 190. HIt comprises a VH comprising a CDR3, and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 169, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 170, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 171.

[0285] In certain embodiments, the anti-DLL3 scFv comprises a V scFv comprising the amino acid sequence set forth in SEQ ID NO: 172. H and V comprising the amino acid sequence set forth in SEQ ID NO: 173 L In certain embodiments, V H and V L are linked via a linker. In certain embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 177.

[0286] In certain embodiments, the heavy chain variable region (V H ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V H -V L In certain embodiments, the light chain variable region (V L ) is positioned at the N-terminus. In certain embodiments, the variable region is positioned from N-terminus to C-terminus: V L -V H . [Table 23]

[0287] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof is selected from Table 24. H Area and V L In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a V region or CDR comprising the amino acid sequence set forth in SEQ ID NO: 187, as shown in Table 24. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 187 is set forth in SEQ ID NO: 189. In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 188.L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 188 is set forth in SEQ ID NO: 190. In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 187. H and V comprising the amino acid sequence set forth in SEQ ID NO: 188 L SEQ ID NOs: 187-190 are provided in Table 24. In certain embodiments, the antibody or antigen-binding fragment thereof is designated as "G23."

[0288] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 183 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 184 or a conservative modification thereof. H SEQ ID NOs: 21, 183 and 184 are provided in Table 24.

[0289] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 185 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 186 or a conservative modification thereof. L SEQ ID NOs: 50, 185 and 186 are provided in Table 24.

[0290] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:21 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:184 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:185 or a conservative modification thereof. H and a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 186 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 187 or a conservative modification thereof. LIncludes:

[0291] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:21, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:183, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:184. H and V comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 185, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 186. L Includes: [Table 24]

[0292] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof is selected from Table 25. H Area and V L In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a V region or CDR comprising the amino acid sequence set forth in SEQ ID NO: 197, as shown in Table 25. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 197 is set forth in SEQ ID NO: 199. In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 198. L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 198 is set forth in SEQ ID NO: 200. In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 197. H and V comprising the amino acid sequence set forth in SEQ ID NO: 198 L SEQ ID NOs: 197-200 are provided in Table 25. In certain embodiments, the antibody or antigen-binding fragment thereof is designated as "I1."

[0293] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 191 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 192 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 193 or a conservative modification thereof. H SEQ ID NOs: 191-193 are provided in Table 25.

[0294] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 194 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 195 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 196 or a conservative modification thereof. L SEQ ID NOs: 194-196 are provided in Table 25.

[0295] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 191 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 192 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 193 or a conservative modification thereof. H and a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 194 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 195 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 196 or a conservative modification thereof. L Includes:

[0296] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 191, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 192, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 193. H and V comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 194, CDR2 having the amino acid sequence set forth in SEQ ID NO: 195, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 196. LIncludes: [Table 25]

[0297] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof is selected from Table 26. H Area and V L In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a V region or CDR comprising the amino acid sequence set forth in SEQ ID NO:204, as shown in Table 26. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 204 is set forth in SEQ ID NO: 206. In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 205. L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 205 is set forth in SEQ ID NO: 207. In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 204. H and V comprising the amino acid sequence set forth in SEQ ID NO: 205 L SEQ ID NOs:204-207 are provided in Table 26. In certain embodiments, the antibody or antigen-binding fragment thereof is designated as "C8."

[0298] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 201 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 202 or a conservative modification thereof. H SEQ ID NOs: 11, 201 and 202 are provided in Table 26.

[0299] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:203 or a conservative modification thereof. L SEQ ID NOs: 4, 5 and 203 are provided in Table 26.

[0300] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 201 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 202 or a conservative modification thereof. H and a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:203 or a conservative modification thereof. L Includes:

[0301] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 201, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 202. H and V comprising CDR1 having the amino acid sequence set forth in SEQ ID NO:4, CDR2 having the amino acid sequence set forth in SEQ ID NO:5, and CDR3 having the amino acid sequence set forth in SEQ ID NO:203. L Includes: [Table 26]

[0302] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof is selected from Table 27. H Area and V LIn certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a V region or CDR comprising the amino acid sequence set forth in SEQ ID NO:212, as shown in Table 27. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 212 is set forth in SEQ ID NO: 214. In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 213. L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 213 is set forth in SEQ ID NO: 215. In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 212. H and V comprising the amino acid sequence set forth in SEQ ID NO: 213 L SEQ ID NOs:212-215 are provided in Table 27. In certain embodiments, the antibody or antigen-binding fragment thereof is designated as "O18."

[0303] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 208 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 209 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 210 or a conservative modification thereof. H SEQ ID NOs: 208-210 are provided in Table 27.

[0304] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 211 or a conservative modification thereof. L SEQ ID NOs: 57, 58 and 211 are provided in Table 27.

[0305] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 208 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 209 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 210 or a conservative modification thereof. H and a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 211 or a conservative modification thereof. L Includes:

[0306] In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 201, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 209, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 210. H and V comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 57, CDR2 having the amino acid sequence set forth in SEQ ID NO: 58, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 211. L Includes: [Table 27]

[0307] 5.3.2 Monoclonal antibodies The presently disclosed subject matter provides antibodies (e.g., human antibodies, e.g., human monoclonal antibodies) that specifically bind to DLL3 (e.g., human DLL3). Anti-DLL3 antibodies J8, L22, B2, A18, E9, G3, M11, O24, P4, J23, K19, N10, B16-v1, B16-v2, E23, F9, L12, B22, C22, D8, G16, F21, N12, G23, I1, C8, and O18 V HThe amino acid sequences are set forth in SEQ ID NOs: 7, 17, 24, 34, 42, 52, 60, 66, 76, 83, 92, 102, 108, 119, 126, 131, 141, 147, 153, 157, 163, 172, 187, 197, 204, and 212, respectively. L The amino acid sequences are set forth in SEQ ID NOs: 8, 18, 25, 35, 43, 53, 61, 67, 77, 84, 93, 103, 109, 113, 120, 127, 132, 142, 148, 154, 158, 164, 173, 188, 198, 205, and 213, respectively.

[0308] Considering that each of the J8, L22, B2, A18, E9, G3, M11, O24, P4, J23, K19, N10, B16-v1, B16-v2, E23, F9, L12, B22, C22, D8, G16, F21, N12, G23, I1, C8, and O18 antibodies can bind to DLL3, V H Sequence and V L Sequences can be "mixed and matched" to create other anti-DLL3 binding molecules. DLL3 binding of such "mixed and matched" antibodies can be tested using binding assays known in the art, including, for example, ELISAs, Western blots, RIAs, and Biacore analysis. Preferably, V H Chain and V L When chains are mixed and matched, a particular V H / V L V from involution H The sequence is structurally similar to V H Similarly, a particular V H / V L V from involution L The sequence is structurally similar to V L It is replaced by an array.

[0309] In certain embodiments, the presently disclosed subject matter provides a heavy chain variable region (V) comprising an amino acid sequence selected from the group consisting of: (a) SEQ ID NOs: 7, 17, 24, 34, 42, 52, 60, 66, 76, 83, 92, 102, 108, 119, 126, 131, 141, 147, 153, 157, 163, 172, 187, 197, 204, and 212. H ), and (b) a light chain variable region (V) comprising an amino acid sequence selected from SEQ ID NOs: 8, 18, 25, 35, 43, 53, 61, 67, 77, 84, 93, 103, 109, 113, 120, 127, 132, 142, 148, 154, 158, 164, 173, 188, 198, 205, and 213. L ), wherein the antibody or antigen-binding fragment specifically binds to DLL3, e.g., human DLL3. In certain embodiments, V H and V L teeth, (a) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 8; (b) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 17, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 18; (c) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 24, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 25; (d) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 34, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 35; (e) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 42, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 43; (f) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 52, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 53; (g) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 60, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 61; (h) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 66, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 67; (i) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 76, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; (j) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 83, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 84; (k) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 92, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 93; (l) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 102, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 103; (m) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 108, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 109; (n) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 108, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 113; (o) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 119, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 120; (p) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 126, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 127; (q) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 131, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 132; (r) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 141, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 142; (s) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 147, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 148; (t) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 153, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 154; (u) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 157, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 158; (v) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 163, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 164; (w) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 172, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 173; (x) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 187, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 188; (y) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 197, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 198; (z) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 204, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 205; (aa) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 212, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 213.

[0310] In certain embodiments, the presently disclosed subject matter provides antibodies or antigen-binding fragments thereof comprising the heavy and light chain CDR1s, CDR2s, and CDR3s of J8, L22, B2, A18, E9, G3, M11, O24, P4, J23, K19, N10, B16-v1, B16-v2, E23, F9, L12, B22, C22, D8, G16, F21, N12, G23, I1, C8, and O18.

[0311] J8, L22, B2, A18, E9, G3, M11, O24, P4, J23, K19, N10, B16-v1, B16-v2, E23, F9, L12, B22, C22, D8, G16, F21, N12, G23, I1, C8, and O18 V HThe amino acid sequences of CDR1 are shown in SEQ ID NOs: 1, 11, 21, 28, 46, 70, 87, 96, 135, 151, 191, and 208, respectively. H The amino acid sequences of CDR2 are set forth in SEQ ID NOs: 2, 12, 29, 38, 47, 71, 80, 88, 97, 106, 115, 136, 167, 183, 192, 201, and 209, respectively. H The amino acid sequences of CDR3 are set forth in SEQ ID NOs: 3, 13, 22, 30, 39, 48, 56, 64, 72, 81, 89, 98, 107, 116, 123, 137, 145, 152, 161, 168, 184, 193, 202, and 210, respectively.

[0312] J8, L22, B2, A18, E9, G3, M11, O24, P4, J23, K19, N10, B16-v1, B16-v2, E23, F9, L12, B22, C22, D8, G16, F21, N12, G23, I1, C8, and O18 V L The amino acid sequences of CDR1 are set forth in SEQ ID NOs: 4, 14, 31, 40, 49, 57, 73, 90, 99, 117, 124, 138, 169, 185, and 194, respectively. LThe amino acid sequences of CDR2 are set forth in SEQ ID NOs: 5, 15, 32, 50, 58, 74, 100, 139, 146, 170, 195, and 216. The V sequences of J8, L22, B2, A18, E9, G3, M11, O24, P4, J23, K19, N10, B16-v1, B16-v2, E23, F9, L12, B22, C22, D8, G16, F21, N12, G23, I1, C8, and O18 are set forth in SEQ ID NOs: 5, 15, 32, 50, 58, 74, 100, 139, 146, 170, 195, and 216. L The amino acid sequences of CDR3 are set forth in SEQ ID NOs: 6, 16, 23, 33, 41, 51, 59, 65, 75, 82, 91, 101, 112, 118, 125, 130, 140, 162, 171, 186, 196, 203, and 211, respectively. CDR regions are delineated using the IMGT system. In certain embodiments, CDR regions are delineated using the IMGT numbering system, accessible at http: / / www.imgt.org / IMGT_vquest / input.

[0313] Given that each of these antibodies or antigen-binding fragments thereof can bind to DLL3 and that antigen-binding specificity is provided primarily by the CDR1, CDR2, and CDR3 regions, V H CDR1 sequence, V H CDR2 sequence, and V H CDR3 sequence and V L CDR1 sequence, V L CDR2 sequence, and V L CDR3 sequences can be "mixed and matched" to create other anti-DLL3 binding molecules (i.e., CDRs from different antibodies can be mixed and matched, but each antibody must have the same V H CDR1, V H CDR2 and V H CDR3 and V L CDR1, V L CDR2 and V L CDR3). DLL3 binding of such "mixed and matched" antibodies can be tested using the binding assays described above. H When CDR sequences are mixed and matched, a particular V HThe CDR1, CDR2, and / or CDR3 sequences from the sequence are replaced with structurally similar CDR sequence(s). L When mixing and matching CDR sequences, a particular V L The CDR1, CDR2, and / or CDR3 sequences derived from the sequence are preferably replaced with structurally similar CDR sequences. H Sequence and V L The sequences are structurally similar to the CDR sequences of the antibodies or antigen-binding fragments thereof disclosed herein, including J8, L22, B2, A18, E9, G3, M11, O24, P4, J23, K19, N10, B16-v1, B16-v2, E23, F9, L12, B22, C22, D8, G16, F21, N12, G23, I1, C8, and O18, and H CDR region sequences and / or V L It will be readily apparent that these can be produced by substituting CDR region sequences.

[0314] In certain embodiments, the subject matter disclosed herein comprises: (a) a heavy chain variable region CDR1 comprising an amino acid sequence selected from SEQ ID NOs: 1, 11, 21, 28, 46, 70, 87, 96, 135, 151, 191, and 208; (b) a heavy chain variable region CDR2 comprising an amino acid sequence selected from SEQ ID NOs: 2, 12, 29, 38, 47, 71, 80, 88, 97, 106, 115, 136, 167, 183, 192, 201, and 209; (c) a heavy chain variable region CDR3 comprising an amino acid sequence selected from SEQ ID NOs: 3, 13, 22, 30, 39, 48, 56, 64, 72, 81, 89, 98, 107, 116, 123, 137, 145, 152, 161, 168, 184, 193, 202, and 210; (d) a light chain variable region CDR1 comprising an amino acid sequence selected from SEQ ID NOs: 4, 14, 31, 40, 49, 57, 73, 90, 99, 117, 124, 138, 169, 185, and 194; (e) a light chain variable region CDR2 comprising an amino acid sequence selected from SEQ ID NOs: 5, 15, 32, 50, 58, 74, 100, 139, 146, 170, 195, and 216; and (f) An antibody or antigen-binding fragment thereof is provided, which comprises a light chain variable region CDR3 comprising an amino acid sequence selected from SEQ ID NOs: 6, 16, 23, 33, 41, 51, 59, 65, 75, 82, 91, 101, 112, 118, 125, 130, 140, 162, 171, 186, 196, 203, and 211.

[0315] In certain embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5; and (f) A light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO:6.

[0316] In certain embodiments, the antibody or antigen-binding fragment comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15; and (f) A light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16.

[0317] In certain embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 22; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5; and (f) A light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 23.

[0318] In certain embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 28; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 29; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 31; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 32; and (f) A light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 33.

[0319] In certain embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 39; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 40; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5; and (f) A light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 41.

[0320] In certain embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 46; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 47; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 51;

[0321] In certain embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 56; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59;

[0322] In certain embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 70; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 71; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 75;

[0323] In certain embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 80; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 81; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 82;

[0324] In certain embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 87; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 88; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 89; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 90; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 216; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 91;

[0325] In certain embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 97; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 98; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 99; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 100; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 101;

[0326] In certain embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 107; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 82;

[0327] In certain embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 107; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112.

[0328] In certain embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 95; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 115; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 116; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 117; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 100; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 118;

[0329] In certain embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 123; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 125.

[0330] In certain embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 56; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 130;

[0331] In certain embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 135; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 136; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 137; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 138; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 139; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 140.

[0332] In certain embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 145; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 146; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 125.

[0333] In certain embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 151; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 82;

[0334] In certain embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 123; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59;

[0335] In certain embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 136; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 161; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 162.

[0336] In certain embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 167; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 168; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 169; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 170; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 171;

[0337] In certain embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 183; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 184; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 185; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 186;

[0338] In certain embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 191; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 192; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 193; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 194; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 195; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 196.

[0339] In certain embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 201; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 202; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 203.

[0340] In certain embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 208; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 209; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 210; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 211;

[0341] The constant / framework regions of the anti-DLL3 antibodies disclosed herein can be modified, for example, by amino acid substitutions, to alter the properties of the antibody (e.g., to increase or decrease one or more of antigen binding affinity, Fc receptor binding, antibody carbohydrate, e.g., glycosylation, fucosylation, etc., number of cysteine ​​residues, effector cell function, complement function, or introduction of conjugation sites).

[0342] In certain embodiments, the anti-DLL3 antibodies disclosed herein are fully human antibodies, such as any one of J8, L22, B2, A18, E9, G3, M11, O24, P4, J23, K19, N10, B16-v1, B16-v2, E23, F9, L12, B22, C22, D8, G16, F21, N12, G23, I1, C8, and O18. Fully human mAbs cause serious side effects when administered to humans, including anaphylactic and hypersensitivity reactions.

[0343] The use of phage display libraries has made it possible to select large antibody repertoires for unique, rare Abs directed against highly defined epitopes (for further details on phage display, see McCafferty et al., Phage antibodies: filamentous phage displaying antibody variable domains. Nature, 348:552-554). Thus, rapid identification of human Fab or single-chain Fv (scFv) fragments highly specific for tumor antigen-derived peptide-MHC complex molecules has become possible. In addition, by using Fab fragments to engineer full-length monoclonal antibodies (mAbs), it is possible to directly generate therapeutic human mAbs, bypassing the several months of time-consuming work typically required for developing therapeutic mAbs. The subject matter disclosed herein includes, for example, the development of fully human mAbs that recognize a human DLL3 polypeptide (e.g., a polypeptide having the amino acid sequence set forth in SEQ ID NO: 116) for cancer therapy.

[0344] 5.3.3 Homologous antibodies In certain embodiments, the antibodies or antigen-binding fragments thereof disclosed herein comprise heavy and light chain variable regions comprising amino acid sequences that are homologous or identical to the amino acid sequences of the antibodies described herein (e.g., J8, L22, B2, A18, E9, G3, M11, O24, P4, J23, K19, N10, B16-v1, B16-v2, E23, F9, L12, B22, C22, D8, G16, F21, N12, G23, I1, C8, and O18 antibodies), and the antibodies or antigen-binding fragments thereof retain the desired functional properties of the subject anti-DLL3 antibodies or antigen-binding fragments thereof disclosed herein.

[0345] For example, the presently disclosed subject matter includes an antibody or antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region, (a) the heavy chain variable region comprises an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:60, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:83, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:108, SEQ ID NO:119, SEQ ID NO:126, SEQ ID NO:131, SEQ ID NO:141, SEQ ID NO:147, SEQ ID NO:153, SEQ ID NO:157, SEQ ID NO:163, SEQ ID NO:172, SEQ ID NO:187, SEQ ID NO:197, SEQ ID NO:204, or SEQ ID NO:212; (b) the light chain variable region is selected from SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:61, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:84, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:109, SEQ ID NO:113, SEQ ID NO:120, SEQ ID NO:127, SEQ ID NO:132, SEQ ID NO:142, SEQ ID NO:148, SEQ ID NO:154, SEQ ID NO:158, SEQ ID NO:164, SEQ ID NO:173, SEQ ID NO: The present invention provides an antibody or antigen-binding fragment thereof comprising an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO:188, SEQ ID NO:198, SEQ ID NO:205, or SEQ ID NO:213.

[0346] In certain embodiments, V H Amino acid sequence and / or V L The amino acid sequence can be at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the sequences set forth above. H Area and V L V with high (i.e., 80% or more) homology or identity to the region H Area and V L Antibodies having regions can be obtained by mutagenesis (e.g., site-directed or PCR-mediated mutagenesis) followed by testing the encoded modified antibody for retained function (i.e., binding affinity) using the binding assays described herein.

[0347] As used herein, the percent homology between two amino acid sequences corresponds to the percent identity between the two sequences. The percent identity or homology between two sequences is a function of the number of identical positions shared by the sequences (i.e., % homology = number of identical positions / total number of positions x 100), taking into account the number of gaps and the length of each gap that need to be introduced for optimal alignment of the two sequences. Comparing sequences and determining percent identity between two sequences can be accomplished using a mathematical algorithm, as described in the non-limiting examples below.

[0348] The percent homology or identity between two amino acid sequences can be determined using the algorithm of E. Meyers and W. Miller (Comput Appl Biosci (1988); 14:11-17) incorporated into the ALIGN program (version 2.0) using a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4. Additionally, the percent homology between two amino acid sequences can be determined using the algorithm of Needleman and Wunsch (J Mol Biol (1970); 48:444-453) incorporated into the GAP program in the GCG software package (available at www.gcg.com) using either a Blossum62 matrix or a PAM250 matrix, and gap weights of 16, 14, 12, 10, 8, 6, or 4, and length weights of 1, 2, 3, 4, 5, or 6.

[0349] Additionally or alternatively, the subject protein sequences described herein can be further used as a "query sequence" to conduct a search against public databases, for example, to identify related sequences. Such searches can be performed using the XBLAST program (version 2.0) of Altschul et al., J Mol Biol (1990); 215:403-10. To obtain amino acid sequences homologous to the antibody molecules of the present invention, BLAST protein searches can be performed with the XBLAST program, score = 50, word length = 3. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., Nucleic Acids Res (1997); 25(17):3389-3402. When utilizing BLAST, Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used.

[0350] 5.3.4 Antibodies with Conservative Modifications In certain embodiments, the antibodies or antigen-binding fragments thereof disclosed herein comprise a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences, wherein one or more of these CDR sequences comprise a specific amino acid sequence or conservative modification thereof based on a preferred antibody described herein (e.g., J8, L22, B2, A18, E9, G3, M11, O24, P4, J23, K19, N10, B16-v1, B16-v2, E23, F9, L12, B22, C22, D8, G16, F21, N12, G23, I1, C8, and O18 antibodies), and the antibody retains desired functional properties of the subject anti-DLL3 antibodies or antigen-binding fragments thereof disclosed herein. The presently disclosed subject matter includes an antibody or antigen-binding fragment thereof, comprising a heavy chain variable region comprising a CDR1 sequence, a CDR2 sequence, and a CDR3 sequence, and a light chain variable region comprising a CDR1 sequence, a CDR2 sequence, and a CDR3 sequence, (a) the heavy chain variable region CDR3 sequence comprises an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 3, 13, 22, 30, 39, 48, 56, 64, 72, 81, 89, 98, 107, 116, 123, 137, 145, 152, 161, 168, 184, 193, 202, and 210, and conservative modifications thereof; (b) An antibody or antigen-binding fragment thereof, wherein the light chain variable region CDR3 sequence comprises an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 6, 16, 23, 33, 41, 51, 59, 65, 75, 82, 91, 101, 112, 118, 125, 130, 140, 162, 171, 186, 196, 203, and 212, and conservative modifications thereof.

[0351] In certain embodiments, the heavy chain variable region CDR3 sequence comprises an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 3, 13, 22, 30, 39, 48, 56, 64, 72, 81, 89, 98, 107, 116, 123, 137, 145, 152, 161, 168, 184, 193, 202, and 210, and conservative modifications thereof; and the light chain variable region CDR3 sequence comprises an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 6, 16, 23, 33, 41, 51, 59, 65, 75, 82, 91, 101, 112, 118, 125, 130, 140, 162, 171, 186, 196, 203, and 212, and conservative modifications thereof.

[0352] In certain embodiments, the heavy chain variable region CDR2 sequence comprises an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 2, 12, 29, 38, 47, 71, 80, 88, 97, 106, 115, 136, 167, 183, 192, 201, and 209, and conservative modifications thereof, and the light chain variable region CDR2 sequence comprises an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5, 15, 32, 50, 58, 74, 100, 139, 146, 170, 195, and 216, and conservative modifications thereof.

[0353] In certain embodiments, the CDR1 sequence of the heavy chain variable region comprises an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 1, 11, 21, 28, 46, 70, 87, 96, 135, 151, 191, and 208, and conservative modifications thereof, and the CDR1 sequence of the light chain variable region comprises an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 4, 14, 31, 40, 49, 57, 73, 90, 99, 117, 124, 138, 169, 185, and 194, and conservative modifications thereof.

[0354] As used herein, the term "conservative sequence modifications" is intended to refer to amino acid modifications that do not significantly affect or significantly alter the binding characteristics of the antibody containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions, and deletions. Modifications can be introduced into the antibodies of the disclosure by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis.

[0355] A conservative amino acid substitution is one in which an amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues with similar side chains have been defined in the art. Representative conservative amino acid substitutions are shown in Table 24. Amino acid substitutions can be introduced into an antibody of interest, and the products screened for a desired activity, e.g., retained / improved antigen binding, reduced immunogenicity, or improved ADCC or CDC. In certain embodiments, the sequences disclosed herein, e.g., CDR sequences, V H Sequence, or V L The sequence can have up to about 1, up to about 2, up to about 3, up to about 4, up to about 5, up to about 6, up to about 7, up to about 8, up to about 9, or up to about 10 amino acid residues modified and / or substituted. [Table 24-2]

[0356] Amino acids can be classified according to general side chain properties: Hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile, ●Neutral hydrophilicity: Cys, Ser, Thr, Asn, Gln, ●Acidic: Asp, Glu, ●Basic: His, Lys, Arg, Residues that affect chain orientation: Gly, Pro, ●Aromatics: Trp, Tyr, Phe.

[0357] Non-conservative substitutions entail exchanging a member of one of these classes for a member of another class.

[0358] 5.3.5 Anti-DLL3 Antibodies that Cross-Compete with Anti-DLL3 Antibodies of the Invention for Binding to DLL3 The presently disclosed subject matter provides antibodies or antigen-binding fragments thereof that cross-compete with any of the disclosed anti-DLL3 antibodies for binding to DLL3 (e.g., human DLL3). For example, without limitation, a cross-competing antibody can bind to the same epitope region, e.g., the same epitope, an adjacent epitope, or an overlapping region, as any of the anti-DLL3 antibodies or antigen-binding fragments thereof of the presently disclosed subject matter. In certain embodiments, the reference antibody or reference antigen-binding fragment thereof for cross-competition studies can be any one of the anti-DLL3 antibodies or antigen-binding fragments thereof disclosed herein, such as the J8, L22, B2, A18, E9, G3, M11, O24, P4, J23, K19, N10, B16-v1, B16-v2, E23, F9, L12, B22, C22, D8, G16, F21, N12, G23, I1, C8, and O18 antibodies.

[0359] Such cross-competing antibodies can be identified based on their ability to cross-compete with any one of the anti-DLL3 antibodies or antigen-binding fragments thereof disclosed herein in standard DLL3 binding assays. For example, Biacore analysis, ELISA assays, or flow cytometry can be used to demonstrate cross-competition with the antibodies of the presently disclosed subject matter. The ability of a test antibody to inhibit the binding of, for example, any one of the anti-DLL3 antibodies disclosed herein (e.g., J8, L22, B2, A18, E9, G3, M11, O24, P4, J23, K19, N10, B16-v1, B16-v2, E23, F9, L12, B22, C22, D8, G16, F21, N12, G23, I1, C8, and O18 antibodies) to DLL3 (e.g., human DLL3) demonstrates that the test antibody can compete with any one of the anti-DLL3 antibodies or antigen-binding fragments thereof disclosed herein for binding to DLL3 (e.g., human DLL3) and thus binds to the same epitope region on DLL3 (e.g., human DLL3) as any one of the anti-DLL3 antibodies or antigen-binding fragments thereof disclosed herein. In certain embodiments, the cross-competing antibody or antigen-binding fragment thereof binds to the same epitope on DLL3 (e.g., human DLL3) as any one of the anti-DLL3 antibodies or antigen-binding fragments thereof disclosed herein.

[0360] 5.3.6 Characterization of antibody binding to antigen The subject antibodies or antigen-binding fragments thereof disclosed herein can be tested for binding to DLL3, for example, by standard ELISA. To determine whether selected anti-DLL3 antibodies bind to unique epitopes, each antibody can be biotinylated using commercially available reagents (Pierce, Rockford, IL). Competition studies using unlabeled and biotinylated monoclonal antibodies can be performed using the DLL3-coated ELISA plates described above. Biotinylated mAb binding can be detected using a strep-avidin-alkaline phosphatase probe.

[0361] To determine the isotype of purified antibodies, isotype ELISAs can be performed using reagents specific for antibodies of a particular isotype. Anti-DLL3 human IgG can be further tested for reactivity with the DLL3 antigen by Western blotting.

[0362] In certain embodiments, K D is measured by radiolabeled antigen binding assay (RIA). In certain embodiments, an RIA is performed on the Fab version of the antibody of interest and its antigen. For example, the solution binding affinity of the Fab for the antigen is measured by measuring the binding affinity of the Fab to the antigen at the lowest concentration ( 125 I) It is measured by equilibrating Fab with labeled antigen and then capturing the bound antigen with an anti-Fab antibody-coated plate (see, e.g., Chen et al., J Mol Biol (1999); 293:865-881).

[0363] In certain embodiments, K D is measured using a BIACORE® surface plasmon resonance assay, for example, an assay using a BIACORE®-2000 or BIACORE®-3000 (BIAcore, Inc., Piscataway, NJ).

[0364] 5.3.7 Immunoconjugates The presently disclosed subject matter provides anti-DLL3 antibodies or antigen-binding fragments thereof conjugated to a therapeutic moiety, such as a cytotoxin, a drug (e.g., an immunosuppressant), or a radiotoxin. Such conjugates are referred to herein as "immunoconjugates." Immunoconjugates that include one or more cytotoxins are referred to as "immunotoxins." A cytotoxin or cytotoxic agent includes any agent that is detrimental to (e.g., kills) cells. Non-limiting examples of cytotoxins include taxol (such as ricin, diphtheria, gelonin), cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin, and analogs or homologs thereof. In addition, examples of therapeutic agents include calicheamicin, aureastatin, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine, thioepachlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomatin, and the like). These include cis-dichlorodiamineplatinum(II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), hypomethylating agents (azacytidine and decitabine), and antimitotic agents (e.g., vincristine and vinblastine).

[0365] Other examples of therapeutic cytotoxins that can be conjugated to the anti-DLL3 antibodies disclosed herein include duocarmycin, calicheamicin, maytansine, and auristatin, as well as their derivatives. Cytotoxins can be conjugated to the anti-DLL3 antibodies or antigen-binding fragments thereof disclosed herein using linker technology available in the art. Examples of linker types used to conjugate cytotoxins to antibodies include, but are not limited to, hydrazone, thioether, ester, disulfide, and peptide-containing linkers. Linkers can be selected that are susceptible to cleavage, for example, by the low pH in lysosomal compartments or by proteases preferentially expressed in tumor tissue, such as cathepsins (e.g., cathepsins B, C, and D). For further discussion of types of cytotoxins, linkers, and methods for conjugating therapeutic agents to antibodies, see also Saito, G. et al. (2003) Adv. Drug Deliv. Rev. 55:199-215; Trail, PA et al. (2003) Cancer Immunol. Immunother. 52:328-337; Payne, G. (2003) Cancer Cell 3:207-212; Allen, TM (2002) Nat. Rev. Cancer 2:750-763; Pastan, I. and Kreitman, RJ (2002) Curr. Opin. Investig. Drugs 3:1089-1091; Senter, PD and Springer, CJ (2001) Adv. Drug Deliv. Rev. 53:247-264.

[0366] The anti-DLL3 antibodies or antigen-binding fragments thereof of the presently disclosed subject matter can also be conjugated to radioisotopes to generate cytotoxic radiopharmaceuticals, also referred to as radioimmunoconjugates. An exemplary graphical representation is shown in Figure 3. Non-limiting examples of radioisotopes that can be conjugated to antibodies for diagnostic or therapeutic use include: 47 Sc, 67Cu, 90 Y, 131 I, 149 Tb, 161 Tb, 177 Lu, 225 Ac, 213 Bi, 223 Ra, 89 Zr, and 227 In certain embodiments, the radioisotope is 177 In certain embodiments, the radioisotope is 89 Zr is a radioisotope. Methods for preparing radioimmunoconjugates are established in the art. Examples of radioimmunoconjugates include commercially available ones such as Zevalin™ (IDEC Pharmaceuticals) and Bexxar™ (Corixa Pharmaceuticals), and similar methods can be used to prepare radioimmunoconjugates using the anti-DLL3 antibodies disclosed herein.

[0367] In certain embodiments, an anti-DLL3 antibody or antigen-binding fragment thereof of the presently disclosed subject matter can be conjugated to a radioisotope and a chelating agent can be used to generate a radioimmunoconjugate. As used herein, the term "chelating agent" refers to a compound in the form of a heterocyclic ring or surrounding structure containing a metal ion coordinately bound to at least two non-metal ions. Non-limiting examples of chelating agents include 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 2,2'-(7-(1-carboxy-4-((4-isothiocyanatobenzyl)amino)-4-oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid (NODA), 2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA), diethylenetriamine-N,N,N',N,N-pentaacetic acid, pentetic acid, (carboxymethyl) 2-pyridinol-1-oxide (HOPO), N-(5-(3-((5-aminopentyl)hydroxycarbamoyl)propionamido)pentyl)-3-((5-N-hydroxyacetamido)pentyl)carbamoyl)propionohydroxamic acid (DFO), and 2-[1,4,7-triazacyclononan-1-yl-4,7-bis(tBu-ester)]-1,5-pentanedioic acid (NODAGA).Additional exemplary chelating agents encompassed by the presently disclosed subject matter include AAZTA and its derivatives, BAT, BARAC, BPCA, TE2A, CB-TE2A, CBOTEA1P, CB-TE2P, MM-TE2A, DM TE-2A, CP356, DATA, DBCO, DiAmSar and its derivatives, DIBO, DIMA, DFO, DGO, DOTA and its derivatives (e.g., Ac-DOTA, benzo-DOTA, dibenzo-DOTA, CB-DO2A, 3p-C-DEPA, oxo-DO3A), its DOTMA derivatives (e.g., benzo-DOTMA), DTPA and its derivatives (e.g., benzo-DTPA, dibenzo-DTPA, phenyl-DTPA, diphenyl-DTPA, benzyl-DTPA, dibenzyl-DTPA, 1B4M-DTPA, CHX-A''-DTPA), EDTA, EGTA, EHPG and its derivatives (e.g., 5-Cl-EHPG, 5-Br-E HPG, 5-Me-EHPG, 5t-Bu-EHPG, 5-sec-Bu-EHPG), H2dedpa, H4octapa, H2azapa, H5decapa, H6phospa, HBED and its derivatives, SHBED, HEHA, HYNIC, LICAM and its derivatives, MECAM, NODASA, NODAGA, NOPO, NOTA and its derivatives (e.g., benzo-NOTA), NETA, PEPA, PCTA, PDTA, TACN-TM, TCMC, TETA and its derivatives (e.g., benzo-TETA), TETMA and its derivatives (e.g., benzo-TETMA), TRAP (PRP9), TRITA, TTHA and its derivatives.

[0368] The antibody conjugates of the presently disclosed subject matter can be used to modify a given biological response, and the drug moiety should not be construed as limited to classical chemotherapeutic agents. For example, the drug moiety can be a protein or polypeptide possessing a desired biological activity. Such proteins can include, for example, enzymatically active toxins or active fragments thereof (e.g., abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin), proteins (e.g., tumor necrosis factor (TNF) or interferon-γ), or biological response modifiers (e.g., lymphokines, interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte-colony-stimulating factor (G-CSF), or other growth factors).

[0369] Techniques for conjugating such therapeutic moieties to antibodies are well known and are described, for example, in Arnon et al., "Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy," Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss, Inc. 1985); Hellstrom et al., "Antibodies For Drug Delivery," in Controlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe, "Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review," Monoclonal Antibodies '84: Biological And Clinical Applications, Pinchera et al. (eds.), pp. 475-506 (1985); "Analysis, Results, And Future Prospects Of The See "Therapeutic Use Of Radiolabeled Antibodies In Cancer Therapy," Monoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al. (eds.), pp. 303-16 (Academic Press 1985), and Thorpe et al., "The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates," Immunol. Rev., 62:119-58 (1982).

[0370] 5.3.7.1 Exemplary Immunoconjugates In certain embodiments, the radioimmunoconjugate of the presently disclosed subject matter comprises a VCR comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:11, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:201, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:202. H and V comprising CDR1 having the amino acid sequence set forth in SEQ ID NO:4, CDR2 having the amino acid sequence set forth in SEQ ID NO:5, and CDR3 having the amino acid sequence set forth in SEQ ID NO:203. L In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 204. H and V comprising the amino acid sequence set forth in SEQ ID NO: 205 L In certain embodiments, the antibody or antigen-binding fragment thereof is designated as "C8." In certain embodiments, the radioimmunoconjugate comprises a chelating agent. In certain embodiments, the chelating agent is N-(5-(3-((5-aminopentyl)hydroxycarbamoyl)propionamido)pentyl)-3-((5-(N-hydroxyacetamido)pentyl)carbamoyl)propionohydroxamic acid (DFO). In certain embodiments, the radioimmunoconjugate comprises a radioisotope. In certain embodiments, the radioisotope is 89 It is a radioactive isotope of Zr.

[0371] In certain embodiments, the radioimmunoconjugate of the presently disclosed subject matter comprises a VCR comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:11, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:201, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:202. H and V comprising CDR1 having the amino acid sequence set forth in SEQ ID NO:4, CDR2 having the amino acid sequence set forth in SEQ ID NO:5, and CDR3 having the amino acid sequence set forth in SEQ ID NO:203. L In certain embodiments, the anti-DLL3 antibody or antigen-binding fragment thereof comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 204.H and V comprising the amino acid sequence set forth in SEQ ID NO: 205 L In certain embodiments, the antibody or antigen-binding fragment thereof is designated as "C8." In certain embodiments, the radioimmunoconjugate comprises a chelating agent. In certain embodiments, the chelating agent is N-(5-(3-((5-aminopentyl)hydroxycarbamoyl)propionamido)pentyl)-3-((5-(N-hydroxyacetamido)pentyl)carbamoyl)propionohydroxamic acid (DFO). In certain embodiments, the radioimmunoconjugate comprises a radioisotope. In certain embodiments, the radioisotope is 177 It is a radioactive isotope of Lu.

[0372] 5.3.8 Multispecific molecules The presently disclosed subject matter provides multispecific molecules comprising the anti-DLL3 antibodies disclosed herein, or fragments thereof. The antibodies disclosed herein or antigen-binding fragments thereof can be derivatized or linked to one or more functional molecules, such as one or more peptides or proteins (e.g., one or more antibodies or ligands for receptors), to generate multispecific molecules that bind to two or more different binding sites or target molecules. The anti-DLL3 antibodies or antigen-binding fragments thereof disclosed herein can, in fact, be derivatized or linked to two or more other functional molecules to generate multispecific molecules that bind to more than two different binding sites and / or target molecules. To generate multispecific molecules, the anti-DLL3 antibodies or antigen-binding fragments thereof disclosed herein can be operatively linked (e.g., by chemical bond, genetic fusion, noncovalent association, or other methods) to one or more other binding molecules, such as another antibody, antibody fragment, peptide, or binding mimetic, resulting in a bispecific molecule.

[0373] In certain embodiments, the multispecific molecule is a bispecific molecule. In certain embodiments, the bispecific molecule comprises at least a first binding specificity for DLL3 and a second binding specificity for a second target epitope region. The second target epitope region can be a DLL3 epitope or a non-DLL3 epitope, e.g., a different antigen. In certain embodiments, the multispecific molecule comprises a first binding specificity for DLL3, a second binding specificity for a second target, and a third binding specificity for a third target. In certain embodiments, the second target is an antigen expressed on the surface of an immune cell (e.g., a T cell or a human immune effector cell). In certain embodiments, the multispecific molecule can specifically bind to an effector antigen on a human immune effector cell, thereby mobilizing the activity of the immune effector cell and thereby enhancing effector function. In certain embodiments, the third target is an antigen expressed on a senescent cell.

[0374] The multispecific molecules of the presently disclosed subject matter can be prepared by conjugating the component binding specificities using methods known in the art. For example, each binding specificity for a multispecific molecule can be generated separately and then conjugated to one another. When the binding specifici...

Claims

1. an anti-DLL3 antibody or antigen-binding fragment thereof, comprising a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:60, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:83, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:108, SEQ ID NO:119, SEQ ID NO:126, SEQ ID NO:131, SEQ ID NO:141, SEQ ID NO:147, SEQ ID NO:153, SEQ ID NO:157, SEQ ID NO:163, or SEQ ID NO:

172.

2. an anti-DLL3 antibody or antigen-binding fragment thereof, comprising a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:61, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:84, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:109, SEQ ID NO:113, SEQ ID NO:120, SEQ ID NO:127, SEQ ID NO:132, SEQ ID NO:142, SEQ ID NO:148, SEQ ID NO:154, SEQ ID NO:158, SEQ ID NO:164, or SEQ ID NO:

173.

3. a) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:60, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:83, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:108, SEQ ID NO:119, SEQ ID NO:126, SEQ ID NO:131, SEQ ID NO:141, SEQ ID NO:147, SEQ ID NO:153, SEQ ID NO:157, SEQ ID NO:163, or SEQ ID NO:172; and b) an anti-DLL3 antibody or antigen-binding fragment thereof, comprising a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:61, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:84, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:109, SEQ ID NO:113, SEQ ID NO:120, SEQ ID NO:127, SEQ ID NO:132, SEQ ID NO:142, SEQ ID NO:148, SEQ ID NO:154, SEQ ID NO:158, SEQ ID NO:164, or SEQ ID NO:

173.

4. An anti-DLL3 antibody or antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region and the light chain variable region are: a) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:7, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:8; b) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 17, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 18; c) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:24, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:25; d) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 34, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 35; e) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 42, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 43; f) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 52, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 53; g) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 60, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 61; h) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 66, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 67; i) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 76, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 77; j) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 83, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 84; k) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 92, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 93; l) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 102, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 103; m) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 108, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 109; n) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 108, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 113; o) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 119, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 120; p) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 126, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 127; q) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 131, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 132; r) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 141, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 142; s) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 147, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 148; t) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 153, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 154; u) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 157, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 158; v) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 163, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 164; and w) an anti-DLL3 antibody or antigen-binding fragment thereof selected from the group consisting of a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 172; and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:

173.

5. An anti-DLL3 antibody or antigen-binding fragment thereof, comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:60, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:83, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:108, SEQ ID NO:119, SEQ ID NO:126, SEQ ID NO:131, SEQ ID NO:141, SEQ ID NO:147, SEQ ID NO:153, SEQ ID NO:157, SEQ ID NO:163, or SEQ ID NO:

172.

6. An anti-DLL3 antibody or antigen-binding fragment thereof, comprising a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:61, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:84, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:109, SEQ ID NO:113, SEQ ID NO:120, SEQ ID NO:127, SEQ ID NO:132, SEQ ID NO:142, SEQ ID NO:148, SEQ ID NO:154, SEQ ID NO:158, SEQ ID NO:164, or SEQ ID NO:

173.

7. a) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:60, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:83, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:108, SEQ ID NO:119, SEQ ID NO:126, SEQ ID NO:131, SEQ ID NO:141, SEQ ID NO:147, SEQ ID NO:153, SEQ ID NO:157, SEQ ID NO:163, or SEQ ID NO:172; and b) an anti-DLL3 antibody or antigen-binding fragment thereof comprising a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:61, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:84, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:109, SEQ ID NO:113, SEQ ID NO:120, SEQ ID NO:127, SEQ ID NO:132, SEQ ID NO:142, SEQ ID NO:148, SEQ ID NO:154, SEQ ID NO:158, SEQ ID NO:164, or SEQ ID NO:

173.

8. a) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:7 and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:8; or b) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 17 and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 18; or c) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:24 and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:25; or d) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 34 and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 35; or e) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 42 and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 43; or f) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 52 and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 53; or g) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 60 and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 61; or h) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:66 and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:67; or i) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 76 and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 77; or j) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 83 and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 84; or k) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 92 and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 93; or l) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 102 and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 103; or m) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 108, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 109; n) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 108, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 113; o) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 119, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 120; p) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 126, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 127; q) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 131, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 132; r) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 141, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 142; s) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 147, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 148; t) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 153, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 154; u) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 157, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 158; v) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 163, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 164; or w) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 172, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:

173. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 7.

9. a) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:7 and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:8; or b) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 34 and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 35; or c) The antibody or antigen-binding fragment thereof according to any one of claims 1 to 7, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 42 and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:

43.

10. An anti-DLL3 antibody or antigen-binding fragment thereof, comprising a heavy chain variable region comprising a CDR1 domain, a CDR2 domain, and a CDR3 domain, and a light chain variable region comprising a CDR1 domain, a CDR2 domain, and a CDR3 domain, wherein the CDR3 domain of the heavy chain variable region and the light chain variable region is a) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6 and conservative modifications thereof; b) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16 and conservative modifications thereof; c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 22 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 23 and conservative modifications thereof; d) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 33 and conservative modifications thereof; e) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 39 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 41 and conservative modifications thereof; f) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 51 and conservative modifications thereof; g) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 56 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59 and conservative modifications thereof; h) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 64 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 65 and conservative modifications thereof; i) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 75 and conservative modifications thereof; j) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 81 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 82 and conservative modifications thereof; k) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 89 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 91 and conservative modifications thereof; l) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 98 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 101 and conservative modifications thereof; m) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 107 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 82 and conservative modifications thereof; n) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 107 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112 and conservative modifications thereof; o) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 116 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 118 and conservative modifications thereof; p) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 123 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 125 and conservative modifications thereof; q) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 56 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 130 and conservative modifications thereof; r) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 137 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 140 and conservative modifications thereof; s) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 145 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 125 and conservative modifications thereof; t) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 82 and conservative modifications thereof; u) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 123 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59 and conservative modifications thereof; v) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 161 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 162 and conservative modifications thereof; or w) an anti-DLL3 antibody or antigen-binding fragment thereof selected from the group consisting of a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 168 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 171 and conservative modifications thereof.

11. the CDR2 domains of the heavy chain variable region and the light chain variable region are a) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 and conservative modifications thereof; b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15 and conservative modifications thereof; c) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 29 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 32 and conservative modifications thereof; d) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 and conservative modifications thereof; e) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 47 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50 and conservative modifications thereof; f) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO:58 and conservative modifications thereof; g) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5 and conservative modifications thereof; h) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 71 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74 and conservative modifications thereof; i) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 80 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 and conservative modifications thereof; j) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 88 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 216 and conservative modifications thereof; k) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 97 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 100 and conservative modifications thereof; l) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 and conservative modifications thereof; m) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 and conservative modifications thereof; n) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 115 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 100 and conservative modifications thereof; o) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 and conservative modifications thereof; p) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 136 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 139 and conservative modifications thereof; q) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 146 and conservative modifications thereof; r) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 136 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74 and conservative modifications thereof; and s) The antibody or antigen-binding fragment thereof according to claim 10, wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 167 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 170 and conservative modifications thereof.

12. the CDR1 domains of the heavy chain variable region and the light chain variable region are a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4 and conservative modifications thereof; b) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14 and conservative modifications thereof; c) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4 and conservative modifications thereof; d) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 28 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 31 and conservative modifications thereof; e) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 40 and conservative modifications thereof; f) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 46 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49 and conservative modifications thereof; g) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57 and conservative modifications thereof; h) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 70 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73 and conservative modifications thereof; i) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 87 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 90 and conservative modifications thereof; j) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 99 and conservative modifications thereof; k) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 117 and conservative modifications thereof; l) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124 and conservative modifications thereof; m) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 135 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 138 and conservative modifications thereof; n) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 151 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57 and conservative modifications thereof; o) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73 and conservative modifications thereof; and p) The antibody or antigen-binding fragment thereof according to claim 10, wherein the antibody or antigen-binding fragment is selected from the group consisting of a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 169 and conservative modifications thereof.

13. The antibody or antigen-binding fragment thereof of claim 10, wherein one or more of the CDR sequences has up to about five amino acid substitutions.

14. The antibody or antigen-binding fragment thereof of claim 10, wherein one or more of the CDR sequences has up to about three amino acid substitutions.

15. a) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3; b) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13; c) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:21, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:22; d) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 28, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 29, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30; e) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:21, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:38, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:39; f) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 46, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 47, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48; g) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:21, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:56; h) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:21, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:64; i) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 70, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 71, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72; j) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:21, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:80, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:81; k) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 87, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 88, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 89; l) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 97, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 98; m) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 107; n) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 115, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 116; o) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:21, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:123; p) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 135, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 136, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 137; q) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 145; r) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 151, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152; s) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 136, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 161; t) An anti-DLL3 antibody or antigen-binding fragment thereof, comprising a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 167, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO:

168.

16. a) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:6; b) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16; c) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:23; d) an immunoconjugate comprising a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 31, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 32, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 33; e) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 40, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 41; f) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 51; g) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59; h) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:65; i) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 75; j) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 82; k) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 90, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 216, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 91; l) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 99, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 100, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 101; m) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:112; n) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 117, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 100, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 118; o) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 125; p) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 130; q) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 138, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 139, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 140; r) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 146, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 125; s) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59; t) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 162; or u) An anti-DLL3 antibody or antigen-binding fragment thereof comprising a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 169, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 170, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO:

171.

17. a) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6; b) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16; c) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO:21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO:22, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4, CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO:23; d) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO:31, CDR2 comprising the amino acid sequence set forth in SEQ ID NO:32, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO:33; e) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO:21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO:38, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO:39, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO:40, CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO:41; f) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 46, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 47, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 51; g) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO:21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO:56, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO:57, CDR2 comprising the amino acid sequence set forth in SEQ ID NO:58, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO:59; h) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO:21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO:64, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4, CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO:65; i) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 70, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 71, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 75; j) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO:21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO:80, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO:81, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO:57, CDR2 comprising the amino acid sequence set forth in SEQ ID NO:58, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO:82; k) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 87, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 88, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 89, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 90, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 216, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 91; l) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 97, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 98, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 99, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 100, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 101; m) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO:21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO:106, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO:107, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO:57, CDR2 comprising the amino acid sequence set forth in SEQ ID NO:58, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO:82; n) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 107, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112; o) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 115, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 116, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 117, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 100, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 118; p) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 123, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 125; q) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO:21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO:123, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO:124, CDR2 comprising the amino acid sequence set forth in SEQ ID NO:58, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO:125; r) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO:21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO:56, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO:57, CDR2 comprising the amino acid sequence set forth in SEQ ID NO:58, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO:130; s) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 135, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 136, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 137, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 138, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 139, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 140; t) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO:21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO:145, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO:57, CDR2 comprising the amino acid sequence set forth in SEQ ID NO:146, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO:125; u) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 151, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 82; v) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO:21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO:123, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO:124, CDR2 comprising the amino acid sequence set forth in SEQ ID NO:58, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO:59; w) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 136, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 161, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 162; or x) an anti-DLL3 antibody or antigen-binding fragment thereof, comprising a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO:96, CDR2 comprising the amino acid sequence set forth in SEQ ID NO:167, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO:168, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO:169, CDR2 comprising the amino acid sequence set forth in SEQ ID NO:170, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO:

171.

18. a) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6; b) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 28, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 29, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 31, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 32, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 33; or c) The antibody or antigen-binding fragment thereof according to claim 17, comprising a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 21, CDR2 having the amino acid sequence set forth in SEQ ID NO: 38, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 39, and a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 40, CDR2 having the amino acid sequence set forth in SEQ ID NO: 5, and CDR3 having the amino acid sequence set forth in SEQ ID NO:

41.

19. 19. The antibody or antigen-binding fragment thereof of any one of claims 1 to 7 and 10 to 18, wherein the antibody or antigen-binding fragment thereof binds to DLL3 comprising the amino acid sequence set forth in SEQ ID NO:215 or a fragment thereof.

20. The antibody or antigen-binding fragment thereof of any one of claims 1 to 7 and 10 to 18, wherein the antibody comprises human variable region framework regions.

21. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 7 and 10 to 18, which is fully human or an antigen-binding fragment thereof.

22. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 7 and 10 to 18, which is a chimeric antibody or antigen-binding fragment thereof.

23. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 7 and 10 to 18, which is a humanized antibody or antigen-binding fragment thereof.

24. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 7 and 10 to 18, wherein the antigen-binding fragment is a Fab, a Fab', a F(ab')2, a variable fragment (Fv), or a single-chain variable region (scFv).

25. 25. The antibody or antigen-binding fragment of claim 24, wherein the antigen-binding fragment is an scFv.

26. An antibody or antigen-binding fragment thereof that cross-competes with the antibody or antigen-binding fragment thereof of any one of claims 1 to 7 and 10 to 18 for binding to DLL3.

27. An antibody or antigen-binding fragment thereof that binds to the same epitope region on DLL3 as the antibody or antigen-binding fragment thereof according to any one of claims 1 to 7 and 10 to 18.

28. A composition comprising an antibody or antigen-binding fragment thereof according to any one of claims 1 to 7 and 10 to 18.

29. 30. The composition of claim 28, which is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

30. An immunoconjugate comprising the antibody or antigen-binding fragment thereof of any one of claims 1 to 7 and 10 to 18 linked to a therapeutic agent.

31. 31. The immunoconjugate of claim 30, wherein the therapeutic agent is a drug, a cytotoxin, or a radioisotope.

32. 31. The immunoconjugate of claim 30, further comprising a chelating agent.

33. The chelating agent is AAZTA, BAT, BARAC, BPCA, TE2A, CB-TE2A, CB0TE1A1P, CB-TE2P, MM-TE2A, DM 33. The immunoconjugate of claim 32, selected from the group consisting of TE-2A, CP356, DATA, DBCO, DiAmSar, DIBO, DIMA, DFO, DGO, DOTA, DOTMA, DTPA, EDTA, EGTA, EHPG, H2dedpa, H4octapa, H2azapa, H5decapa, H6phospa, HBED, SHBED, HEHA, HYNIC, LICAM, MECAM, NODASA, NODAGA, NOPO, NOTA, NETA, PEPA, PCTA, PDTA, TACN-™, TCMC, TETA, TETMA, TRAP (PRP9), TRITA, TTHA, and derivatives thereof.

34. 33. The immunoconjugate of claim 32, wherein the chelating agent is DFO.

35. The radioisotope is ４７ Sc, ６７ Cu, ９０ Y. １３１ I, １４９ Tb, １６１ Tb, １７７ Lu, ２２５ Ac, ２１３ Bi, ２２３ Ra, ８９ Zr, and ２２７ 32. The immunoconjugate of claim 31 , wherein the immunoconjugate is selected from the group consisting of Th.

36. The radioisotope is １７７ 36. The immunoconjugate of claim 35, wherein said immunoconjugate is Lu.

37. The radioisotope is ８９ 36. The immunoconjugate of claim 35, wherein Zr is

38. A composition comprising the immunoconjugate of claim 30.

39. 39. The composition of claim 38, which is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

40. A multispecific molecule comprising an antibody or antigen-binding fragment thereof according to any one of claims 1 to 7 and 10 to 18 linked to one or more functional moieties.

41. 41. The multispecific molecule of claim 40, wherein the one or more functional moieties have a binding specificity different from that of the antibody or antigen-binding fragment thereof.

42. 41. A composition comprising the multispecific molecule of claim 40.

43. 43. The composition of claim 42, which is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

44. A nucleic acid encoding the antibody or antigen-binding fragment thereof according to any one of claims 1 to 7 and 10 to 18.

45. A vector comprising the nucleic acid molecule of claim 44.

46. A host cell comprising the vector of claim 45.

47. 19. A composition comprising the antibody or antigen-binding fragment thereof of any one of claims 1 to 7 and 10 to 18 for use in a method for detecting DLL3 in a whole cell, tissue, or blood sample, the method comprising: a) contacting a cell, tissue, or blood sample with the antibody or antigen-binding fragment thereof of any one of claims 1 to 7 and 10 to 18, wherein the antibody or antigen-binding fragment thereof comprises a detectable label; b) determining the amount of labeled antibody or antigen-binding fragment thereof bound to the cells, tissue, or blood sample by measuring the amount of detectable label associated with the cells or tissue, wherein the amount of bound antibody or antigen-binding fragment thereof indicates the amount of DLL3 in the cells, tissue, or blood sample.

48. 1. A composition for treating or ameliorating a DLL3-associated disease or disorder in a subject, said composition comprising: The antibody or antigen-binding fragment thereof according to any one of claims 1 to 7 and 10 to 18. an immunoconjugate comprising the antibody or antigen-binding fragment thereof linked to a therapeutic agent; or a multispecific molecule comprising said antibody or antigen-binding fragment thereof linked to one or more functional moieties; contains, or The composition comprises: The antibody or antigen-binding fragment thereof and a pharmaceutically acceptable carrier the immunoconjugate and a pharmaceutically acceptable carrier; or The multispecific molecule and a pharmaceutically acceptable carrier The composition is a pharmaceutical composition comprising:

49. 49. The composition of claim 48, wherein the disease or disorder is a tumor.

50. 50. The composition of claim 49, wherein the tumor is a cancer.

51. 49. The composition of claim 48, wherein the disease or disorder is selected from the group consisting of neuroendocrine tumors of the lung, extrapulmonary neuroendocrine carcinoma, melanoma, neuroendocrine prostate cancer, breast cancer, neuroendocrine tumors of the gastrointestinal tract, pancreatic cancer, medullary thyroid carcinoma, small cell bladder cancer, small cell ovarian carcinoma, low-grade glioma, glioblastoma, and neuroblastoma.

52. 52. The composition of claim 51, wherein the lung neuroendocrine tumor is selected from the group consisting of lung neuroendocrine carcinoma, large cell neuroendocrine carcinoma, and small cell lung carcinoma.

53. 49. The composition of claim 48, wherein the subject is a human.

54. 20. A kit for treating or ameliorating a disease or disorder in a subject, comprising the antibody or antigen-binding fragment thereof of any one of claims 1 to 7 and 10 to 18, an immunoconjugate comprising the antibody or antigen-binding fragment thereof linked to a therapeutic agent, a multispecific molecule comprising the antibody or antigen-binding fragment thereof linked to one or more functional moieties, a composition comprising the antibody or antigen-binding fragment thereof, immunoconjugate, or multispecific molecule, or a pharmaceutical composition comprising the antibody or antigen-binding fragment thereof, immunoconjugate, or multispecific molecule and a pharmaceutically acceptable carrier.

55. 55. The kit of claim 54, wherein the kit further comprises written instructions for using the antibody or antigen-binding fragment thereof, immunoconjugate, multispecific molecule, or composition to treat or ameliorate a disease or disorder in a subject.

56. 1. An immunoconjugate comprising an anti-DLL3 antibody or antigen-binding fragment thereof linked to a therapeutic agent, wherein the anti-DLL3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:187, SEQ ID NO:197, SEQ ID NO:204, or SEQ ID NO:

212.

57. 1. An immunoconjugate comprising an anti-DLL3 antibody or antigen-binding fragment thereof linked to a therapeutic agent, wherein the anti-DLL3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:188, SEQ ID NO:198, SEQ ID NO:205, or SEQ ID NO:

213.

58. 1. An immunoconjugate comprising an anti-DLL3 antibody or antigen-binding fragment thereof linked to a therapeutic agent, wherein the anti-DLL3 antibody or antigen-binding fragment thereof is a) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:187, SEQ ID NO:197, SEQ ID NO:204, or SEQ ID NO:212; and b) An immunoconjugate comprising a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:188, SEQ ID NO:198, SEQ ID NO:205, or SEQ ID NO:

213.

59. 1. An immunoconjugate comprising an anti-DLL3 antibody or antigen-binding fragment thereof linked to a therapeutic agent, wherein the anti-DLL3 antibody or antigen-binding fragment thereof is a) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 187, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 188; b) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 197, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 198; c) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:204, and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:205; and d) an immunoconjugate comprising a heavy chain variable region and a light chain variable region selected from the group consisting of: a heavy chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:212; and a light chain variable region comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:

213.

60. 1. An immunoconjugate comprising an anti-DLL3 antibody or antigen-binding fragment thereof linked to a therapeutic agent, wherein the anti-DLL3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:187, SEQ ID NO:197, SEQ ID NO:204, or SEQ ID NO:

212.

61. 1. An immunoconjugate comprising an anti-DLL3 antibody or antigen-binding fragment thereof linked to a therapeutic agent, wherein the anti-DLL3 antibody or antigen-binding fragment thereof comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:188, SEQ ID NO:198, SEQ ID NO:205, or SEQ ID NO:

213.

62. 1. An immunoconjugate comprising an anti-DLL3 antibody or antigen-binding fragment thereof linked to a therapeutic agent, wherein the anti-DLL3 antibody or antigen-binding fragment thereof is a) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 187, SEQ ID NO: 197, SEQ ID NO: 204, or SEQ ID NO: 212; and b) An immunoconjugate comprising a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 188, SEQ ID NO: 198, SEQ ID NO: 205, or SEQ ID NO:

213.

63. a) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 187, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 188; b) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 197, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 198; c) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 204, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 205; and d) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 212, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:

213. The immunoconjugate of any one of claims 56 to 62.

64. 1. An immunoconjugate comprising an anti-DLL3 antibody or antigen-binding fragment thereof linked to a therapeutic agent, wherein the anti-DLL3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising a CDR1 domain, a CDR2 domain, and a CDR3 domain, and a light chain variable region comprising a CDR1 domain, a CDR2 domain, and a CDR3 domain, and the CDR3 domain of the heavy chain variable region and the light chain variable region is a) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 184 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 186 and conservative modifications thereof; b) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 193 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 196 and conservative modifications thereof; c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 202 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 203 and conservative modifications thereof; and d) an immunoconjugate selected from the group consisting of a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 210 and conservative modifications thereof, and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 211 and conservative modifications thereof.

65. the CDR2 domains of the heavy chain variable region and the light chain variable region are a) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 183 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50 and conservative modifications thereof; b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 192 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 195 and conservative modifications thereof; c) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 201 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 and conservative modifications thereof; and d) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 209 and conservative modifications thereof, and a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 and conservative modifications thereof.

66. the CDR1 domains of the heavy chain variable region and the light chain variable region are a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 185 and conservative modifications thereof; b) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 191 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 194 and conservative modifications thereof; c) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4 and conservative modifications thereof; and d) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 208 and conservative modifications thereof, and a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57 and conservative modifications thereof, selected from the group consisting of:

67. 65. The immunoconjugate of claim 64, wherein one or more of the CDR sequences has up to about five amino acid substitutions.

68. 65. The immunoconjugate of claim 64, wherein one or more of the CDR sequences has up to about three amino acid substitutions.

69. 1. An immunoconjugate comprising an anti-DLL3 antibody or antigen-binding fragment thereof linked to a therapeutic agent, wherein the anti-DLL3 antibody or antigen-binding fragment thereof is a) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 183, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 184; b) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 191, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 192, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 193; c) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 201, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 202; or d) An immunoconjugate comprising a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:208, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:209, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:

210.

70. 1. An immunoconjugate comprising an anti-DLL3 antibody or antigen-binding fragment thereof linked to a therapeutic agent, wherein the anti-DLL3 antibody or antigen-binding fragment thereof is a) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 185, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 186; b) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 194, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 195, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 196; c) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:203; or d) An immunoconjugate comprising a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:

211.

71. 1. An immunoconjugate comprising an anti-DLL3 antibody or antigen-binding fragment thereof linked to a therapeutic agent, wherein the anti-DLL3 antibody or antigen-binding fragment thereof is a) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 183, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 184, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 185, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 186; b) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 191, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 192, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 193, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 194, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 195, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 196; c) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 201, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 202, and a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 203; or d) An immunoconjugate comprising a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO:208, CDR2 comprising the amino acid sequence set forth in SEQ ID NO:209, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO:210, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO:57, CDR2 comprising the amino acid sequence set forth in SEQ ID NO:58, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO:

211.

72. 72. The immunoconjugate of any one of claims 56-62 and 64-71, wherein the antibody or antigen-binding fragment thereof binds to DLL3 comprising the amino acid sequence set forth in SEQ ID NO:215 or a fragment thereof.

73. The immunoconjugate of any one of claims 56-62 and 64-71, wherein the antibody comprises human variable region framework regions.

74. 72. The immunoconjugate of any one of claims 56 to 62 and 64 to 71, wherein the antibody or antigen-binding fragment thereof is fully human or an antigen-binding fragment thereof.

75. 72. The immunoconjugate of any one of claims 56 to 62 and 64 to 71, wherein the antibody or antigen-binding fragment thereof is a chimeric antibody or antigen-binding fragment thereof.

76. 72. The immunoconjugate of any one of claims 56 to 62 and 64 to 71, wherein the antibody or antigen-binding fragment thereof is a humanized antibody or antigen-binding fragment thereof.

77. 72. The immunoconjugate of any one of claims 56 to 62 and 64 to 71, wherein the antigen-binding fragment is a Fab, a Fab', a F(ab')2, a variable fragment (Fv), or a single chain variable region (scFv).

78. 78. The immunoconjugate of claim 77, wherein the antigen-binding fragment is an scFv.

79. The immunoconjugate of any one of claims 56-62 and 64-71, wherein the therapeutic agent is a radioisotope.

80. The immunoconjugate of any one of claims 56 to 62 and 64 to 71, further comprising a chelating agent.

81. The chelating agent is AAZTA, BAT, BARAC, BPCA, TE2A, CB-TE2A, CB0TE1A1P, CB-TE2P, MM-TE2A, DM 81. The immunoconjugate of claim 80, selected from the group consisting of TE-2A, CP356, DATA, DBCO, DiAmSar, DIBO, DIMA, DFO, DGO, DOTA, DOTMA, DTPA, EDTA, EGTA, EHPG, H2dedpa, H4octapa, H2azapa, H5decapa, H6phospa, HBED, SHBED, HEHA, HYNIC, LICAM, MECAM, NODASA, NODAGA, NOPO, NOTA, NETA, PEPA, PCTA, PDTA, TACN-™, TCMC, TETA, TETMA, TRAP (PRP9), TRITA, TTHA, and derivatives thereof.

82. 81. The immunoconjugate of claim 80, wherein the chelating agent is DFO.

83. The radioisotope is ４７ Sc, ６７ Cu, ９０ Y. １３１ I, １４９ Tb, １６１ Tb, １７７ Lu, ２２５ Ac, ２１３ Bi, ２２３ Ra, ８９ Zr, and ２２７ 80. The immunoconjugate of claim 79, wherein the immunoconjugate is selected from the group consisting of Th.

84. The radioisotope is １７７ 84. The immunoconjugate of claim 83, wherein said immunoconjugate is Lu.

85. The radioisotope is ８９ 84. The immunoconjugate of claim 83, wherein Zr is

86. 72. A composition comprising the immunoconjugate of any one of claims 56 to 62 and 64 to 71.

87. 87. The composition of claim 86, which is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

88. 100. A composition comprising the immunoconjugate of any one of claims 56 to 62 and 64 to 71 for use in a method for detecting DLL3 in a whole cell, tissue, or blood sample, said method comprising: a) contacting a cell, tissue, or blood sample with an immunoconjugate of any one of claims 56 to 62 and 64 to 71; and b) determining the amount of said immunoconjugate bound to said cells, tissue or blood sample by measuring the amount of detectable label associated with said cells or tissue, wherein said amount of bound immunoconjugate indicates the amount of DLL3 in said cells, tissue or blood sample.

89. 72. A composition comprising the immunoconjugate of any one of claims 56-62 and 64-71, or a pharmaceutical composition comprising said immunoconjugate and a pharmaceutically acceptable carrier, for treating or ameliorating a DLL3-associated disease or disorder in a subject.

90. 90. The composition or pharmaceutical composition of claim 89, wherein the disease or disorder is a tumor.

91. 91. The composition or pharmaceutical composition of claim 90, wherein the tumor is a cancer.

92. 90. The composition or pharmaceutical composition of claim 89, wherein the disease or disorder is selected from the group consisting of neuroendocrine tumors of the lung, extrapulmonary neuroendocrine carcinoma, melanoma, neuroendocrine prostate cancer, breast cancer, neuroendocrine tumors of the gastrointestinal tract, pancreatic cancer, medullary thyroid carcinoma, small cell bladder cancer, small cell ovarian carcinoma, low-grade glioma, glioblastoma, and neuroblastoma.

93. 93. The composition or pharmaceutical composition of claim 92, wherein the lung neuroendocrine tumor is selected from the group consisting of lung neuroendocrine carcinoma, large cell neuroendocrine carcinoma, and small cell lung carcinoma.

94. 90. The composition or pharmaceutical composition of claim 89, wherein the subject is a human.

95. 72. A kit for treating or ameliorating a disease or disorder in a subject, comprising the immunoconjugate of any one of claims 56-62 and 64-71, a composition comprising said immunoconjugate, or a pharmaceutical composition comprising said immunoconjugate and a pharmaceutically acceptable carrier.

96. 96. The kit of claim 95, wherein the kit further comprises written instructions for using the antibody or antigen-binding fragment thereof, immunoconjugate, multispecific molecule, or composition to treat or ameliorate a disease or disorder in a subject.

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